The Growing Application of Multiparticulate Technologies for Pediatric and Beyond
Introductory Statement
Multiparticulates are multiple discrete, repetitive, drug-containing particles, a sum of which makes a unit dosage form. These units are typically spherical in shape and often described as particles, pellets, mini-tablets, microspheres, granules, or beadlets. Multiparticulates are usually delivered in capsule or sachet formats and dosed directly or sprinkled with food or liquids especially for specialized populations such as pediatrics and geriatrics where swallowability is a critical issue. Multiparticulates are a proven life cycle management tool and highly flexible for achieving modified release delivery profiles, improved dosing regimens, and fixed dose combinations. Between 2012 and 2016, 22 new drug products with multiparticulates were approved by the U.S. Food and Drug Administration.1 Nearly seventy five percent utilized the 505(b)2 approval pathway, and more than half were for extended or delayed release products. Ten of the 22 approvals were for pediatric applications where multiparticulate formats are accepted as having superior dosing flexibility and ease of administration vs. monolithic formats.
Why are multiparticulate dosage forms finding increased use?
Multiparticulates are frequently used for oral drug delivery when the compound is in need of microencapsulation, modified release, or solubilization. The multi-unit particle approach presents advantages over other oral solids through reduced PK variability, flexibility in dosing, and versatility in dosage form presentations. The surge in utilizing multiparticulate technology is primarily attributed to the development of pediatric products. This is motivated by, (1) the need for medicines to be developed for our children, (2) the rarity of regulatory waivers for new drug applications, and (3) the economic incentive of additional marketing exclusivity for the adult product.
The unique attributes that multiparticulates offer compensate for the perceived cost and complexity of the approach, especially when designing products for children. Compared to traditional tablet or capsule formulations, the plurality of the dose and small size of multiparticulates makes them easier to swallow – reaching a broader patient population based on age and ability, while gaining the flexibility of dose adjustment by mass or volume. Multiparticulates are readily accepted with the youngest of patients when dispersed in liquid, and with all but neonates in their solid form. They offer similar dose flexibility as liquid solutions and suspensions; have improved physical and chemical stability; and don’t require solubilizers, stabilizers, flavorings, or preservatives to be formulated.
How does design criteria for the product drive the selection of this technology?
It is important to remember that the product drives the selection of the technology – not the other way around. Whether you call it design criteria, a target product profile, or a user specification: clearly defining the product concept is the first step. This serves as a communication tool to establish and track the evolving objectives for the product over its development life cycle. This profile includes the indication, population, route of administration, dose or dose range, dosing frequency, duration of treatment, and metrics for PK/PD and safety/tolerability. The process of technology selection is to screen the best-suited approaches for delivering the defined product with the highest probability of success in development. This requires not only breadth in available technologies, but sufficient depth of the respective formulation, process and methods; allowing for the final decision to be weighted in favor of the most desired product attributes and the technology that will present only a few, yet manageable risks.
Within multiparticulate technologies there are several categories, including: mini-tablets, pelletization (e.g., extrusion-spheronization), granulation, fluid bed layered beads, and lipid-based microspheres, or lipid multiparticulates. Each of these technologies presents a different design space defined by: (1) the drug loading that can be achieved, (2) the tunability of drug release, (3) the mechanism of drug delivery, and (4) the amenability to taste masking and pediatric dosing. Different particle sizes and morphologies are inherent to each technology. For pelletization and mini-tablets particle sizes can be up to several millimeters, amounting to 10-100 particles per hundred milligrams of formulation – a number you can count. This is in contrast to granules, beads, and microspheres, which are a few tenths of a millimeter in size, or 1,000-10,000 particles per hundred milligrams of formulation. Mass or volume is more common means of quantifying these particles. Morphologies span from smooth spheres for lipids, to the rough, irregular shape of milled granules.
Formulating excipients and manufacturing process should also be evaluated for any potential sources of incompatibilities of the drug. Coating, granulation, and pelletization processes commonly use solvents, whereas heat is often used for lipid-based processes. The number and types of excipients used in the formulation space of each technology can impact product stability and your ability to predict shelf life, and in the case of special populations like pediatrics, a safety profile for the excipients requires careful analysis.
Can you describe some key challenges in pediatric product development?
Pediatric product development presents several unique challenges. Pediatrics includes patients from birth up to the age of 21. They are a vulnerable population, under the care of adults and at the peak of changes in both anatomy and physiology. In practice, the population is sub-categorized by age to account for differences not only in the PK/PD and safety of the formulation, but also the preference, tolerance, and ease of administration for the patient and caregiver. A broad range of doses and flexible dosing strategies are needed to accommodate differences of roughly an order of magnitude in mass or body surface area that exists between the youngest to oldest subpopulations. Drug loading should also be part of the formulation strategy, keeping an eye toward the most age-appropriate dosage form and/or dispensing device. The loading will establish the mass of the formulation to deliver for a given age group and dose. It is a balance between the excipient exposure and accuracy in dosing. Higher drug loadings will result in the lowest formulation and excipient burden, however, it will be constrained by a minimum mass that can be accurately dispensed and administered.
While there are several guidelines for product preference within the age-appropriate definition, being predictive of compliance remains a challenge. Too often, there is little to no data being collected to assess the taste of a compound or formulation. Because taste is typically not considered during the development of traditional dosage forms for adults, the palatability factor is often unknown going into pediatric studies. Where possible, design within early adult clinical trials, the ability to generate data on the palatability of the compound or formulation should be conducted. More complex dosage forms are needed for products that face a hurdle of unpleasant taste.
Another challenge is the need to achieve reliable bioavailability to promote safe dosing at the start of a pediatric trial. If an adult product is available to reference, achieving similar bioperformance will aid in the development of predictive models for the new dosage form. Having a good understanding of the drug form and release mechanism, in combination with a suitable dissolution method, promotes forecasting success. These challenges are also accompanied by regulatory commitments and timelines. There is a demand for rapid development, which implores robust manufacturing, and predictive tools for product stability as early as feasible in development. Within these constraints, the goal is to design and develop the single-most versatile product to meet the target product profile: meant to avoid lost time and additional efforts to later incorporate taste masking, make a switch in technology, or address product stability after the start of a pediatric clinical trial.
Are there special considerations needed to make these pediatric products commercial?
There is an increased frequency of pediatric dosage forms being developed, inclusive of both pediatric-specific indications and supporting pediatric study plans submitted with filings. Some of these products may be supplied clinically for long periods of time, limited by enrollment, or low demand. To meet the unmet pediatric need and decrease off-label uses of the drug, products that demonstrate success in the clinic should pursue commercialization as the next step. The catch – in general, the products tend to be niche: high value, low volume products. Often, specialized equipment or testing requirements are required, and only a few reputable contract partners with the capabilities to support multiparticulate product development are available.
As with all programs, transitioning from the clinic to commercial readiness requires attention and care. Even for low commercial volumes, scaling up from clinical trial supplies is required. Understanding the technology platform and manufacturing processes across these scales is an important consideration, not only for the initial scale-up, but also for the technology transfer. For the most efficient and effective tech transfers seek out scientific continuity from development through production and form multi-disciplinary teams to cover the book ends of the product: from formulation to stability. In order to make a marketable product, consider manufacturing flexibility and promote an on-demand manufacturing schedule that best fits the shelf life of the product. Most importantly, find a reliable partner with a customer-focused history that demonstrates safe operations, superior quality & compliance systems, and on-time delivery of products & services.
What trends do you anticipate for multiparticulate-based products?
Although the increasing popularity of multiparticulate technologies have been driven in a large part by pediatric medicines, the particles have universal properties that can be adapted within a broad number of dosage forms for adults as well, evidenced by the number of 505(b)2 approvals. There is an opportunity to establish a platform-view on product development by having a single development pathway for all ages going right into first-in-human trials. This approach could realize affordable medicines especially for niche indications, low margin markets, or even the geriatric population. Furthermore, it would enable speed to market by building product knowledge right out of the gate, thus minimizing the number of bridging studies during the product development.
As multiparticulates continue to demonstrate acceptability by patients, expect to see new, evolving presentations of the product and how it is administered – motivated by personalizing the delivery of medicine. Examples of personalization could include the development of reusable devices for dispensing that maintain the dosing flexibility, or offer patient choices to dosing aids that are more controlled than suggesting foods and beverages on the label. Lastly, with solubilized drug forms and high potency compounds becoming more common place in the industry, control strategies for multiparticulate technologies will need to adapt to see these compound through to the market.
References
- Internal Capsugel analysis based on our analysis of each MP approval for the 5 year period 2012-16. Sources: https://pharmacircle.com/; https://www.accessdata.fda.gov/scripts/cder/daf/ https://dailymed. nlm.nih.gov/dailymed/index.cfm.