Following on from the issues covered in part I, the discussion turns to patient centricity. Oral solid dosage (OSD) forms administered by swallowing remains the preferred “pill” for patients and consumers. For example, of the approximately 50 drugs approved last year, nearly 40% were OSD forms.
And, of those 21 newly approved OSD products, 14 were tablets and seven were capsules, which poses the question: what is driving drug developers to choose one form instead another in terms of formulation, manufacturing and markets?
Torkel Gren, Senior Director, Technology Officer and Strategic Investments at Recipharm, jumps straight in. “Tablets and capsules remain the most convenient choice for patients as they are generally easy for patients to administer themselves without the need for professional support or supervision. They also deliver benefits for drug formulators too, as they are particularly efficient to manufacture compared with alternative dosage forms.”
“Regarding both patient and manufacturer benefits, both capsules and tablets are very similar in many respects. Tablets are generally more cost-effective to manufacture and it’s possible to manufacture smaller pills that give the same-sized dose. Smaller tablets can be easier to swallow, making them more desirable for vulnerable patients, such as the elderly or the young.”
“Capsules do have advantages,” he notes: “They allow the use of pellet technology to create modified release (MR) and fixed dose combination products quickly and efficiently. Using pellets can also allow versions of the same product with differing strengths to be created efficiently without the need for separate production lines."
"Also, capsules don’t need to be coated — which is often required for tablets containing drugs with a bad taste. This is a relatively common occurrence, which can make patients reluctant to take their medication, leading to compliance consequences. This further enhances manufacturing efficiency without impacting on the patient experience.”
Thomas B. “Brad” Gold, Vice President of Pharmaceutical Development at Metrics Contract Services, lists the following benefits of OSDs:
- OSDs, and tablets in particular, are generally cheaper to manufacture than other dosage forms; this makes them more affordable for payers, insurers and consumers
- there are well-established supply chains and capacities for OSDs; the CDMO and broader contract space (packaging, logistics and storage) that can handle OSDs is highly competitive; there are some niches, such as with HPAPIs where capacity is at a premium, but established expertise is available
- tablets are usually very stable and typically have a longer shelf-life than any other format
- innovation in tablet formulation is driving the development of more patient-friendly and faster-acting orally dissolving tablet forms and variable release profiles, which broaden their application and efficacy.
“Since 1987,” comments Vincent Jannin, Capsules and Health Ingredients, Lonza, “there has been a steady rise in the number of indications using lipid-based formulations (LBFs) or amorphous solid dispersions (ASDs) to manage solubility, as well as an increasing number of scientific papers on using these techniques."
"How to deliver a formulation most effectively to achieve the desired therapeutic effect will always drive the dose-form decision. For certain formulations, including highly potent APIs (HPAPIs), ASDs and LBFs by encapsulating them may be the most effective and efficient route.”
“LBFs can deliver a variety of attributes to help manage the solubility of compounds in vivo, for example. Straightforward emulsifying and micro-emulsifying formulations have demonstrated consistently they are able to address low water solubility in a broad range of commercially marketed compounds. To overcome some of the more challenging aspects of delivering today’s poorly water-soluble APIs, developers are likely to consider using a capsule.”
“In commercial practice, for most of today’s LBFs in development or on the market, both softgel and hard capsule technologies are being applied. However, traditional hard capsule technologies offer drug developers a range of highly leverageable functional and aesthetic properties. For both ASDs and LBFs, hard capsules offer physical properties beyond shape, such as smoothness, colour and a quality appearance that patients prefer.”
“Hard capsules are now available in a variety of materials that are suitable for HPAPI applications. In addition, capsules offer developers new avenues for product differentiation by colour coding for dose identity. Hard capsules also help to broadly ameliorate distribution, mobility and shelf-life issues related to all OSD drug forms."
"Lastly, drug manufacturers have access to highly engineered capsule filling technologies, materials and designs, and can rely on faster, more accurate/compliant filling and sealing techniques to precisely fill thousands of capsules per hour.”
KSR: What recent OSD or excipient technologies are proving to be capable of improving a given formulation’s chances for approval and success? And, perhaps more importantly, what technologies are formulators not taking advantage of but should?
“As mentioned previously,” continues Vincent, “LBFs and ASDs are highly effective at overcoming the most challenging solubility and drug delivery obstacles. Furthermore, key excipients are also proving to be useful during development, especially HPMC, which demonstrates robust solubility optimising characteristics in the gastrointestinal (GI) tract.”
“However, now that advanced HPMC-based capsule technologies are readily and commercially available, formulators may be missing an opportunity to leverage its characteristics and the ability to precisely manage the bioavailability of their poorly water-soluble drugs more cost-effectively. It’s becoming increasingly evident that with HPMC-based hard capsules, dose form can play a leading role in creating a more integrated finished drug product that’s precisely specified to deliver therapeutic performance and desired patient outcomes.”
“I think pellet technology in capsules should be used more than it is now,” says Torkel: “It is highly efficient and convenient for drug formulators looking to manufacture MR products and fixed dose combination drugs. Strength and release profile are easily adjusted; plus, it’s relatively easy to combine and recombine different APIs to create new fixed dose combination products.”
“With all of this in mind, pellet technology can present drug formulators with a flexible technology that can significantly enhance drug innovation — all while optimising development and manufacturing efficiency. Minitablets is another technology that I think we’ll see more of in the future. Although relying on traditional tablet compaction, they still allow a lot of flexibility in dosing.”
“As part of the solubility and bioavailability conundrum that challenges much of today’s OSD formulations, poor permeability in vivo can pose a further problem,” advises Brad. “To address this, cocrystallisation has emerged as a more contemporary approach to improving bioavailability. Improving physicochemical properties such as solubility, dissolution rate, stability and melting point makes cocrystals an attractive option for poorly soluble APIs.”
“It’s important to note, though, that although cocrystals are more stable than ASDs, they suffer the same “spring and parachute” phenomenon without the additive crystallisation inhibition effects afforded by many ASD polymers. There is also evidence that cocrystals can impact membrane permeability (positively and negatively), although this is not yet fully understood.
"There is also potential for cocrystals to interrupt cellular integrity, which has raised concerns about their toxicity, as well as the physiological effects to the GI tract exerted by some coformers that affect absorption.”