October 3, 2023 PAO-09-23-CL-04
Patients suffering from dysphagia have difficulty swallowing due to structural deficiencies in the upper gastrointestinal tract and/or functional impairment. Symptoms can develop with age; in association with diseases such as cancer, multiple sclerosis, Parkinson’s, dementia, and chronic obstructive pulmonary disease; and following stroke or brain injury.1 The World Health Organization identifies dysphagia as a major public health issue worldwide. In the United States alone, it is reported that more than half of people over 60 suffer from dysphagia.2,3 On a global basis, it is estimated that approximately 8% of the world’s population has some type of swallowing issue.4
Dysphagia also occurs in children as the result of physical damage or disease. In addition, the very young (babies up through toddlers) simply have not yet developed the ability to swallow objects such as larger pills and capsules.
Adherence to treatment regimens tends — not surprisingly — to be poor for patients with swallowing issues due to the challenges involved in taking their medications.
Aside from swallowing issues, poor medication adherence with oral dosage forms (solutions, suspensions, orally disintegrating tablets (ODTs), and multiparticulates, including powders, granules, and minitablets) can often be attributed to taste and palatability issues, particularly among children and older patients with mental disabilities.5 The percentage of active pharmaceutical ingredients (APIs) that have a noticeable bitter taste is increasing. It has been found that unpleasant taste is one of the main challenges in getting children to complete prescribed dosing regimens.6 For these patient populations, ideal drug products are easy to administer, have minimal dosing frequencies, provide dosing flexibility, and have acceptable taste.5
Palatability is a more comprehensive attribute than taste and considers the five basic tastes (sweet, sour, salty, bitter, and umami), along with aroma, mouthfeel, and texture.5 In addition to the need to overcome bitterness, some APIs present challenges with respect to bad odors, burning of the throat and tongue, grittiness, and so on. Addressing these problems becomes increasingly difficult as dosage levels increase, and in many cases the traditional approach of using sweeteners or viscosity-modifying agents is not sufficient. Even so, the value of the global market for taste-masking excipients was estimated to be $877.4 million in 2022 and to be expanding at a compound annual growth rate of 4.8% to $1.5 billion by the end of 2033.7
Unlike swallowing issues, which are most significant for infants, taste becomes an issue as children get a little older. Toddlers in particular care about taste and palatability. Taste is much less of an issue with geriatric patients, except for patients that are mentally disabled. Taste and dosage form preferences are also quite different for children and adults. Kids prefer sour, bold flavors and medicines that are chewy or gummy, while adults prefer more subtle flavors and smooth and/or creamy texture.
It is also worth noting that, while in the past there was significant concern about making pediatric medicines taste too much like candy, it is the appearance of medicines that must be carefully controlled. Children are attracted to bright colors, so appropriate (child-proof, plain) packaging is essential.
Addressing swallowing and taste/palatability issues known to occur with pediatric and geriatric patient populations has become increasingly important as regulatory agencies and the industry as a whole have recognized the importance of providing patient-centric formulations designed to increase medication adherence.
In April 2023, the U.S. Food and Drug Administration (FDA) issued its fourth and final guidance on patient-focused drug development (PFDD).8 The four guidance documents discuss patient experience data, collection and submission of PFDD data from patients and caregivers, and the use of clinical outcomes assessments in clinical trials and to support products. The FDA’s PFDD program “leads initiatives and provides strategic, regulatory, program, and policy assistance within the Center for Drug Evaluation and Research (CDER) to facilitate the incorporation of patient input into decision-making.”9
Separately, both in the United States and Europe, there are now requirements for the development of pediatric formulations designed to ensure that medications meet the specific needs of children of different ages. These regulations include requirements for addressing the palatability of pediatric formulations during clinical development.5
Fortunately, there are several different oral dosage forms available today that can help address swallowability issues. Unfortunately, because these products typically dissolve in the mouth, it is necessary to overcome taste and palatability challenges.5
Liquid solutions and suspensions can be ideal for both children and adults with swallowing difficulties. Other options include orally disintegrating tablets and chewables. Hydrophobic APIs that are soluble in aqueous bases may sometimes be dissolved in lipid bases, but formulations with lipid bases typically do not have good mouthfeel.
Many companies pursuing 505(b)(2) applications prefer to focus on liquid products whenever possible, as they are the easier type of dosage form to swallow. Solutions are the simplest. If the API is stable in liquid but insoluble in water such that a simple solution isn’t possible, the next step is to try to create a suspension. Although suspensions typically have slightly higher viscosities than solutions, they are attractive because the taste is often improved owing to the reduced solubility of the active. Currently, however, there are few CDMOs with expertise in the development and production of suspension formulations.
In all oral dosage forms, artificial sweeteners, flavors, anti-bitterness flavoring ingredients, and so forth can be added in order to make these products as palatable as possible. Specific flavorants may be used to cover up certain types of flavors. Sometimes, use of sodium chloride can alter the flavor profile of some APIs. Actives can also be bound to complexing agents to prevent their taste. For instance, there is a trend in suspension formulations to incorporate an ion-exchange resin that absorbs the API, making it unavailable to the tongue until it enters the gastrointestinal tract, where the API is released and then enters the bloodstream. This technology has been used in multiple commercial products, including Delsym®10 and Dynavel XR and Quillivant XR Suspensions.11
Chewable tablets mostly comprise a diluent that is sweet, such as mannitol. The API can be dispersed in the diluent in multiple different ways. Low-dose drug products with APIs that are not too bitter may just contain the API, the diluent, and some added flavors and sweeteners. For APIs that are more bitter and/or formulated at high doses, a coating is often applied to act as a barrier, preventing dissolution of the drug product in the mouth. Such coatings are generally formed using specific polymers that create the desired release profile. The ideal formulation does not allow release of the API for the first five minutes while the tablet is being chewed and swallowed. It is only released once it arrives in the GI tract.
For people with significant swallowing issues and toddlers, ODTs are the ideal form of chewable. They are designed to disintegrate rapidly in the mouth and be readily swallowed. Children do not have time to chew them up and spit them out, and they dissolve rapidly enough to prevent choking. As a result, ODTs have become an increasingly popular platform for the pediatric and geriatric populations from an oral solid perspective. Because the drug product dissolves in the mouth, a taste-masking coating is generally applied to the API to prevent direct interaction with the tongue as the drug product disintegrates.
Alternatively, coated particles can be incorporated into a base and formulated as sprinkle products that are added to applesauce, yogurt, pudding, or other foods of similar consistency for administration. They can be in the form of multiparticulate products, such as a sugar sphere with the API layered onto it, an extruded spheronized bead, or a simple powder. Sprinkle products with larger particle sizes may not require as much taste masking and can therefore be easier to formulate from a taste perspective; the interaction with the tongue is not as significant as that seen with powdered or chewable products.
Minitablets are yet another option being pursued largely for pediatric formulations. They are challenging to produce, however. Weight variation can be a real issue. Handling (counting) and visual observations are also more complex; a microscope or magnifying system of some kind must be used to perform quality assessments. Despite these issues, minitablets are more suitable for children and adults with swallowing issues than regular tablets. They also provide innovator companies with some protection against generic competition due to their increased formulation and manufacturing complexity.
Freeze-dried dosage forms also merit consideration. In these products, a liquid or suspension formulation is freeze-dried to make it nearly instantaneously dissolvable in the mouth due to the porous structure generated by the freeze-drying process. However, this technology is considerably more expensive to implement than the manufacture of straight chewables and ODTs. In addition, it often is not suitable for high-dose formulations because there is insufficient base and too much API in the mouth when the product disintegrates, leading to a strong bitter taste and poor mouthfeel.
Approximately 60% of tablet products on the market are uncoated, despite the fact that film coatings can improve swallowability; act as barriers to prevent dissolution in the mouth, thus avoiding exposure of bitter-tasting APIs; and can allow control of the release profile.
Those advantages and the shift toward alternative dosage forms that emphasize patient convenience and meeting the specific needs of pediatric and geriatric populations are creating more demand for coating solutions. The ability of specially designed coatings to provide both taste-masking and controlled-release functionalities is driving interest in their use for reformulation of oral solid dosage products that are losing patent protection. In particular, as more products leverage ODT, multiparticulate, sprinkle, and other formats that enable differentiation but require prevention of exposure of the API in the mouth, film coatings are becoming more widely used.
Ultimately, a balance must be achieved in terms of swallowability, taste, and palatability, including mouthfeel and texture. Decisions must be made on a project-by-project basis considering the nature of the API, the desired dosage form, and the target patient population.
While liquid formulations are ideal for patients with swallowability issues, the API might not be stable in a liquid solution or suspension. In addition, taste may be a challenge if it is a high-dosage product with an extremely bitter API. A chewable product with appropriate taste-masking technology may be a better solution. Of course, more complicated platforms involve longer development timelines and often higher costs, which also must be factored into the decision-making process.
Mikart is a CDMO offering support for formulation development and manufacturing of patient-centric pediatric and geriatric drug products that address swallowing, taste, and palatability concerns. We have expertise in both liquid solutions and suspensions, having recently brought onstream a new liquids manufacturing area that can handle both standard liquids and suspensions.
In addition, Mikart has established capabilities in multiparticulates, minitablets, sprinkle formats, ODTs, and chewable and sublingual tablets, among other dosage forms, as well as aqueous-based coating and other taste-masking and controlled-release technologies. We can produce complexes, including those based on ion-exchange resins and incorporate them into several dosage platforms.
Complementing these offerings is Mikart’s ability to package drug products in high-density polyethylene and glass bottles for liquids, solids, and powders for reconstitutable solutions and suspensions. We also have a liquid filler machine that can be used to fill unit-dose cups and sachets. Other packaging solutions include both cold-form and thermoform blisters that enable the production of products in child-resistant packaging that can still be opened by elderly patients.
Mikart can support customers that have a chosen platform and are seeking direct tech transfer and manufacturing support, as well as customers looking for guidance regarding the optimum platforms for their APIs and target patient populations. For the latter group, we have a small non-GMP laboratory set up to support feasibility studies via rapid screening of multiple platforms.
Gus LaBella, director of formulation development at Mikart, has over 30 years of experience in oral dosage form development. He is responsible for the management of the formulation development team and the development, transfer, and scale-up of new products. Gus’ role also provides support in Mikart’s manufacturing area regarding troubleshooting and process improvements of currently manufactured products. Prior to joining Mikart, Gus worked as a formulation technologies manager at Colorcon®, a pharmaceutical excipients manufacturer. Gus’ experience also includes various positions within the research and development group at McNeil Consumer Products, a Johnson & Johnson company. While at McNeil, Gus held positions in product development, investigational supplies, support to marketed products, and R&D technologies. His skills range from pre-formulation of novel dosage forms to post-launch support of marketed products. His areas of interest are wet granulation and design of experiments. Gus holds a B.S. in materials engineering from Drexel University in Philadelphia, Pennsylvania.