Beyond the Boundaries

Pharma delivery methods, like medicines themselves, have become increasingly customized. This holds true even for one of the most common formats: the two-piece capsule.

There is good reason that capsules have been go-to drug delivery solutions for so long. In addition to the inherent versatility of typical two-piece capsules, a standard ingredient—gelatin—provides favorable attributes such as high mechanical robustness, fast aqueous dissolution, taste and odor masking, bi-chromatic differentiation and ease of swallowing. But as both global needs and pharma products themselves evolve, new challenges have arisen; these obstacles span a spectrum from access to medicines in developing countries to sophisticated drug products treating previously unaddressed conditions.

Meeting these modern needs means incorporating innovative two-piece capsules with specific characteristics or functionalities, while maintaining the key features of versatility and commercial viability for which the standard gelatin capsule has become known. Typically, these particulars are derived from a drug’s Target Product Profile (TPP), which defines the crucial aspects a medicine must achieve.¹ A variety of factors (Table 1) must be considered, including a medicine’s molecular makeup and therapeutic components (or combinations thereof), preferred delivery form(s), targeted patient populations, specific markets and regions, technology accessibility and, of course, overall manufacturing costs.

Formulation and process design
Defining a drug’s TPP is a mission statement and roadmap rolled into one: it allows for a clear-eyed, prioritized view of the medicine’s overarching goals and, with these data points logically laid out, helps forge a detailed plan toward its formulation, process and product development. The multifactorial nature of drug development requires a systematic approach that gives added emphasis on required attributes over requested ones—a delineation between “must have” and “want to have.”

This approach is the most efficient route to developing a product that meets all required elements and most (and potentially even all) of the desired ones. A well-executed TPP process offers an evidence-based, non-biased assessment of formulation strategies and delivery possibilities.

Always, the process must include a formal risk assessment to identify known or predicted critical material attributes or process parameters that could impact its performance consistency or manufacturability. These critical material attributes and process parameters are evaluated via experiments, simulation and/or predictive modeling to assure ultimate viability.^2,3

A proper TPP also prevents pharma companies from “overdoing it” from a formulation perspective, preventing the unnecessary use of extraneous excipients and avoidable additional processing steps. Like most production strategies, pharma product development has a “Goldilocks Zone” that, once discovered, prevents over-engineering and the unnecessary complexities and costs associated with it.

In an increasingly competitive market, formulation and process simplicity can be key to widespread product adoption by key target population segments, as it becomes a determining factor in manufacturing efficiency, effectiveness and cost mitigation.^4,5

Evolving capsule technology
Within this overarching discussion on defining a drug’s TPP, it becomes clear that one way to work toward streamlined, cost-effective production for a broad array of products is to favor versatile delivery technology platforms that meet formulation needs while addressing existing and emerging industry issues. The new challenges arising from shorter development timelines (including drugs gaining expedited designations such as Fast Track, Breakthrough, Priority Review, and Accelerated Approval), pediatric formulations, therapy personalization, demographic changes, decentralization of manufacturing, cost containment and sustainability require, to varying degrees, advanced excipients, formulations, processes and flexible dosing. 

Hydroxypropyl methycellulose, also called Hypromellose or HPMC, is a cellulose-based semisynthetic polymer established as a pharmaceutical excipient in the early 1970s. Four types of HPMC—suitable for applications ranging from a film forming agent in coatings to a matrix former for modified release tablets—are detailed in pharmaceutical monographs6 HPMC also is considered a crystallization inhibitor, which helps increase solubility and bioavailability for poorly soluble low ionized drugs containing a neutral amine group.⁷ Additional benefits of HPMC are its largely temperature- and humidity-independent viscoelastic properties, and its relative inertness against reactive chemicals.⁸

Extensive research and technology development have been undertaken to introduce capsules that marry HPMC’s unique material properties with the advantages of common two-piece capsules. These include a set of HPMC capsules created through an innovative thermogelation process that continues to broaden the range of functionalities and applications of capsules in drug development and manufacturing. The thermogelation technology utilizes the reversible sol-gel transformation of HPMC upon heating to 50-90° C to form pure HPMC capsules.

The result is a capsule that allows specifically desired product characteristics, as defined in a drug’s TPP, to be integrated and delivered. This flexible functionality can help avoid the need for intensive formulation and process development programs prompted by the addition of multiple excipients and processing steps—which, of course, in turn lead to complex manufacturing processes, added risks and increased costs.

Key functionalities of thermogelated HPMC capsules
Thermogelated HPMC capsules, including ACGcaps H+ from my company, ACG Capsules, are characterized by a homogeneous, smooth surface structure with glasslike transparency. As with common two-piece capsules, colorants can be added to produce colored-yet-transparent or opaque capsules that, in turn, can be further customized by mono- and/or bi-chromatic printing.

This flexibility allows varying dose strengths of drug combinations in fixed dose combination products, and products with multiple release profiles, yet being distinctively differentiated within an overarching brand. This clearly distinguishes differing drug products for reduced medication errors and increased safety, which is especially important with instances of polypharmacy. In addition, the glasslike transparency of the capsules allows inhalation therapy patients to verify both the presence and release of the drug during administration.  

Using standard dissolution tests (e.g. USP type II apparatus with sinker) and acetaminophen as a model drug formulation, the capsule ruptures and releases its contents within 5-10 minutes in all media—pH 1.2 – 0.1N HCl; pH 4.5 – acetate buffer; pH 6.8 – phosphate buffer (see Figure 1).


The dissolution profiles align with pharmacopeial requirements for immediate release oral formulations. However, for weak acid or weak base drugs with poor aqueous solubility, such as dabrafenib, HPMC capsules may act as a crystallization inhibitor and increase bioavailability.⁹ For such BCS class 2 compounds, the thermogelated HPMC capsules provide superior dissolution and bio-enhancement functionality, which also might contribute to a reduced inter- and intra-subject variability.

For a variety of reasons, multi-particulates like pellets, mini-tablets or granules are increasingly being explored as treatment options for special patient populations. Here, factors include increased palatability and swallowability, individual dosing according to body weight, body surface, age or kidney function.^10,11 Modified release (e.g. enteric formulations) are preferred in oral forms due to gradual and predictable release from the stomach.^12,13 Many of these multi-particulate formulations are designed to protect acid- and moisture-sensitive drugs, and to ensure quick dissolution in the duodenum through hydrophilic excipients.

To achieve sufficient stability for moisture-sensitive products, headspace humidity in two-piece capsules needs to be within a defined range. The capsule moisture (LOD) of HPMC capsules is directly correlated with headspace humidity, and is adjustable without impacting the mechanical and elastic properties of the capsule or its dissolution. For example, if product manufacturing conditions of 22°C and 20% RH are required, HPMC capsules provide the respective design space for robust product performance.

Likewise, interactive powder blends or engineered particles for dry powder inhalation require specific headspace humidity; HPMC capsules allow for easy adjustment without negatively impacting the performance of the capsules in the diverse inhalation devices.¹⁴

Advanced drug delivery technologies targeting specific areas in the GI tract (e.g. colonic delivery), and emerging sensitive therapeutics (e.g. live microbiota) require oral dosage forms that do not use compression, and release the therapeutic agent within a specific gastric environment quickly. The coating of filled capsules has demonstrated to be highly suitable for targeted delivery to the gastrointestinal tract. Aqueous coating compositions have demonstrated favorable adhesion characteristics on HPMC and, as such, on HPMC capsules. By using different types of coating polymers, and varying the coating thickness, in-vivo release could be targeted to different areas within the gastrointestinal tract.¹⁵

Conclusion
The two-piece capsule is an established dosage form with proven viability for a diverse range of compounds, formulations, drug delivery technologies and applications. Because a capsule product can be efficiently manufactured in just two straightforward steps (blending & filling), encapsulation is used from early product development through full-scale commercial manufacturing due to its global availability.

Innovation and evolving technology continue to provide new and improved therapeutic options for acute, chronic and life-threatening diseases, and relevant new drug delivery technologies to enable their therapeutic efficacy and site-specific delivery. The growing demand for affordable medicines from low- and middle-income countries presents a global responsibility to produce high-quality medicines more efficiently, cost effectively and locally.

To meet these emerging requirements, the inherent advantages of capsules can be introduced to a variety of pharma products by developing capsules with specific properties. HPMC capsules manufactured by a thermogelation process are fast-dissolving delivery vehicles.

As such, HPMC capsules are highly resistant across environmental temperature and moisture conditions. Moreover, they can be adjusted to specific moisture or headspace humidity while maintaining critical elastic properties even under stress (e.g. piercing or shearing). For products sensitive to compression, liquid or semi-solids, or life microbiota requiring targeted delivery in the gastrointestinal tract, the capsules can be easily coated with different solutions at varying thicknesses. Using standard capsule filling equipment at known machineability performance, HPMC capsules can help simplify both formulation and process procedures, each of which are crucial factors in increasing cost efficiency in pharmaceutical manufacturing. 

References

1. ICH Q8 R2 Pharmaceutical Development Guideline (2009)
2. Stranzinger et al Int J Pharm: X (2019) 1: 100004
3. Madlmeier et al Int J Pharm (2019) 567:118441
4. Cogdill et al J Pharm Innov (2007) 2:38–50
5. Friedli et al  J Pharm Innov (2010) 5:181–192
6. HPMC Monograph – USP 41, Pharm Eur 10th edition
7. Zarmpi et al AAPS J (2020) 22:49
8. Handbook of pharmaceutical excipients. Eds: Rowe RC, Sheskey PJ, Quinn ME. pp. 326-329 (2009)
9. Ouellet et al J Pharm Sci (2013) 102(9): 3100–3109
10. Klingmann et al J Pediatr (2012) 163:1728-32
11. Klingmann et al J Pediatr (2015) 167:893-6
12. Digenis et al J Clin Pharmacol (1990) 30, 621-631
13. Abrahamsson et al Int J Pharm (1996) 140, 229-235
14. Geller et al J Aerosol Med Pulmo Drug Del (2011) 24(4):175-182
15. Cole et al Int J Pharm (2002) 231: 83-95

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Prof. Dr. Sven Stegeman is Global Head of Scientific Business Development at ACG Capsules, and a professor of patient centric drug design and manufacturing at the Graz University of Technology, Austria. ACG Group is an integrated pharma manufacturing solutions company whose divisions include Capsules, Films & Foils, Engineering, and Inspection.