Can you tell us about some of the latest technologies for controlled release? What are their benefits?
Diffusion and erosion mechanisms are the essentials of controlled release technologies. Excipients play an important role in such technologies, and they aid in dissolution of drugs by slow diffusion through the polymeric matrix via dissolving of a hydrophilic polymer or solubilizer. At the same time, the erosion allows the slow dissolution of drugs via the polymeric solubility stemming either by deformation/melting, gelling or viscosity enhancement, or insolubility or sparingly solubility of excipients and APIs as well. Developing drugs with higher solubility with controlled release profiles is challenging. The advantages, however, are far greater due to lack of infrequent dosing and minimizing the risks for abuse and/or adverse effects. For example, tamper resistant formulations utilizing CR material reduce frequent dosing and help prevent abuse, especially, those critical in pain management. Intac® technology for opioids, for example, requires certain polymers (e.g. class of PEOs) and technology (e.g. HME) for blending of drug into the polymers to minimize the risks for abuse and meet the agency’s requirements. Other excipients such as long chain triglyceride lipids have also been used in abuse deterrent formulations to minimize extraction and hence, reduce the chances for abuse by complete blending of drugs into the lipid matrix.
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Are there dosage forms or treatments that are difficult to formulate into a controlled release form? What types of products make for the best controlled release candidates?
With the continued increase of insoluble molecules (70%-90%), attempts have been made to develop immediate release dosages with improved efficacy and bioavailability. How these poorly soluble molecules can be delivered effectively to target the upper and lower GI tract has been a subject of continued interest in the industry. With fewer polymers available to target the lower part of GI tract and colon, there is unmet demand for excipients compatible with higher pH changes along the GI tract. As a result, drug layering technology offers unique advantages over other technologies. By creating a coating barrier around the drug with excipients that have appropriate pH characteristics, a very selective and targeted delivery in the stomach and GI can be achieved. Desired release profiles can be attained by controlling the thickness or barrier around the APIs in pellets or granules. For instance, using enteric polymers such as Kollicoat MAE30 D or 100 P, can by-pass the gastric pH, but it will be dissolved at pH 5.5 or higher, as it moves through the pH of the duodenum and upper intestine. Likewise, by selecting the pH and coating level susceptible to higher pHs, such as neutral/pH Independent Kollicoat SR30D or alkaline reverse enteric Kollicoat Smartseal, will by-pass the pHs in the GI tract, and target the lower GI and colon by providing a desired coating thicknesses and controlling the dissolution.
Are advanced controlled release technologies breathing new life into some older products on the market? Is examining a product for new controlled release capabilities a way to extend a products shelf life?
OROS® technology has been the gold standard in the past for development of several controlled release marketed drugs. With the advent of excipients that tackle the challenges with drug soluble or highly insoluble APIs, companies like BASF are working on introducing excipients to overcome the challenges with dose dumping and other unmet formulation challenges. These challenges could stem from an API’s stability and compatibility associated with degradation and/or longer dissolution in bioequivalent media. For instance, excipients such as Kollicoat SR30D and Kollidon SR which are neutral and compatible with many drugs, acidic and alkaline alike, may help attain the desired release time in a dependent manner without yielding an adverse effect due to API toxicity, and help maintain a longer shelf life. CR excipients such as Kollicoat SR30 for functional coating and Kollidon SR for matrix tablets provide the flexibility to design a solid oral dosage formulation (SODF) that alleviates the need for frequent dosing and makes it possible to develop a once a day tablet, reducing the pill burden on patients. Selecting high functional excipients with certain desired attributes may help in extending the shelf life of drug products with CR properties.
What are some regulatory requirements manufacturers have to be aware of when formulating new controlled release products?
The safety requirements for novel excipients are just as stringent as those for new drug molecules, whether they be controlled release or immediate release products. Regulatory requirements of controlled release drug products depend on the safety of the excipients and the amount of use in a specific dosage. The guiding principles on usage level of these excipients is based on the no observed adverse effective level (NOAEL) which is an estimated daily intake in humans calculated from the NOAEL divided by a safety factor of 100. Excipient manufacturers like BASF go above and beyond to ensure the safety and toxicology of their ingredients. For example, regulatory requirements of Kollicoat Smartseal, a novel functional polymer for tastemasking of bitter APIs and controlled release applications, have been demonstrated by full toxicological studies in animal models, and the estimated daily intake calculated based on the NOAEL and safety factor of 100. For co-processed CR excipients like Kollidon SR and Kollicoat, derived from Polyvinyl acetate and Povidone K30, the regulatory requirements are less stringent as both the ingredients are compendial and listed in the inactive ingredient database (IID).
What do you see as the future for controlled release products? Will more become available? Will the expansion of products into under-served markets result in the demand for controlled release products?
The future of controlled release drugs is bright. This is due to availability of novel as well as co-processed excipients to support the new chemical entities (NCEs). With the continued patent cliff and increasing agency demands for patient compliance, the industry is open to accept safer, co-processed or new excipients to produce the CR dosages with desired release profiles and aims to reduce adverse effects. Life cycle management for controlled release drugs is yet another example that brings the excipient manufacturers and users closer to collaborate as more NCEs require the modified release dosages for long term use. BASF is working closely with the industry to address the dosage and safety needs of the patient by innovating novel and co-processed excipients and technologies for development of future drugs to treat the life-threatening ailments.