How is the release rate modified and controlled?
This novel technology uses the combination of apertures in functional film coatings with traditional polymer matrices. Unlike
typical polymer matrices, these formulations use a low-viscosity polymer to control the mechanism of core erosion and diffusion.
The low-viscosity polymers are more suitable because the hydration of the polymer is constrained by the film coating in the
gastric environment so there is little erosion occurring prior to the gelstructure formation.
Figure 2: In vitro dissolution data of a single input batch varying in aperture sizes. The drug product was exposed to pH
1.2 media during the first two hours, followed by pH 6.8 media for the remaining six hours.
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The ability to combine these matrices with a functional film coating also provides dual control mechanisms conferring several
advantages. Difficult or distinct release rates can be achieved, which show little food effect; the patient is doubly protected
by the control mechanisms, reducing the risk of dose dumping; a single batch of tablets can be used to develop a suite of
release rates simply by modifying the exposed core surface area, as shown in Figure 2.
During the first few hours when the functional coating is insoluble in the acidic environment, the exposed surface area is
the dominant control mechanism, and the release rate is controlled by the size of the apertures. As the exposed surface area
increases, the core formulation shows increasing influence on the release rate. Once the aperture size is large enough, the
core formulation and API characteristics become dominant in controlling the release. A high-dose, soluble drug is used in
this example to demonstrate this effect. After four hours, when the drug product is exposed to media at pH 6.8, the functional
coating becomes soluble, and the core characteristics drive the rate of release.
Throughout the development process, a range of doses will often need to be developed to identify the most appropriate dose
to treat varying degrees of patient condition or simply for dose titration. When designing combination products, large numbers
of dose combinations can make development programs somewhat complex.
Figure 3: Varying aperture sizes allows for consistent product performance for a range of different doses on a combination
product.
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The data in Figure 3 show a product covering four doses across two APIs. Using platform granulations and varying only the aperture sizes, doses
were designed to have overlaying profiles.
How is a formulation designed to obtain a clinical outcome using this approach?
The formulation is developed based upon defining the physiological, pharmacodynamic, and pharmacokinetic (PK) data as a clinical
requirement. Once the solubility profile and PK target is clear with key requirements (i.e., area under the curve [AUC] and
maximum concentration achieved [Cmax]) the appropriate release rate and in vitro profile for the finished product can be established. The ability to use a selection of proven product types, for example
bilayer DiffCORE, or multiple release profiles from a single batch allows rapid product manufacture for clinical testing against
the defined target profile(s).
Table I: Number of formulations evaluated in clinical studies with and without DiffCORE (GlaxoSmithKline).
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One of the benefits associated with DiffCORE has been the reduction in the number of clinical trials for formulation evaluation.
Each clinical trial is costly to resource in terms of equipment, materials, planning, and patient recruitment. A review of
six compounds that have used the DiffCORE technology showed that half required a single visit to the clinic to define the
formulation for final development (see Table I). It also showed that the technology enabled development of a suitable formulation for compounds that were historically difficult
to develop as MR products.
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