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With the right excipients, formulators can control when, where, and how an API is released.
Demand for controlled-release formulations is expanding as patients’ expectations for greater convenience are increasing. Extended-release products have reduced dosing frequencies, which are particularly beneficial for pediatric and geriatric patients, but are appreciated by most patients and in general lead to improved medication adherence (1). Reformulation of branded drugs in controlled-release formats is one of the most common methods for extending the product lifecycle. Generic drugs are also often formulated with controlled-release properties (2).
Controlled-release behavior can be achieved using polymer coatings on solid dosage forms or by the incorporation of various types of polymer matrix systems, enzyme-activated systems, or systems that respond to changes in physical conditions within the formulation. Mechanisms include dissolution, diffusion, osmotic pressure, maintaining a hydrologic or hydrodynamic balance, and ion exchange. Newer approaches are currently being developed based on nanotechnology and novel matrix technologies and include gastro-retentive drug delivery for controlled release, buoyant systems, and mucoadhesive systems for regulated release of antiviral medications (1,2).
Excipients are key ingredients in controlled-release formulations. They act as matrix formers in matrix delivery systems and as polymeric membranes for drug powders and multi-particulate systems in oral solid dosage (OSD) forms, according to Bujar Muça, technical product manager, IMCD. Plasticizers and pore formers impact drug release in coated products, and, often, two-polymer chemistries are used to provide tailored drug release. In oral liquid products, excipients can also provide taste masking and protection for the gastric mucosa, he adds. In specific cases, excipients can provide abuse deterrence and aid in the avoidance of alcohol-induced dose dumping, according to Evonne Brennan, technical marketing manager at IMCD.
“Ultimately,” says Shawn Branning, strategic marketing leader for controlled release at DuPont Nutrition & Health, “excipients that provide controlled-release characteristics to oral solid dosage forms allow not only control of the rate of the API release, but also targeting of where that release occurs.” He adds that when considering OSD forms, controlled-release formulations can refer to various types of sustained-release or targeted-(delayed) release profiles.
Several factors must be considered when selecting specific excipients for controlled-release formulations, according to Chhanda Kapadia, technical manager, IMCD. Dosage form type and design need to be considered along with the solubility of the API to ensure that the desired dissolution profile can be achieved with a given excipient, and/or that a good in vitro-in vivo correlation is obtainable. Issues that relate to patient compliance and safety should also be considered, according to True Rogers, technologies leader at Dow Pharma Solutions.
Ethylcellulose remains the polymer of choice in multi-particulate drug delivery systems with or without an additional coating platform, the use of which is dependent on the characteristics and dosage form type of the drug, according to Brennan. Methacrylate polymers are broadly used in delayed-release dosage forms and also provide gastro-resistant functionality. In monolithic delivery systems, hydroxypropyl methylcellulose (HPMC) continues to be the excipient of choice, although the use of two-polymer matrix systems is growing. “This approach can provide unique synergies and enable fine-tuning of the drug release pattern via modification of polymer entanglement and matrix texture,” Muça explains.
The key for pharmaceutical formula tors, concludes Rogers, is to have proven and flexible polymers such as cellulosics along with knowledgeable partners that can help provide solutions to formulation challenges.
Formulators can, in fact, face many challenges-from achieving desirable dissolution and release profiles for poorly soluble drugs to risk management of dose dumping to the selection of biocompatible materials with the desired controlled-release properties (1). Controlled-release products also require high API dosages, which can in some cases be difficult to formulate into the desired dosage forms with acceptable properties (2).
Newer APIs present some unique formulating difficulties, according to Rogers, such as small therapeutic windows or sensitivity to certain pH environments. On the other hand, formulating controlled-release alternatives to already-marketed products can be challenging if it is necessary to select different polymer chemistries and excipients to avoid patent infringement issues, according to Lies d’Olieslager, technical product manager, IMCD. Consistently matching the drug release profile, the scale-up of controlled-release coating processes (which requires extensive process knowledge), the curing of aqueous coating systems-particularly under dynamic conditions-and resistance to ethanol-induced dose dumping are additional challenges, she adds.
“Controlled-release excipients are excellent solutions to these particular challenges,” Rogers asserts. For instance, he notes that some excipients can now offer dual functionality, both controlling the release of the API and providing increased solubility to poorly soluble APIs. Understanding polymer chemistry and exploring synergies are also important to overcoming these difficulties, according to Brennan. “Formulator experience is crucial; with movement of personnel, the loss of expertise can impact development times in an already costly process,” she says.
Given that excipients are key ingredients in controlled-release formulations, it may seem surprising that excipient choices are somewhat limited, particularly for certain patient populations, notably children. Suppliers are developing “novel” excipients that may provide solutions and support to move existing formulations into new areas, according to Mary Tanenbaum, technical manager, IMCD, but excipients do not have their own approval pathway. “Pharmaceutical companies are hesitant to take on the responsibility of toxicology and clinical trials with an untested material and run the risk of jeopardizing approval of their new drug applications,” Tanenbaum observes.
Most new excipients, therefore, are modifications or combinations of previously approved excipients. For instance, Muça points to granular Carbopol developed by Lubrizol to address flowability issues in direct-compression processing of matrix delivery systems. The Dow Chemical Company has also developed and commercialized Methocel DC2, a more flowable morphology of HPMC for streamlined direct-compression manufacture of modified-release matrix tablets, according to Rogers. In addition, custom grades of Benecel HPMC from Ashland fill a gap in HPMC polymer choice for matrix systems, providing formulators with more predictable release profiles and reducing batch-to-batch variability previously observed due to HPMC blending, according to Brennan.
Meanwhile, FMC Health & Nutrition, now part of DuPont Nutrition & Health, has promoted the use of surfactants for in-situ curing while coating with Aquacoat ECD, a 30% by weight aqueous dispersion of ethylcellulose polymer. “This pseudolatex dispersion has advantages over solvent systems because it has a high-solids content with low viscosity, and thus a shorter processing time,” notes Engin Sari, technical product manager, IMCD. DuPont has also developed a coating with a robust sustained-release profile in the presence of alcohol that helps formulators create products with resistance to alcohol-induced dose dumping, he adds. Aquacoat ARC is a blend of Aquacoat ECD and guar gum in an aqueous system for multi-particulate drug delivery systems.
IMCD represents a wide portfolio of products and continually pursues a training program covering excipient functionality to ensure ongoing knowledge transfer, according to Brennan. “Engaging with formulators to review any challenges they face is key to successful development of solutions. Continued education is also fundamental; excipient manufacturers regularly provide information on product functionality, product consistency, and product variability, and we need to stay up-to-date,” she comments.
As an industry group, the Controlled Release Society provides a forum for networking and the development of connections within other formulation groups. It does not provide an avenue for the discussion of intimate formulation details, however, which remains challenging, according to Brennan. “Using confidentiality agreements is one approach, but these take time. Good relationships with development teams, therefore, continue to be of primary importance,” she says.
Excipient manufacturers need to work side-by-side with drug product manufacturers as early as possible in the drug product development process in order to not only identify the issues, but to mitigate the impact of the issues proactively, agrees Rogers. He adds that excipient manufacturers must understand every detail of their processes and polymers in order to achieve the best solutions for their customers.
“Dow Pharma Solutions works closely with our customers to understand their specific needs, and, over time, we have developed new solutions to meet controlled release formulation challenges as they have arisen,” Branning remarks. “Partnering with our customers not only helps us in suggesting the right solutions for their formulations, but also helps drive our development of new excipients to meet the ever-changing needs of the market. We have found this type of partnership to be the best strategy for addressing the challenges faced by the pharmaceutical market today,” he concludes.
The Dow Chemical Company has also been busy combining different businesses to expand its excipient offerings to the broader market. The excipient portfolios of The Dow Chemical Company, DuPont, and FMC’s Health & Nutrition division will be combined when the three businesses are merged to form DuPont Nutrition and Health. “The new company will have the expert teams from all three businesses working together and with customers and channel partners to understand their needs and unresolved challenges as well as provide unique combination solutions,” Branning says.
1. Future Market Insights, “Controlled-Release Drug Delivery Technology Market: Global Industry Analysis and Opportunity Assessment 2017–2027,” Report Description (to be published July 2018).
2. Future Market Insights, “Oral Controlled Release Drug Delivery Technology Market: Diffusion Controlled Release System Anticipated to be the Most Attractive Segment During the Forecast Period: Global Industry Analysis 2012–2016 and Opportunity Assessment 2017–2027,” Press Release, July 20, 2017.
Vol. 42, No. 7
When referring to this article, please cite it as C.Challener, “Selecting Excipients for Controlled Release" Pharmaceutical Technology 42 (7) 2018.