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GlaxoSmithKline recently developed a novel technology for the formulation of modified-release tablets. The authors describe the route from development to commercialization.
There are a number of approaches to developing a modified-release (MR) formulation, which include traditional polymer matrices, such as a hypromellose matrix (1), and more complex multilayered matrices with or without additional functional excipients (2). There are benefits and restrictions to every approach, which include technology requirements, and applicability to drug type/concentration range. A new MR approach has recently been developed and commercialized by GlaxoSmithKline (GSK) under the trade name of DiffCORE. This article describes the MR approach, its in vivo, in vitro, and industrial commercial performance, and potential benefits of the approach.
What is the background to the MR approach and its technological development?
The approach involves using mechanical drilling of functional film-coated tablets (see Figure 1) to form apertures of known size and position in the film coat. The release rate of the drug can be modified and controlled through altering the exposed surface area and the composition of the tablet core. The manufacture of the tablets utilizes standard manufacturing unit operations (i.e., blending, granulation, and compression). The core formulation and the manufacturing process impact the performance of the final product as it would on any traditional solid dose.
Figure 1: Film-coated tablets with apertures of known size, 2 mm (blue), 3 mm (brown), and 4mm (green).
GSK purchased an original patent in 1993, which used a film coating based upon ethylcellulose. While this film coating was a semipermeable coating, when used in the DiffCORE process, it behaves essentially as an impermeable barrier. The coating retards the release of the API from the majority of the core surface area. The apertures in the coating maintain the release rate of the API from the core throughout the entire gastrointestinal tract. This approach was found to be suitable for compounds which had high solubility, primarily weak acids. Weak bases, which at that time formed a large part of the MR portfolio, were found to exhibit reduced release on leaving the gastric environment due to the pH-driven reduction in solubility and thereby availability.
Using targeted experiments, a new film coating system was developed, which enabled the technology for use with weak bases (3). The increase in potential products that could benefit from the new film-coating system prompted further investment of time and resources to fully explore the capabilities of this technology.
The new coating system developed was an enteric film coat based upon previous research into different detackifiers. For weak bases, this coating initially retards the release of the active material to the drilled apertures while within the high-solubility gastric environment. Upon reaching the higher pH of the intestines, the coating dissociates and becomes soluble. The dissolution of the coat increases the exposed surface area of the core, which increases the availability of the exposed drug substance, thereby compensating for the decreased solubility. By making use of established polymer matrix techniques, the core is formulated to ensure a controlled release rate is maintained.
Further refinements have been made for specific compounds, dependant on the product's pharmacodynamics. The use of a bilayer core enables the combination of an immediate-release (IR) layer and a MR layer. The IR layer reduces the time to reach the minimum therapeutic dose for the patient while the MR layer provides a maintenance dose. This bilayer approach can obviously be extended to combination products though this has not been trialled at this time (4). GSK has several products utilizing this technology under development at various clinical stages, with Lamictal XR (lamotrigine) being the first product commercially available on the market.
How did the technology become commercialized?
There were several aspects that required alignment for this technology to mature. The most fundamental was the initial drive or need to use a technology. Without this, there was little interest in investing potentially large sums of money with the risk of no return. The second was having compounds to work on, otherwise the resources associated with the technology are not just non-value adding but costly in a budget constrained environment. Using development compounds, by necessity, to drive a technology development ties the two processes intimately together in terms of risk—both the chance of the process not being technically deliverable for specific milestones, and the potential for a compound not progressing reducing the commitment on the technology side. The final aspect was that there was a clear strategic intent on developing commercial platforms that delivered rapid development on a wide range of active compounds.
This technology was well-placed with regards to commercialization as there was a genuine need, strong sponsorship, and was simple to apply in development. The ability to manually drill apertures on low numbers of tablets or caplets allowed for very quick in vitro proof of concept (PoC), typically under a week including analysis, enabling rapid development programs.
Once PoC had been proven, the technology program accelerated in line with the compound. Having a manual low-volume manufacturing method does not enable a technology to be used to manufacture clinical supplies for Phase IIb or Phase III, let alone commercial production. Therefore, post PoC development, a prototype automated machine had to be proven and validated at the same pace as the compound needs.
The final and perhaps the most costly step in establishing a commercial technology was to develop the prototype into a true manufacturing process (equipment, facility, and ways of working) with the full support of the commercial organization. The ability to complete the development process on a commercial scale at a manufacturing site requires great organization and cooperation between the development and manufacturing teams as both are working against aggressive timelines. The requirements for establishing a new technology from a business and industry perspective were broad, and encompassed well-documented validation and regulatory requirements. As this was a novel technology, education of external parties, such as FDA, was required to increase understanding of the technology to enable appropriate assessment of the control measures. This whole process enabled GSK to cover the entire gamut of scales in manufacturing with the benefit of having a scale-independent technology from development to commercialization.
Isn't this just a modified osmotic pump?
At first glance, this MR approach has some similarity to osmotic pump tablets (5) in that they both have apertures in their coatings, but the aperture sizes are significantly larger in this approach with an aperture on each face of the tablet (6). The larger apertures ensure that no hydrostatic pressures build up, and that release is controlled by the exposed surface area, which is typical of polymer systems, and not osmotic pumps (7).
There are two main control mechanisms:
What API types and doses can the approach be used for?
Due to the nature of this technology, there has been a perceived level of risk associated with "being the first" so the initial uptake has been with compounds that have had a number of challenges or difficulties in developing a more traditional MR dose form. However, in summary, a range of compounds across the Biopharmaceutics Classification System (BCS) have been tested and shown great success. More recently, the launch of a commercial product has helped to reduce this perceived risk and embed the technology within GSK.
Three late-phase compounds have shown the breadth of the technology. Two products utilized doses as low as 2 mg, and have proven to be consistent and reproducible in their delivery while a high-dose product, at 1000 mg, has been kept to a single daily tablet to aid patient compliance without having to use unnecessary levels of polymers.
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.
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.
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.
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.
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.
Figure 3: Varying aperture sizes allows for consistent product performance for a range of different doses on a combination product.
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).
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.
Table I: Number of formulations evaluated in clinical studies with and without DiffCORE (GlaxoSmithKline).
What controls do you need over the apertures?
GSK identified four potential quality attributes throughout the development lifecycle to ensure consistent and robust performance of the product: presence, size, position, and depth of the apertures.
The effect these have on the performance of the product are dependent on the API and core formulation. Those products with greater robustness are evidenced by a wide tolerance of the aperture size (± 1 mm) with little impact of aperture position and depth, which provides a broad manufacturing control strategy using generic process controls. Those products that require more rigorous process controls around the aperture formation will require a unique process recipe, for instance, a high sensitivity to aperture depth, ± 10 µm, would require specific drill movement parameters to ensure precise aperture formation. Typical process controls maintain the aperture size within ± 0.2 mm, the position to within 0.3 mm and the depth to within 50 µm of target.
The online inspection systems, visual imaging, and laser displacement, measure every aperture formed in terms of size, position, and depth. The recipe-controlled specifications are used to categorize the product as acceptable or nonacceptable. Products that do not meet the specification are automatically removed from the process flow with a confirmation of removal. During routine production, the current process efficiencies are being measured at greater than 99.9%.
Does the drilling process affect uniformity or stability?
For the products developed to date, GSK typically observed no change in release profile on stability for the drilled products. Figure 4 shows stability dissolution performance of one product over 56 months with no discernible difference indicating very good stability and reproducibility. Since the drilling process only exposes a small surface area of the product while the remainder is coated with a reduced permeability enteric film coating, the shelf life does not appear to be, nor is expected to be, any different to a cosmetically film coated product.
Figure 4: Dissolution performance of the initial product and after 56 months storage at 30 Â°C/65 % relative humidity (RH).
Dedusting and metal checking are used as part of manufacturing, similarly to compression, reducing potential operator exposure and contamination downstream. The potential for product damage on downstream processing, such as packaging, was investigated showing that, using typical equipment, the process was optimized to eliminate potential defects.
How do you scale up the process for commercial production?
Post PoC, a development machine has been purpose built to manufacture these products (see Figure 5). This machine will manufacture up to 10,000 units per hour with online inspection of the product quality attributes impacting performance.
Figure 5: Development equipment with on-line inspection systems.
For commercial production, GSK uses machines that are currently installed in its global manufacturing facility in North Carolina (see Figure 6). These machines have the same functionality and process parameters as the small-scale equipment, thereby eliminating scale-up and increasing output (approximately 120,000 units per hour). The process is scale-independent, and the final development process is transferred directly to the commercial machines. The current manufacturing process exhibits consistent content uniformity with good variability (mean = 99%, standard deviation = 0.82, based on 14 commercial batches).
Figure 6: Commercial manufacturing equipment with online inspection systems.
What are the advantages and limitations of this MR approach compared with other approaches?
Development of modified release products can be a costly activity, which may involve several clinical studies and formulation activities before a desired PK profile is obtained. There are several enabling features of this MR approach that minimizes these costs:
Technology development can be a risky process for a business and seems to be increasingly left to academia to prove the principles and prototype. The success of this technology within GSK shows that this need not always be the case. A small investment in targeted work can lead to advances that benefit the business as well as the patient, provided that relevant risk/benefits are monitored at all stages of the process.
Kevin D. Altria is senior scientific investigator, firstname.lastname@example.org, and James Taylor* is investigator, email@example.com, both with Pharmaceutical Development, GSK R&D, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK.
*To whom all correspondence should be addressed.
Submitted: Feb. 15, 2012. Accepted: Mar 15, 2012.
This article is dedicated to the memory of Dr. John Hempenstall who greatly supported the development and commercialization of this technology. John was a great friend and mentor to many GSK colleagues.
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