OSD
With the ability to control the rate and site of drug release to reach clinical objectives that cannot be achieved using conventional dosage forms, modified-release (MR) drug delivery offers many advantages. For example, MR oral dosage forms can improve efficacy and prevent adverse events as well as increase convenience and patient compliance.
MR pellet technology has even more benefits to manufacturers, as it allows them to modify the rate of release as well as reduce the number of doses required per day which is ultimately more efficient for the patient. This is done by using different filling masses when filling capsules with pellets. Two or more drug products can also be combined in a single carrier, such as capsules, in order to achieve a fixed-dose combinations (FDCs).
Modified Release demand
There are various factors driving the demand for MR systems. For example, manufacturers are increasingly interested in developing new products with improved properties based on existing molecules. Although these products offer lower revenues than new chemical entities (NCEs), such products also have lower development costs and fewer associated risks when compared to NCEs.
Within the last 15 years, there have been several medicines, including a number of blockbuster products, that have reached the end of their patent protection and have become accessible on the generics market. Reformulation with extended release properties presents manufacturers with a lifecycle management opportunity to prolong patent protection. Additionally, the MR development of an existing immediate-release (IR) formulation provides an extended market authorisation for the intellectual property (IP) owner.
MR products also offer several potential therapeutic benefits. The primary benefits that can be achieved are referred to as extended release and delayed release. The benefits of these formulations include:
- Sustained blood level
- Attenuation of adverse effects
- Improved convenience and patient compliance
- Protecting acid-sensitive drugs
Therapeutic advantages of MR pellet technology
MR dosage forms can be separated into two forms: monolithic and multiple unit formulations. Monolithic forms generally entail a simple manufacturing process, as they can be produced using conventional tableting processes. Multiple unit preparations, such as pellets, require a more complex manufacturing process but do provide less variable progression in the gastrointestinal (GI) tract. As such, it’s easier to combine components with different drugs or release profiles through the use of pellets.
When pellets are in a capsule, the adjustment of the dose can be made without any formulation modification. This is because the mass of the pellets can be modified to contain the correct dosage. The diversity of pellet materials (for example, capsules, sachets or liquid suspension) help to make medicine suitable for multiple patient populations – particularly for those that struggle to swallow whole tablets or capsules.
In addition, by using pH-sensitive or time-controlled polymer coatings for pellet formulations, the enteric deliver can be controlled and make the progression of pellets in the GI track less sensitive to variation in comparison to monolithic forms following meal consumption. Pellets also present a lesser chance of dose dumping caused by a bad coating.
Benefits of FDCs
The application of FDCs is beneficial when a specific combination of APIs in a fixed ratio of doses is found to be safe, effective and facilitate the overall therapeutic effect for a patient population.
FDC development is currently motivated by various public health concerns, particularly as they are largely used in the management of HIV/ AIDS, malaria and tuberculosis, which are currently deemed as a few of the most threatening diseases in the world. On top of this, FDCs enhance patient compliance and convenience of administration as they minimise the number of doses to be taken each day.
Combining different types of pellets, demonstrating stability in a final dosage form and attaining regulatory approval for each individual API is a simple process for manufacturers. Additionally, these combinations can reduce costs of manufacture compared to the costs of producing individual products to be administered concurrently. It also helps to decrease the amount of packaging and minimises logistical complexity in terms of distribution.
Manufacturing MR pellets
There are two key steps involved in the manufacturing process for MR pellets, depending upon the extended-release properties required. The layering process is carried out first, whereby the drug substance is coated onto neutral spheres (from 90µm to 1.5mm) in order to acquire immediate-release (IR) pellets. After that, coating with a functional polymer is performed to obtain MR pellets, then a seal-coat may be added between IR and MR pellets depending on the compatibility between drugs and excipients.
Film coating can be expressed as a percentage coating level. When performing film coating, a suitable ratio between polymer and possible water-soluble pore-forming agent is sought to adjust the permeability characteristics of the coating. The pellet size is then considered when determining the percentage coating level to reach the target product profile (TPP). For example, a batch of smaller pellets means a larger total pellet surface area and will therefore require an increased percentage coating level to successfully attain a controlled-release film of an appropriate thickness.
In cases where aqueous polymer dispersions are used, it is important that there is a good coalescence of coating in order to mitigate membrane porosity. A curing step towards the end of coating, in a fluidised bed or an oven at a temperature above the minimum film-forming temperature, can achieve this.
On popular method is Wurster Fluid Bed Coating (FBC) technology. This is typically applied by companies during the manufacturer of MR pellets, as it has the ability to apply high-quality films. FBC technology is distinguished by the location of a spay nozzle, situated at the bottom of a fluidised bed of solid particles. The fluidising air stream enables a cyclic particle flow upward past the spray nozzle, thus transferring the particles through a central column. The nozzle sprays coating solution or suspension simultaneously with particle flow and passing particles move upward into an expansion chamber. The reduction in air velocity within the expansion chamber enables particles to move back to the coating chamber and detach from one another for a short period of time. This helps to prevent the potential for particle agglomeration.
Film-coating processes also require the evaporative removal of an organic solvent or aqueous vehicle for the depositing of the film coat. In cases where organic solvents are removed, nitrogen will be used and recycled within the system. As for evaporated solvents, they are recovered in condensers. Additionally, atmospheric air will be used in a once-through system when there is a removal of water.
Moving products to commercial scale using QbD and DoE
When developing a MR dosage form manufacturers will initially define the target product profiled based on clinical needs. As well as the pharmacokinetic (PK) profile, both the strength and capsule size must be defined in order to determine the most suitable drug-assay target for MR pellets.
After that, pre-formulation investigations take place to evaluate the compatibility between the active substance and the selected excipients. The assessment can be carried out by combining both the API and excipients and monitoring the degradation during a six-week period at 40 degrees Celsius / 75% relative humidity (RH) in open and closed flasks.
The subsequent step in the development process involves choosing the correct excipients and process parameters that will produce robust products. It is essential for companies to consider the future scale-up, robustness and manufacturability of the product throughout the entire process, even in cases where the development is performed at laboratory scale.
Formulation development is performed in the laboratory, with a batch size around 1kg. There are various factors impacting the success of a scale-up in Wurster processing, such as batch size, spray rate, atomisation pressure, fluidisation flow rate and product temperature so it is imperative to take all these factors into consideration at this stage.
A quality by design (QbD) approach can be employed to develop the coated pellet manufacturing process and maintain the quality of the product. The systematic approach to development is initiated with predefined objectives and highlights product and process understanding, as well as process control as defined by the International Council for Harmonisation (ICH) Q8 (R2) in Pharmaceutical Development. A complex matrix of input and output parameters, including critical process parameters (CPPs) and critical quality attributes (CQAs) also impact the process for manufacturing MR pellets.
Whether its a result of the equipment, raw material quality or operators, there is always difficulty in understanding the effects that variances will have on the quality of a product. In order to ensure product quality and provide flexibility in future processes, it is critical to manage and control CPPs effectively. QbD approaches offer close monitoring of these factors.
A parametric study based on DoE will then be carried out. The statistical design of experiments in the coating process gives a good understanding of the impact of multi-dimensional combinations and the interactions of different parameters on the product quality. In doing so, the CPPs are defined and the parameters that impact CQA can be identified. Applying a DoE strategy facilitates the establishment of a “design space” as well as a manufacturing control strategy. As such, this approach can be utilised from lab-scale to industrial scale activities. Lastly, industrial scale-up and a robustness study is performed to gain confidence in the fluid bed process and solidify parameter limits for the commercial coating processes. This allows the process to mitigate any negative impacts upon product quality.
MR development challenges
Despite the industry making progress in the development of high-performance polymers and aqueous-based polymeric dispersions for the manufacture of MR dosage forms, using alcohol-resistant properties to develop MR formulations remains a challenge. When consuming an MR product with alcohol, the MR mechanism can sometimes be adversely affected, which may result in alcohol dose dumping (ADD). This type of dose dumping has the potential to cause serious adverse events, particularly for compounds such as opioids. Under guidelines published by both the United States and European Union, manufacturers are required to assess ADD when developing MR formulations.
Despite their many benefits, there remains a limited number of experienced manufacturers across the pharmaceutical sector. MR formulation development requires highly specialised equipment and regulatory knowledge to fully facilitate these capabilities and many pharmaceutical firms don’t have the capacity of projects or internal resource to justify an investment in MR development.
At Recipharm, our team regularly supports customers in developing MR oral dosage formulations.