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Several factors must be considered when reformulating APIs for pediatric, geriatric, and other specialty patient populations.
Increasing emphasis on patient centricity is driving the development of different oral dosage forms of APIs used in adult products for specialty patient populations. Poor patient compliance is a significant issue in the pharmaceutical industry that can be addressed to a significant degree through the formulation of dosage forms designed for convenience and ease of use.
Modification of adult medications for children by dividing tablets or capsules into smaller segments to achieve lower doses or aid in swallowing, however, can lead to incorrect and/or nonuniform doses and compromise the performance of any sustained-release coating in the product. In some cases, excipients suitable for adult formulations can pose safety issues for children.
Age-appropriate medications are now required by regulatory agencies for children. Elderly patients and patients suffering from dementia and disorders that lead to problems with swallowing also benefit from specialty dosage forms. In all of these cases, the emphasis is placed on patient acceptability, which can be impacted by physiological, physical, and psychological factors.
“Overall, the practicality of administering an existing drug to a different patient population will determine its acceptability,” says Rob Harris, director, science and technology at Catalent.
Specifically, there are several factors to consider. The first, according to Jim Jingjun Huang, founder and CEO of Ascendia Pharmaceuticals, is efficacy and safety, which is determined by extrapolating the pharmacokinetics and pharmacodynamics for the existing formulation to the targeted population. The acceptability of the excipients in the existing formulation in the target population-taking their use levels into consideration-must also be established. For many specialty populations, the swallowability and taste of the existing formulation may need to be modified. Finally, dose accuracy, and if appropriate flexibility, must also be assured for the target population.
“Taste-masking, swallowability, dose flexibility, and excipient acceptability are all important for pediatric formulations, whereas dosing accuracy, swallowability, and the capability for multi-drug administration are important for geriatric formulations,” Huang notes.
For instance, Harris points to tablets, which are suitable for teenagers, but not patients two years old or younger. The pediatric patient group is unique, adds Anthony Qu, vice-president of scientific affairs for Cambrex. “The pediatric patient population includes infants, children, and adolescents. You cannot simply cut an adult dosage down. Pediatric formulations should vary from adult formulations depending on the patient age, body size, swallowing capability, and pharmacokinetic (PK) and pharmacodynamic (PD) profiles,” he asserts.
It is also important to note, according to Qu, that pediatric formulations can benefit other patient groups that have swallowing issues, such as the elderly, patients who have had a stroke, or patients with long-term diseases such as Parkinson’s or Alzheimer’s.
There are many sources of information to assess patient acceptability. “The fastest and least costly method of evaluation is to review relevant publications, the content of which include results of patient focus groups or patient and caregiver surveys,” Harris says.
There are numerous challenges to reformulating existing adult products for specialty patient populations. For all of these types of projects, accurate extrapolation of the PK/PD can present real difficulties, according to Huang.
For most specialty populations, swallowability and palatability are key elements in the design of suitable dosage forms. “Most drugs have an unpleasant taste, and therefore due consideration needs to be given to making medicines acceptable from this perspective,” observes Harris. For children and the elderly, the actual dose can also be problematic; while an adult may be able to take a large tablet containing 500 mg of drug, administering a similar-sized tablet to a five-year-old child is much more challenging, he notes.
The physical differences of age, body weight, swallowing capability, and tolerance within the pediatric population are also challenging and create the need for dose flexibility, according to Qu. He adds that stability, shelf-life, and bioavailability issues can further complicate formulation development. Ensuring excipient acceptability for pediatric formulations adds another layer of complexity, according to Huang.
The first step in a reformulation project for a specialty population is to consider the age range of the patients and the dose range of the drug to be given. It is then important, observes Harris, to consider the drivers for achieving dose acceptability and compliance for that patient population, and what might the complications be in administering the drug to these patients.
Questions that should be answered when looking to overcome reformulation challenges, according to Qu, are:
“The goal is to determine the formulation strategy that will ensure similar exposure of the API in the new dosage form for new patient population as is achieved with the adult product and address the specific needs of the target population,” Huang explains. The solubility of the API must be considered to determine if a solubilization technology will be needed to achieve this goal. The stability of the API will determine whether a liquid (i.e., solution, syrup, suspension) product is possible, or if a solid dosage form will be necessary, Qu adds.
Once the various factors have been considered and the relevant questions answered, it is possible to determine the optimum formulation and oral dosage approach. The main options include traditional liquid and solid (i.e., tablets, capsules) formulations, as well as newer dosage forms, such as chewable and fast dissolving tablets, rapidly dissolving and mucoadhesive oral thin films and multi-particulate formulations such as mini-tablets.
“The traditional approach has been to use solution or suspension formulations because they are easy to swallow and provide dose flexibility. However, the use of sugars, flavors, and preservatives in these formulations can have detrimental effects on children and are consequently becoming less popular,” says Harris. These formulations also typically need to be refrigerated in-between use, have a shorter shelf-life, and can have overall stability issues compared to other forms, according to Qu. Furthermore, accurate dosing can be an issue due to varying spoon sizes.
Traditional solid-dosage forms are well-established technologies that have stable, long-term shelf-lives, are pre-measured for dosing, and can be coated to mask taste or added to food, according to Qu. “Conversely,” he says, “they can be difficult to swallow for some patients, and certain types of formulations are hydroscopic and require special packaging and storage in a dry place.”
Chewable tablets are another option often suitable for pediatric patients. “These formulations typically benefit from enhanced bioavailability and are convenient because water is not required for consumption and absorption is typically fast,” Qu says. On the other hand, these formulations typically contain sorbitol, which could have potential side effects in children. Other factors to consider, according to Qu, are the material flow, types of lubricants used, disintegration acceptance, taste, compressibility, and stability.
Orally dispersible tablets in which the tablet rapidly disintegrates in the mouth have become popular and certainly allow for easy swallowing of the dose, according to Harris. Qu notes, however, that they present their own hurdles as well, such as lower strength levels and half-lives.
Mini-tablets are the most common type of multi-particulate formulation. These small (typically 2–3 mm in diameter) versions of normal tablets can be readily swallowed by very young children. They also offer great dose flexibility, because the number of minitabs can be varied to achieve the required dose, according to Harris. In addition, unpleasant tastes can be masked using barrier coatings.
A further benefit of mini-tablets is the ability to combine different types of tablets in one dosage form (within a capsule or compressed into a tablet), according to Qu. “It is relatively easy to combine immediate and sustained release mini-tablets in one product. Similarly, mini-tablets facilitate the formulation of fixed-dose combination products containing two or three different APIs,” he observes.
One potential solution to the potential solubility, stability, and taste-masking issues is to utilize nanotechnologies, such as nanoparticles or nanoemulsions, which can encapsulate the molecules into a nano-formulation that can mask the taste and protect the compound from degradation, according to Huang. Another approach, he says, could be a change in the route of administration to injectables; a long-acting injectable for chronic disease would address the taste, dose accuracy, safety, and compliance issues associated with oral dosage forms.
For pediatric formulations, it is essential to ensure that all of the selected excipients are safe for consumption by children. “Excipients play a key role in how a drug product is manufactured, stored, consumed, and delivered in the body. Just like with dosage and formulation, not all excipients that are appropriate for adult formulations will work in pediatric formulations. Children may not be able to metabolize or eliminate the excipient in the same way that an adult can, which can cause issues such as stomach upset (indigestion, flatulence, diarrhea), breathing trouble, intoxication, or worse,” Qu explains.
In some cases, there may be different safety limits for an excipient that is used in an adult formulation versus a pediatric formulation, and guidance exists on this topic. In other cases, an excipient may need to be replaced completely with a different alternative. Formulators must decide what function each excipient is serving in the adult formulation, and then select and assess alternative, child-acceptable excipients that offer similar functionality, according to Harris. He points to the European Paediatric Formulation Initiative Safety and Toxicity of Excipients for Paediatrics database as a good place to start in selecting suitable excipients for use in children-friendly medicines.
“Selecting suitable excipients for a pediatric formulation is not normally challenging, but there are restrictions. The key point here,” Harris stresses, “is that excipients are not inactive ingredients.”
Successful reformulation of adult medicines for specialty patient populations can be successfully achieved by starting with a ‘patient-first’ mind set, which requires consideration of the formulation type that will best suit the needs of the patient, not only for getting the drug into the body, but also for ease of use and patient acceptance, according to Harris.
The development of pediatric and other specialty formulations requires extensive knowledge and expertise in not only a wide variety of dosage forms and technologies, but awareness of the key determinants for patient acceptability. “As a result, many companies rely on experienced [contract development and manufacturing organizations] CDMOs with specialist expertise in this field,” says Qu. “Such CDMOs will be able to provide guidance and develop the right formulations that consider the age and taste preferences of the target population in the context of different dosage forms, in addition to paying attention to regulatory approval early in the development process,” he concludes.
1. European Paediatric Formulation Initiative, Safety and Toxicity of Excipients for Paediatrics.
Vol. 43, No. 11
When referring to this article, please cite it as C. Challener, “Adapting APIs for Specialty Dosage Forms," Pharmaceutical Technology 43 (11) 2019.