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JÃ©rÃ´me Revel is senior development engineer at Recipharm.
Philippe Gorria is senior director of Pharmaceutical Development at Recipharm.
Modified-release oral dosage forms can offer benefits to both formulation scientists and patients.
Modified-release (MR) drug delivery systems are developed to control the rate and/or the site of release of drugs to achieve specific clinical objectives that cannot be attained with conventional dosage forms. There are clear advantages of using MR oral dosage forms, such as improved efficacy, reduced adverse events, increased convenience, patient compliance, and performance.
The use of MR pellet technology offers even more advantages to manufacturers. For example, it is easy to modify the drug dosage by using different filling mass when filling capsules with pellets. It is also possible to combine two or more drug products in a single carrier (i.e., capsules) to obtain a fixed-dose combination (FDC).
In this article, Jérôme Revel, senior development engineer, and Philippe Gorria, Pharmaceutical Development senior director at Recipharm, discuss why more drug developers and manufacturers are exploring the use of MR oral dosage forms and the benefits it can offer both formulation scientists and patients. They also outline the challenges companies need to overcome in order to successfully produce these products.
There are a number of trends contributing to increased interest in MR. Commercially, the interest in developing new products with improved properties based on existing molecules is increasing. The revenues from such products are usually lower than those of new chemical entities (NCEs), but lower development costs and reduced risks make these projects attractive.
Over the past 15 years, a number of medicines, including several blockbuster products, have arrived at the end of their patent protection and have been opened to the generics market. To extend patent protection, reformulation with extended release properties is a lifecycle management opportunity. Similarly, the MR development of an immediate-release (IR) formulation that is already on the market allows an intellectual property owner to take advantage of an extended market authorization.
From a therapeutic perspective, MR products offer several potential benefits. The typical advantages that can be achieved could be described as extended release and delayed release. Benefits of these type of formulations include:
MR dosage forms can be divided into monolithic and multiple unit formulations. Monolithic forms are often simple to manufacture, as they can usually be produced with conventional tableting processes. Multiple unit preparations, such as pellets, require a more complex manufacturing process, but offer less variable progression in the gastrointestinal (GI) tract and make it easier to combine components with different drugs or varying release profiles.
Because of their spheroidal shape, uniform size, and smooth surface, pellets are of particular interest for the manufacturing of MR drug delivery systems and offer a number of benefits to patients as well.
With pellets in a capsule, it is easy to modify the dose without any formulation modification, as the mass of pellets can be adjusted to obtain the right dosage based on the API assay of the pellets. Pellet materials are also incredibly diverse and are ready to be filled into capsules or sachets, compressed into tablets, or dispersed into liquid suspension-making them suitable for patients that cannot swallow whole tablets or capsules.
For patients, pellet formulations may be provided with pH-sensitive or time-controlled polymer coatings when intended for enteric delivery, (e.g., delivery to the intestine without release in the gastric bladder). This makes the progression of pellets in the GI track less sensitive to variation than with monolithic forms after meals. The risk of dose dumping due to a bad coating is also less prominent than with monolithic forms.
FDCs have advantages when there is a patient population for whom treatment with a particular combination of APIs in a fixed ratio of doses has been shown to be safe, effective, and contribute to the overall therapeutic effect.
The development of FDCs is being driven by a number of public health concerns as they continue to be increasingly used in the management of HIV/AIDS, malaria, and tuberculosis, which are considered to be some of the foremost infectious disease threats in the world today. They also help to improve patient compliance and convenience of administration because they decrease the number of doses required each day.
For manufacturers, it’s simple to combine several types of pellets and demonstrate the stability in a final dosage form for registration after developing the MR formulation and obtaining regulatory approval of each API pellet separately. These combinations create advantages, including lower costs of manufacture compared to the costs of producing separate products to be administered concurrently. It can also reduce the amount packaging and simplifies the logistics of distribution.
The process for manufacturing MR pellets consists of two or more steps depending on the extended-release properties required. The first one is the layering process, which consists of coating the drug substance onto neutral spheres (from 90µm to 1.5mm) to obtain immediate-release (IR) pellets. This step is followed by coating with a functional polymer to obtain MR pellets. Depending on the compatibility between drugs and excipients, a seal-coat can be performed between IR and MR pellets.
The quantity of film coating may be expressed as a percentage coating level. The aim is to find a good ratio between polymer and possible water-soluble pore-forming agent, which is added to modify the permeability characteristic of the coating. The percentage coating level then has to be chosen to reach the target product profile, which will depend on pellet size. A batch of smaller pellets contains a greater total pellet surface area and will require a greater percentage coating level to achieve a controlled-release film of a suitable thickness.
When using aqueous polymer dispersions, it is necessary to ensure the good coalescence of the coating to eliminate membrane porosity. This can be achieved by a curing step at the end of coating either in a fluidized bed or an oven at a temperature above the minimum film-forming temperature.
Wurster Fluid Bed Coating (FBC) technology is widely used in the manufacture of MR pellets due to its ability to apply high-quality films. FBC technology is characterized by the location of a spray nozzle at the bottom of a fluidized bed of solid particles. The particles are moved through a central column, with a fluidizing air stream that is designed to induce a cyclic particle flow upward past the spray nozzle. The nozzle sprays coating solution or suspension concurrently with particle flow. Passing particles move upward into an expansion chamber as droplets deposit on their surfaces. The expansion chamber reduces air velocity to allow particles to circulate back to the coating chamber. It also allows particles to further separate from one another temporarily and minimize the potential for particle agglomeration.
Film-coating processes require evaporative removal of an organic solvent or aqueous vehicle as the film coat is deposited. When organic solvents have to be removed, nitrogen is used and is also recycled within the system. The evaporated solvents are recovered in condensers. When water has to be removed, atmospheric air is used in a once-through system.
Development of a MR dosage form starts with the definition of the target product profile based on clinical needs. In addition to the pharmacokinetic (PK) profile, it is important to define the strength and capsule size to evaluate the right drug-assay target for MR pellets.
Then it is necessary to conduct pre-formulation investigations, for example, to assess the compatibility between the active substance and the chosen excipients (binder, lubricant, stabilizer, plasticizer, rate-modifying component, etc.). This can be performed by mixing API and excipients and following the potential degradation during six weeks at 40 °C/75% relative humidity (RH) in open and closed flasks.
Next, the MR dosage form development needs to be performed by selecting the right excipients and process parameters to achieve robust products. Even if the development is performed at laboratory scale, it is important to keep in mind the future scale-up, robustness, and manufacturability of the product.
In the laboratory, formulation development is performed with a batch size around 1 kg. Successful scale-up in Wurster processing depends on a number of factors, such as batch size, spray rate, atomization pressure, fluidization flow rate, and product temperature.
A quality-by-design (QbD) approach can be used to develop the coated pellets manufacturing process and ensure the quality of the product. The QbD concept is a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control as defined by the International Council for Harmonization (ICH) Q8(R2) Pharmaceutical Development, effective August 2009 for Europe (1). The process for manufacturing MR pellets is influenced by a complicated matrix of input and output parameters, including critical process parameters (CPPs) and critical quality attributes (CQAs).
Other sources of variability involve changes in equipment, raw materials, and operators-and it is not easy to understand the effect these have on the quality of the product. Managing and controlling CPPs is crucial to product quality and providing flexibility in future processes. After the formulation development is done at laboratory scale, the manufacturing at pre-pilot scale is performed.
A parametric study based on design of experiment (DoE) is then performed. The statistical design of experiments can be applied in the coating process design to help understand the effects of multi-dimensional combinations and interactions of different parameters, including both FBC and solutions/suspensions preparations, on the product quality. This work helps to define the CPPs-that is to say, parameters which have an impact on CQA such as dissolution profiles for MR pellets. The application of the DoE strategy leads to the establishment of a “design space” and manufacturing control strategy. This approach can then be applied from lab-scale activities to industrial scale. Finally, industrial scale-up is undertaken followed by a robustness study, which aims to provide confidence in the fluid bed process and support claims for parameter limits in commercial coating processes. This is the ability of the process to tolerate variability without negatively impacting product quality.
Over the past decade, progress has been made in the development of high-performance polymers and aqueous-based polymeric dispersions, which are suitable for the manufacture of MR dosage forms. However, developing MR formulations with alcohol-resistant properties remains a challenge. Sometimes when a MR product is consumed with alcohol, the MR mechanism could be adversely affected, which could lead to dose dumping (alcohol dose dumping or ADD). In the case of some compounds such as opioids, the dose dumping could result in serious adverse events. Both the United States and European Union have guidelines in place that require manufacturers to assess ADD when developing MR formulations, for example, the guideline on the PK and clinical evaluation of MR dosage forms (2,3).
MR formulation development requires highly specialized equipment and regulatory knowledge. Many pharmaceutical companies simply neither have a sufficient number of MR projects nor the in-house expertise to justify an investment in these capabilities.
1. ICH, Q8(R2) Pharmaceutical Development, Step 4 (2009).
2. FDA, Guidance for Industry SUPAC-MR: Modified Release Solid Oral Dosage Forms(Rockville, MD, September 1997).
3. EMA, Guideline on Quality of Oral Modified Release Products, (London, March 20, 2014).
Supplement: Solid Dosage Drug Development and Manufacturing
When referring to this article, please cite it as P. Gorria, J. Revel, “Modified-Release Formulations: Improving Efficacy and Patient Compliance," Solid Dosage Drug Development and Manufacturing Supplement (April 2019).
Philippe Gorria is senior director of Pharmaceutical Development, and Jérôme Revel is senior development engineer, both at Recipharm.