The orally disintegrating tablet, or
ODT, offers an easy-to-take alternative form to consumers of over-the-counter
(OTC) treatments who perhaps do not have access to water, and patients of prescribed
drugs who cannot, or will not, swallow standard oral dosage forms, such as
tablets and capsules. It is not only patients at either end of the age spectrum
– the very old and the very young – who suffer from an inability to swallow, or
dysphagia, either, with a recent study indicating that 70% of younger people aged
16-34 who were surveyed reporting that they had difficulties swallowing tablets
and capsules.1 Pre-existing conditions may affect compliance too,
and those with mental health issues may not want to take their medications,
instead, secreting the tablets in their mouth before disposing of them later,
or saving them for misuse or even self-harm in the form of an overdose. It can
be easier to give a medication to a child using an ODT and of course, in the
animal health arena, it can be a significant challenge to get pets or livestock
to swallow tablets.
While liquid formulations can provide
successful dosing options in some cases, the ODT can work in all of these
situations. ODTs are designed to disperse quickly within the oral cavity,
removing the need to swallow a solid tablet or capsule. When a drug is absorbed
within the mouth, it enters the bloodstream directly, thus avoiding the
first-pass metabolism by the liver, where side-effect-causing metabolites may
be formed. It also gives a rapid onset of action, which may be advantageous
before or during acute episodes of conditions such as migraine or psychiatric events.
A number of technologies are available
to create ODTs. These include Catalent’s Zydis® ODTs, which are made
via freeze-drying technology, and others, such as loosely compressed tablets.
Loosely compressed tablets typically take 15-20 seconds to disperse in the
mouth, with a chalky, gritty mouthfeel, unlike Zydis tablets, which will normally
disperse in less than 3 seconds with a smooth mouthfeel.
Zydis technology has been used to
formulate a number of commercial products, particularly those for which a fast
onset of action is beneficial. Recently, higher doses of up to 200 mg have been
launched, and peptide and protein products formulated in this way are also available.
The structure of a Zydis tablet is key
to its rapid dispersal properties, as the tablets are highly porous. This is
achieved via a matrix of fish or bovine gelatin, or by using one of several non-gelatin
polymers, plus structure-forming mannitol, which also aids in the solubilizing
of the tablet. As well as the drug active, other ingredients, such as sweeteners,
colors, flavorings, and acidity modifiers, are often incorporated to increase palatability.
The ingredients are all dissolved or
suspended in water, accurately dosed into blister trays, and then frozen in
liquid nitrogen freeze tunnels before being placed in freeze dryers. There, the
water sublimes, leaving behind the porous matrix structure of the ODT, often
referred to as a wafer. Figure 1 is an electron micrograph image of the matrix.
The choice of packaging materials is important, and each blister strip is
sealed using specially designed, multi-layer foils that are resistant to
moisture ingress. Various options are available to optimize and tailor the
patient’s experience of taking a medication that includes Zydis technology, for
example, blister strips can be customized with multiple combinations of
perforations, thumb-peel tabs to allow for easy opening, and printing options
too, including helpful directions, regimen information or product branding.
After “lidding” the blister strips may be packed into outer cartons.
A significant amount of analytical work
is required when developing a new ODT. X-ray diffraction is used to determine the
crystalline state of the API and relevant excipients; whether it is crystalline
or amorphous will have a bearing on the structural integrity of the final
dosage forms. Differential scanning calorimetry is used to determine the melting
point and other thermal events. This assists in calculating the necessary times
for freeze-drying, while ensuring that the frozen product does not melt during
the drying process.
Another technique, dynamic vapor sorption,
is used to determine the moisture sorption and desorption profiles. This is
important, as a freeze-dried formulation can be sensitive to highly humid
environments and can shrink and lose its rapid disintegration characteristics.
This helps inform the choice of packaging and formulation characteristics,
allowing the products to be marketed in all geographic regions, including those
where high humidity is common.
As an ODT is designed to reside in the
mouth for only a number of seconds; it cannot avoid the taste buds. If the
taste of the active ingredient, or the sensation it generates on the tongue, is
not too unpleasant, the simple strategy of including flavor ingredients and
sweeteners in the formulation can be sufficient to make it acceptable to
patients. For many other APIs, this is not the case. Many taste unpleasant, or
can produce burning, numbing, or tingling sensations. If a patient-friendly ODT
is to be created, then more creative formulation methods will have to be
One way this can be achieved is via the
Zydis Ultra formulation. The taste-masking is provided by the presence of a
coating around particles of the API, which can be as small as 100 μm in size.
This is less than half the size of the smallest particles that can be coated
using more traditional coating processes. Smaller particles make for a better mouthfeel
in an ODT; larger particles give a gritty sensation as the tablets
In place of a fluidized bed coating method,
in the Zydis Ultra process, API particles are mixed with micronized polymer agglomerates
in a vessel that has an acoustic vibrator. When the vibrator is activated, the
contents begin to accelerate rapidly, and the polymer is deposited around the
API. The vibration and collisions within the mixer result in a continuous polymer
layer being formed. It is this layer that confers the desired taste-masking
properties. No solvent is needed for this coating process.
In contrast to a traditional coating,
the coated API inside is released slowly, a phenomenon that indicates that taste-masking
has been achieved, while still meeting the US Pharmacopeial convention (USP)
criteria for immediate release. The API still has 70%-85% potency w/w compared
to uncoated particles. The difference between the release profiles of the two
can be seen in Figure 2.
A common alternative technique for taste-masking
is the incorporation of cyclodextrin excipients. Cyclodextrins are sugar-based,
ring-shaped macromolecules with holes in the middle that can trap smaller molecules
inside if they are the right size. If the cyclodextrin has the appropriate size
of hole, the API will become trapped, which prevents it from touching the taste
receptors on the tongue.
As an example, a beta-cyclodextrin ODT
formulation was created of the very bitter tasting antihistamine, cetirizine. More
than three-quarters of a test group claimed its taste profile was acceptable and
that the reformulated product incorporating Zydis technology was more pleasant tasting
than the standard formulation.
Recent developments have made it possible
to formulate a number of different types of medicine as ODTs that at first sight,
one might think would not be compatible with this type of oral dosage form. For
example, ODTs can be made from very lipophilic APIs, by way of using an oily
emulsion in place of the aqueous solution or suspension that is normally the
starting point for an ODT formulation.
Although no products made in this way
are yet marketed, tablets have been formulated using a mass fraction of 15% olive
oil-in-water emulsion. This has allowed ODTs containing 15 mg of the oil to be
created, and an oil-soluble API could be dissolved in this before the tablet is
formed. This has been proven with ibuprofen, which, if formulated as an ODT,
could offer significant advantage to consumers in speed of onset.
Another innovative possibility is the prospect
of formulating a two-layer ODT that would allow two different ingredients to be
incorporated within each dose. This could be particularly beneficial if those
ingredients were otherwise incompatible, whether it were two different APIs or
an API and an excipient, for example, vitamins B and C; and the artificial
sweetener, aspartame, which is unstable above pH 6.5 and so is incompatible
with many basic excipients and APIs, such as calcium carbonate.
The prospect of formulating biologics as
ODTs offers even more promise for the dose form. Biologics usually have to be dosed
via injection or infusion, because the complex structures can rarely withstand the
highly acidic enzyme-containing environment in the gastrointestinal tract. If
they can be delivered through the mucous membranes in the mouth, they could
enter the bloodstream undamaged as the acidity of saliva is normally close to
neutral, and none of the protease enzymes that digest proteins are present.
There are regional variations in the thickness
of the epithelium that can be exploited; the sublingual epithelium is typically
100-200 μm, while the buccal membrane is thicker, at 500-800 μm. Absorption
enhancers and bioadhesives can be included in the ODT formulation to promote absorption.
Catalent’s Zydis Bio technology was developed as a way of achieving oral
delivery of biologics.
There are various other advantages, such
as room-temperature stability, whereby cold chain distribution will not be required.
This is particularly important for biologic products, such as vaccines, that are
destined for developing countries, where access to refrigeration cannot be
relied upon, and in pandemic situations, where speed of distribution is key to
The peptide drug calcitonin has been successfully
formulated in this way, and vaccine ODTs could be particularly important in the
future. By avoiding the need for injection, there would be none of the pain, and
potential for injection site reactions, that can engender reluctance to
immunization among patients and parents. The mucosal response that can occur is
a further benefit in immunizations against infections, such as human
papillomavirus, influenza, and pneumonia.
Preclinical studies in mice have shown
the potential of an ODT influenza vaccine. The loss of bodyweight is indicative
of disease severity, and those mice infected with influenza but who were
unvaccinated lost significant amounts of weight. In contrast, those who were
given the oral vaccine showed no significant loss in bodyweight, even after
they were challenged with the influenza virus.
Regardless of the type of API that is being
delivered, the fact that ODTs offer a route to pre-gastric absorption instead
of parenteral delivery can offer some significant benefits to patients. Not
only does it offer the potential for a faster onset of action, but by removing
that first-pass metabolism of the liver, side-effect profiles can be greatly
The ability to deliver pre-gastrically
depends very much on the molecular weight, lipophilicity, and required dose level
of the API. Some APIs, even if these properties are favorable, are still not
suitable for pre-gastric absorption. But where it is feasible, if the ODT is
designed correctly, then it is possible to ensure that the active will be
absorbed buccally or sublingually, without being swallowed.
As an example, the monoamine oxidase B
drug selegeline, used in Parkinson’s disease and depression, may cause patients
to suffer side-effects. These result from some of the active metabolites
generated by liver enzymes, including methamphetamine. Therefore, if the drug
enters the bloodstream directly, these metabolites are not formed and the
side-effects they cause cannot occur.
The graph shown in Figure 3 shows the
comparison of metabolites formed in a standard 10-mg selegeline tablet, and a 1.25-mg
ODT formulation of the same active. Figure 4 shows that the lower-dose ODT produces
the same area under curve (AUC) as a conventionally formulated selegeline tablet.
And, importantly, the two are bioequivalent. As can be seen in the graph in
Figure 5, the AUC for the ODT, taken both with and without water, is
essentially the same as a standard 10-mg formulation.
ODTs have become a standard dosage form
for a number of medicines, where the fast onset of action or ease of dosing are
important. They offer significant advantages to both patients and consumers of
OTC medications, and although their advantage over conventional tablets is
perhaps more obvious when thinking of the young and old, there are many people outside
of these groups who have difficulty swallowing tablets and capsules and would welcome
an ODT alternative dose form. Recent developments in ODT technology have
widened the range of actives that can be formulated and product types that are
possible. In particular, the promise of formulating biologics and ODT vaccines that
do not require a healthcare worker to administer them, as with many that are
injected, or that do not require cold storage and transit, often to the less
accessible parts of the world where so many vaccines are required, is hugely
1. In a study commissioned by Hermes Pharma
and conducted by Spiegel Institut Mannheim based on 2,000 individuals in
Germany and North America (www.epmmagazine.com accessed Sep.23, 2016).
To view this issue
and all back issues online, please visit www.drug-dev.com.
Leon Grother is Principal
Scientist at Catalent Pharma Solutions in Swindon, UK. He earned his BSc in
Pharmaceutical Science from the University of Greenwich, London and his Masters
in Industrial Pharmaceutical Science from the University of Manchester, UK. He
has worked within R&D for more than 15 years, primarily on Catalent’s Zydis®
ODT technology formulation and process development. During this time, he has
gained expertise in freeze-drying and is a named inventor on several patents
related to formulation of lyophilized dosage forms.
Mathias Bayru is Catalent Pharma
Solutions’ Group Product Manager for Drug Delivery Solutions. He is responsible
for driving the global marketing strategy for the oral drug delivery solutions
business unit, including patient-centric Solutions, Zydis® ODT
technology, FlexDose solutions for stick pack, and Opti-Dose CR for optimal and
modified controlled release. Mr. Bayru has more than 12 years of experience in
the pharmaceutical industry, and prior to joining Catalent’s marketing team,
held roles as Marketing Manager for several CDMOs and Senior Scientist for Big
Pharma companies. His market knowledge and expertise spans the launch and
development of solid and sterile dosage forms, OTCs, and medical devices. Mr.
Bayru earned his Master’s degree in Pharmacology and his MBA from Montpellier