MULTIPARTICULATE FORMULATIONS - Using Multiparticulate Technology to Develop Pediatric Drug Products

INTRODUCTION

In 1969, the Supreme Court made it clear that drug products must serve public health and that the FDA’s role was to enforce this objective.¹ More recently, the FDA and other regulatory bodies have presented new guidance for drug product  development in serving special populations, such as pediatric patients, and will likely extend regulations for those populations through its latest initiative on “patient-focused drug product development.”^2,3

Currently, the Pediatric Research Equity Act (PREA) requires that all new chemical entities (excluding orphan designations) have pediatric-specific studies (where pediatric use is anticipated) assessing safety and efficacy, as well as pediatric-specific dosage forms as part of the approval process. PREA requirements are triggered by approval applications for new API as well as new indication, dosage form, dosing regimen, or route of administration. Additionally, the Best Pharmaceuticals for Children Act (BPCA) provides financial incentives for companies to voluntarily conduct pediatric studies for existing drug products.

This regulatory guidance has had a marked impact on new drug development pipelines and new drug approvals (NDAs). For the 10-year period from 2007-2017, the FDA approved 202 pediatric, small molecule prescription-bound new drug approvals, inclusive of both new marketing authorizations and new indications. Traditional tablet and liquid formats (liquids, solutions, and suspensions) accounted for the majority of these approvals. However, multiparticulate (MP) formulations accounted for 23 unique product approvals, and we expect this number to increase substantially in the future given MP format advantages over other technologies, including dosing flexibility, stability, safety, ease of administration, taste-masking, and tailored delivery to meet target product profiles.⁴

As pediatric formulations are expected to continue as a core research area in pharmaceutical technology, MP technologies have the potential to play a key role. For pediatric and other specialized patient populations, in which the formulation and dosage form of the drug molecule plays an especially crucial part in achieving the best benefit-to-risk profile during treatment, multiparticulates’ flexibility help meet the combined challenges of specialized patient needs, drug requirements, and industrial and commercial viability.

DEFINING THE DRUG PRODUCT REQUIREMENTS

Today’s formulators have a variety of drug delivery systems to choose from when developing medicines for patients with special needs, such as pediatric, geriatric, or dysphagia patients. Selection of the best drug delivery system, however, requires an efficient, systematic approach that considers a drug’s physical and chemical properties and the targeted patient population’s requirements. Across all drug development processes, the starting point is defining the target product profile. Some general considerations for pediatric drug products are shown in Table 1.

Multiparticulates, which consist of multiple discrete drug-containing particles that together make up a single dose, are an emerging technology particularly well-suited for pediatric applications because they meet the majority of these considerations. Their advantages include tailored dissolution profiles, safe swallowability and taste-masking, high dose flexibility and accuracy of administered dose, improved correlations between in vitro and in vivo test results, and suitability for a variety of dosage forms, including capsules, using standard pharmaceutical manufacturing. But most importantly, recent clinical studies have proven that multiparticulate forms are the most preferred and accepted dosage form among very young to young children.^5,6

SELECTING THE APPROPRIATE MULTIPARTICULATE TECHNOLOGY

Multiparticulates can be called particles, pellets, mini tablets, microspheres, granules, and beadlets and are made using processes including melt-spray congealing (MSC), extrusion-spheronization, tableting, and fluid-bed coating. For pediatric patients, multiparticulates are mainly administered through sprinkling them on 5- to 15-ml portions of child-preferred soft food, an approach that is endorsed by FDA guidance.⁷

The four main multiparticulate technology approaches used for drug delivery in pediatric patients — lipid multiparticulates (LMPs), spray-layered dispersions, pellets, and mini tablets — are differentiated by their manufacturing processes, achievable particle sizes, and typical drug loadings. As Figure 1 shows, each of these delivery options is based on unit operations used in conventional pharmaceutical manufacturing, lending maximum flexibility to technology selection.

Selection of the most appropriate multiparticulate dosage form follows a four-step process, including: (1) a clear definition of the target product profile that includes patient needs; (2) assessment of the compound’s physical/chemical properties and selection of the multiparticulate technology approach; (3) optional addition of a functional and/or cosmetic coating; and (4) preparation of the ultimate dosage form and packaging.

Selection from these options derives from the desired drug form and release target, according to therapeutic needs. In some cases, developers can use the crystalline form of the drug as supplied, while in others a solubility-enhanced or amorphous form may be required. Depending on the desired delivery, an immediate-release product or modified-release characteristic may be preferable. Other attributes come into play in determining the right multiparticulate technology for the product, including (1) an achievable pharmacokinetic profile, (2) a reliable and stable formulation, and (3) reproducible and scalable manufacturing processes. Those considerations, in addition to incorporating the physical and chemical characteristics of the drug molecule –including its size, solubility, dissolution rate, excipient compatibility, and chemical stability – determine a best-choice technology approach for the drug-containing multiparticulate core.

Independent of the technology chosen, functional coatings may be considered to improve product flow or handling, to improve taste-masking, or to further modify the drug-release profile. Examples of coating types include extended release for metering the dose over time, and pH-targeted release or time-targeted release for taste concealment or gastric protection. Coatings do increase the complexity of the formulation and processes.

The selection of the dosage form is a final consideration in developing multiparticulate formulations that match the needs of patients, caregivers, and the industry. Dosage form options include orally disintegrating tablets (ODTs), suspensions, sachets, and sprinkle capsules, comprising a variety of choices for formulators. Moreover, recent innovations in drug-device combinations give more options for presenting both microspheres and mini tablets to patients. Whether a traditional dosage form or a device is selected, the best practice is to evaluate several criteria, including usability, ability for dose adjustment, available technology, cost of goods, stability, and product robustness.

Figure 2 demonstrates the methodology for identifying a product concept to test in the clinic. The approach begins with a decision on the most appropriate technology to accommodate the design attributes based on the patient needs, drug properties, and target product profile (TPP). This is followed by a pragmatic approach to the development of a formulation – one that identifies potential product risks at each step, yet informs a data-driven final decision to be made for progressing the formulation to be studied in human trials.

CASE STUDY: DEVELOPING A PEDIATRIC FORMULATION OF ACETAZOLAMIDE USING LIPID MULTIPARTICULATE (LMP) TECHNOLOGY

FDA guidance on pediatric drug products emphasizes design that promotes safety, accurate dosing, and enhanced acceptability.^8,9 Multiparticulates inherently possess these attributes, making them a well-suited technology platform for pediatric dosage forms.

Presented below is a case study for developing a pediatric formulation of an extended-release product containing the active pharmaceutical ingredient (API) acetazolamide, which is currently available for prescription to adults in the form of a 500-mg capsule. The example outlines selecting lipid multiparticulate technology for the product; jet milling to reduce the API particle size; determining formulation bounds via melt-screening; developing a formulation design space to achieve the desired release rate; manufacturing protoytpes and conducting stability testing; and finally nominating final formulations for clinical testing against an existing acetazolamide product.

Acetazolamide is a weakly acidic crystalline form with a melt point over 200°C and is considered very slightly water soluble. It is a carbonic anhydrase inhibitor and most commonly known for the treatment of glaucoma. The age-appropriate acetazolamide formulation is sought to accommodate children between 6 months to 12 years of age, and requires an oral dose range of 50 to 500 mg. The initial design target was to achieve 80% of the dose released over 12 hours in an in vitro test as a formulation suitable for an early clinical study to test the relative bioavailability of the product in adults. Subsequently, these data could be used to establish models to guide the clinical design for pediatric patients. The requirements for the formulation were to demonstrate delivery of the intended dose, tunable release, and phase-appropriate stability. This was accomplished using material-sparing formulation development approach for the specific technology and accelerated stability conditions to inform formulation stability beyond the clinical timeline.

Lipid multiparticulates (LMP) technology was chosen for particle size, ability to maintain the crystalline form of the drug for release and stability and flexibility in tuning release of the drug through formulation, without the need for an additional coating step. LMP excipients and formulas have good safety profiles and are accepted for use in pediatric patients, as they are absent of stabilizers and preservatives often found in liquids. Additionally, the particles have a small size, narrow distribution, high degree of sphericity with smooth surfaces; promoting palatability, good flow, and easy handling. An accurate dose is delivered by weight, inclusive of thousands of discreet LMPs, allowing multiple doses to be administered with the same formulation. Multiple final dosage forms are also possible when using this technology and can be explored in future clinical studies. By supplying the formulation in bulk for early phases in the clinical trial, flexibility can be maintained for ascending doses and body mass or surface area dose adjustments.

Under a self-imposed constraint of limited API, the formulation design approach for early clinical studies produced small batch sizes on a commercially relevant atomizer at similar flow rates. With the reduction of available materials, the characterization techniques also needed to be modified and scaled down to accommodate initial and stability testing. Because the size distribution of the API had a significant fraction greater than 100 microns, there was a risk of drug dissolution rate impacting release and content uniformity in the 200 micron microspheres. A jet mill was used to reduce the majority of the drug particles to below 20 microns. Two excipients were selected for screening based on release rate models developed by past formulation experience. For the release target, a matrix of glyceryl dibehenate was chosen for its hydrophobicity and low water permeability. This was combined with the water-soluble pore former, poloxamer 407 for tunable release using a porous diffusion mechanism.

Melt screening was used both as a process assessment of the formulations and a means to evaluate the solubility and compatibility of the API crystals in excipient melts. The screen indicated less than 0.1% w/w drug solubility and a maximum API loading of 40% w/w in the excipients. The API dispersed uniformly in the melt and there were no significant color changes after holding the mixture at 90°C for over 10 minutes. All formulations rapidly congealed with no signs of super-cooling, suggesting high yields of spherical particles should have been achievable. Two representative formulations were prepared to bracket process viscosities – having a range of 25 to 200 centipoise, correlated strongly with drug loading. Using a model for atomization, these measurements were used to determine MSC atomization parameters.

The formulation space was constructed as a partial design of experiments (DOE) having three levels and two factors, with drug dissolution being the primary output. The two factors within the formulation were the drug content and the poloxamer fraction of the total excipients in the formulation. The drug content levels were 10%, 25%, and 40%, bracketing intended fill masses of 125 to 500 mg for the lowest dose. The poloxamer fractions were 2%, 4%, and 6%, in an attempt to center the design space on the release target for the drug solubility. The excipient burden bracketed by this study would be 75 to 4200 mg/dose for glyceryl behenate and 4.5 to 340 mg/dose for poloxamer 407. Furthermore, the study design would also be informative on the compatibility of the drug with the two excipients for processing and storage stability using the secondary output of organic impurities. At the extremes, the ratios of poloxamer to drug ranges from 0.08 to 0.67, and for glyceryl behenate to drug from 1.5 to 8.5.

Five different prototypes were manufactured using less than 50 grams of total API with 67% to 86% product yields in batch sizes of less than 30 grams. The atomizer was adjusted based on melt viscosity resulting in spherical particles with a median size of 220 to 270 microns for all compositions. Prototypes were annealed for 7 days at 50°C/75%RH, then tested for dissolution performance using a paddle apparatus scale to a reduced volume of 100 mL. The dissolution performance was based on the two formulation factors as shown in Figure 3 with the actual percentage release at 12 hours in parentheses. The results show the actual design space had more of an extended release than originally predicted from the drug solubility.

Prototypes CR-2 and CR-5 were chosen for stability evaluation at 25°C/60%RH and 40°C/75%RH for 6 months in the open configuration in HDPE bottles. These aggressive storage conditions provide stability data regarding drug dissolution, potency, and purity toward the product’s predicted two-year shelf-life. CR-2 had achieved the dissolution performance target initially and had the highest excipient ratios of the design space. CR-5 demonstrated a differentiated release rate, more appropriate drug loading for dosage form flexibility and the highest overall poloxamer content of the design space. For the accelerated storage condition, CR-2 met the characteristic of 65% to 85% release at 12 hours and CR-5 25% to 55% release. The potency of both formulations met 90% to 110% of the label claim. Drug purity was maintained at 99.8% to 99.9% with no related organic impurity greater than the limit of quantitation (LOQ) of 0.05%.

Two compositions were recommended as clinical formulation for the bioequivalence comparison with the adult product. CR-2 met the target requirements to be one of the recommended compositions. The second formulation recommendation can come from a pharmacokinetic model informing the expected in vivo behavior of these particles compared to the adult capsule. If the LMP delivery is expected to be faster than capsule, one could interpolate the formulation space to select a slower-releasing composition. For example, a composition with 20% drug and a 5% poloxamer fraction would result in slower-releasing particles. If the contrast is true and a faster releasing composition is needed, a second formulation could be extrapolated to achieve 80% release in 6 hours. Given the uncertainty of the model, the preferred approach in this case would be a demonstration prototype or a further built-out design space.

In this case study, the LMP technology approach provides a consistent delivery mechanism with tunable drug release by varying the pore former content. A stable, solid oral product concept was demonstrated with recommendations for clinical prototypes, using knowledge of the formulation space to inform key performance and stability attributes. During scale-up, the LMP technology can maintain atomization parameters, controlling key performance attributes of particle size and content uniformity, and therefore facilitate rapid progression to late clinical and commercial stages. The flexibility to administer multiple accurate doses with multiple final dosage options allows for customization of the final product based on patient needs. The LMP technology provides an age-appropriate formulation design to be tested in a clinical study to first establish safety and is appropriate for quick translation for dosing into the pediatric patient population.

SUMMARY

With guidance and incentives from regulatory authorities, the development and provision of pediatric dosage forms have become an important field in drug delivery. The rise of patient-centric drug product development, along with increasing personalization of drug therapies, requires more flexible industrial manufacturing platforms and new drug development frameworks – to give patients with special needs access to the medicines they urgently require. Multiparticulate technologies have improved throughout the past 40 years and continue to be a source of innovation due to their flexibility in leveraging large-scale, high-throughput bulk manufacturing advantages, coupled with standard capsule filling, to provide a broad range of metered dose strengths that cover neonates through to adolescence. The case study shows the flexibility of lipid multiparticulate technology in modifying drug release for desired clinical target.

Considering the emerging patient demand and regulations for patient-centric drug product design, multiparticulates have the potential for use across all age groups and specific disease populations requiring dose flexibility and ease of oral administration.

REFERENCES

1. United States vs. Bacto-Unidisk 394 U.S. Supreme Court. 1969.
2. Zisowsky et al Drug development for pediatric Pharmaceutics 2, 364-388 (2010).
3. U.S. Food & Drug Administration. Plan for Issuance of Patient-Focused Drug Development Guidance. May 2017.
4. Lonza Pharma & Biotech analysis of Pharmacircle database, U.S. Food & Drug Administration. July 2018.
5. Klingmann V. et al. Acceptability of Multiple Uncoated Minitablets in Infants and Toddlers: A Randomized Controlled Trial. J Pediatr 201:202-207 (2018).
6. Klingmann V. et al. Acceptability of Uncoated Mini-Tablets in Neonates—A Randomized Controlled Trial. J Pediatr 167:893-896 (2015).
7. U.S. Food & Drug Administration. Use of Liquids and/or Soft Foods as Vehicles for Drug Administration: General Considerations for Selection and In Vitro Methods for Product Quality Assessments. July 2018.
8. U.S. Department of Health and Human Services. General Clinical Pharmacology Considerations for Pediatric Studies for Drugs and Biological Products. December 2014.
9. U.S. Food & Drug Administration. Safety Considerations for Product Design to Minimize Medication Errors. April 2016.

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Dr. Sven Stegemann is Director, Pharmaceutical Business Development, Lonza Pharma & Biotech. He has advised major pharmaceutical companies on the design, development, and manufacture of pharmaceutical products for 26 years. During his 20 years at Lonza, he was involved in several major DPI product developments. Since 2014 he is professor for patient centric drug products, to better address the needs of patients.

Matthew Shaffer is Product Development Manager, Lonza Pharma & Biotech. He is a chemical engineer focused on developing new products to reach patients using multiparticulate technologies for drug delivery. He works with customer-oriented, cross-disciplinary teams in areas of formulation design, manufacturing, characterization, and stability testing operations of enabled solid dosage forms. He has over 6 years of experience in developing age-appropriate formulations and over 15 years in oral drug delivery and pharmaceutical technology development. Before joining Lonza, he worked as an engineer at Green Ridge Consulting and Bend Research.

Samantha Saville is Scientist II, Lonza Pharma & Biotech. She is an analytical chemist working with multiparticulate dosage forms for immediate release, modified release, and taste-masking applications. She uses USPII dissolution, assay, related substance, SEM, microtoming, EDS, HPLC, PION, appearance and stability tests to determine drug availability and taste-masking.

Dr. Jaspreet Arora is a Senior Engineer, Product Development, Lonza Pharma & Biotech. He is a chemical engineer focused on multiparticulate drug delivery. Presently, his work focuses on formulation, manufacturing, and analytical characterization of lipid multiparticulates (LMPs) for controlled release.