Robert Louis Ternik

A Report from the Pediatric Formulations Task Force: Perspectives on the State of Child-Friendly Oral Dosage Forms

Despite the fact that a significant percentage of the population is unable to swallow tablets and capsules, these dosage forms continue to be the default standard. These oral formulations fail many patients, especially children, because of large tablet or capsule size, poor palatability, and lack of correct dosage strength. The clinical result is often lack of adherence and therapeutic failure. The American Association of Pharmaceutical Scientists formed a Pediatric Formulations Task Force, consisting of members with various areas of expertise including pediatrics, formulation development, clinical pharmacology, and regulatory science, in order to identify pediatric, manufacturing, and regulatory issues and areas of needed research and regulatory guidance. Dosage form and palatability standards for all pediatric ages, relative bioavailability requirements, and small batch manufacturing capabilities and creation of a viable economic model were identified as particular needs. This assessment is considered an important first step for a task force seeking creative approaches to providing more appropriate oral formulations for children.

Defining Patient Centric Pharmaceutical Drug Product Design

The term “patient centered,” “patient centric,” or “patient centricity” is increasingly used in the scientific literature in a wide variety of contexts. Generally, patient centric medicines are recognized as an essential contributor to healthy aging and the overall patient’s quality of life and life expectancy. Besides the selection of the appropriate type of drug substance and strength for a particular indication in a particular patient, due attention must be paid that the pharmaceutical drug product design is also adequately addressing the particular patient’s needs, i.e., assuring adequate patient adherence and the anticipate drug safety and effectiveness. Relevant pharmaceutical design aspects may e.g., involve the selection of the route of administration, the tablet size and shape, the ease of opening the package, the ability to read the user instruction, or the ability to follow the recommended (in-use) storage conditions. Currently, a harmonized definition on patient centric drug development/design has not yet been established. To stimulate scientific research and discussions and the consistent interpretation of test results, it is essential that such a definition is established. We have developed a first draft definition through various rounds of discussions within an interdisciplinary AAPS focus group of experts. This publication summarizes the outcomes and is intended to stimulate further discussions with all stakeholders towards a common definition of patient centric pharmaceutical drug product design that is useable across all disciplines involved.

Feasibility of mini-tablets as a flexible drug delivery tool

Mini-tablets have potential applications as a flexible drug delivery tool in addition to their generally perceived use as multi-particulates. That is, mini-tablets could provide flexibility in dose finding studies and/or allow for combination therapies in the clinic. Moreover, mini-tablets with well controlled quality attributes could be a prudent choice for administering solid dosage forms as a single unit or composite of multiple mini-tablets in patient populations with swallowing difficulties (e.g., pediatric and geriatric populations). This work demonstrated drug substance particle size and concentration ranges that achieve acceptable mini-tablet quality attributes for use as a single or composite dosage unit. Immediate release and orally disintegrating mini-tablet formulations with 30μm to 350μm (particle size d90) acetaminophen and Compap™ L (90% acetaminophen) at concentrations equivalent to 6.7% and 26.7% acetaminophen were evaluated. Mini-tablets achieved acceptable weight variability, tensile strength, friability, and disintegration time at a reasonable solid fraction for each formulation. The content uniformity was acceptable for mini-tablets of 6.7% formulations with ≤170μm drug substance, mini-tablets of all 26.7% formulations, and composite dosage units containing five or more mini-tablets of any formulation. Results supported the manufacturing feasibility of quality mini-tablets, and their applicability as a flexible drug delivery tool.

Assessment of swallowability and palatability of oral dosage forms in children: Report from an M-CERSI pediatric formulation workshop

The acceptability of pediatric pharmaceutical products to patients and their caregivers can have a profound impact on the resulting therapeutic outcome. However, existing methodology and approaches used for acceptability assessments for pediatric products is fragmented, making robust and consistent product evaluations difficult. A pediatric formulation development workshop took place in Washington, DC in June 2016 through the University of Marylands Center of Excellence in Regulatory Science and Innovation (M-CERSI). A session at the workshop was dedicated to acceptability assessments and focused on two major elements that affect the overall acceptability of oral medicines, namely swallowability and palatability. The session started with presentations to provide an overview of literature, background and current state on swallowability and palatability assessments. Five parallel breakout discussions followed the presentations on each element, focusing on three overarching themes, risk-based approaches, methodology and product factors. This article reports the key outcomes of the workshop related to swallowability and palatability assessments.

Food effects in paediatric medicines development for products Co-administered with food

A small amount of food is commonly used to aid administration of medicines to children to improve palatability and/or swallowability. However the impact of this co-administered food on the absorption and subsequent pharmacokinetic profile of the drug is unknown. Existing information on food effects is limited to standard protocols used to evaluate the impact of a high fat meal in an adult population using the adult medication. In the absence of a substantial body of data, there are no specific guidelines available during development of paediatric products relating to low volumes of potentially low calorie food. This paper brings together expertise to consider how the impact of co-administered food can be risk assessed during the development of a paediatric medicine. Two case studies were used to facilitate discussions and seek out commonalities in risk assessing paediatric products; these case studies used model drugs that differed in their solubility, a poorly soluble drug that demonstrated a positive food effect in adults and a highly soluble drug where a negative food effect was observed. For poorly soluble drugs risk assessments are centred upon understanding the impact of food on the in vivo solubility of the drug which requires knowledge of the composition of the food and the volumes present within the paediatric gastrointestinal tract. Further work is required to develop age appropriate in vitro and in silico models that are representative of paediatric populations. For soluble drugs it is more important to understand the mechanisms that may lead to a food effect, this may include interactions with transporters or the impact of the food composition on gastro-intestinal transit or even altered gastric motility. In silico models have the most promise for highly soluble drug products although it is essential that these models reflect the relevant mechanisms involved in potential food effects. The development of appropriate in vitro and in silico tools is limited by the lack of available clinical data that is critical to validate any tool. Further work is required to identify globally acceptable and available vehicles that should be the first option for co-administration with medicines to enable rapid and relevant risk assessment.

Oral Drug Product Use in the Elderly Patient Population

This chapter explores in detail the many considerations to be factored into the design of oral drug product s for use in the elderly patient . These considerations include characteristics of the dose form and holistic drug product, as well as characteristics of the intended patient population. These characteristics are detailed and discussed. For synthetically manufactured drug substances, oral administration is the most frequent and popular drug administration route used in medical practice today. Subsequently, drug products designed to be administered by the oral route are the most common dosage forms available worldwide. The popularity of the oral route is a result of a number of inherent advantages, and these advantages impact all key stakeholders in the pharmaceutical paradigm, including patients, healthcare providers, manufacturers, and regulators. A few of the advantages of oral drug products over alternative routes of delivery include self-administration, dose accuracy and uniformity, stability, portability, lack of invasiveness, familiarity to patients, and relatively low cost to manufacture. Additionally, to have the best chance at designing an outstanding product, gaining a comprehensive understanding of the target customer behaviors and needs, and incorporating that knowledge into the product design, is a must. The evolution toward drug products that are intentionally designed to meet not only their safety, efficacy and quality requirements, but also provide opportunity for improved outcomes through better patient experience and improved adherence should enhance overall therapeutic outcomes. When designing for an elderly target patient population, the drug product designer and developer should pay particular attention to the specific characteristics of the disease state, target patient population, comorbidities and other emotional, environmental, and sociological factors that have the potential to impact or interfere with the elderly patient’s ability to use the product as intended. Failure to take a diligent approach in this regard can result in a greater likelihood of poor adherence and improper usage of the drug product, resulting in lower effectiveness, poor therapeutic outcomes, and potential safety risks.