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is highly warranted when selecting the polymers for achieving the desired therapeutic index, avoiding toxicity and maintaining zero order plasma concentration of drug.

Kyburz: Controlled release (CR) drug products can be difficult to formulate due to drug substance challenges, including very low solubility, lack of colonic absorption, high dose, gastric fluid degradation and/or rapid clearance rates. Additionally, treatments for elderly and pediatric patients, where swallowing is difficult, can be challenging, as drug loading, inability to crush, excipient amount and dosage size are constraining. Use of enabled technologies, such as amorphous or nano-sized particles, can help, as can flexible multiphase CR options afforded by MPs and multi- layer tablets. Products requiring high drug loading and low solubility are particularly difficult to formulate without being large. Geriatric and pediatric populations have difficulty swallowing large, monolithic CR dosage forms, whereas MPs (particles, pellets, beads, granules/mini-tablets) are more flexible, since the final dosage forms can vary from capsules and tablets to orally dissolving tablets, sachets and sprinkle capsules. Drug- drug incompatibility can be a concern for some fixed-dose CR or IR/CR combination products – multi-layer tablets, or more independent, isolated MP products are approaches to maintain stability while providing drug release flexibility.

One important treatment that has become urgently critical due to the epidemic levels of death and abuse is controlled release, abuse deterrent delivery of prescription opioids. These are challenging due to U.S. Drug Enforcement Administration handling requirements and the drug delivery technologies required to prevent accidental overdose or intentional abuse, such as extraction, crushing and snorting for immediate release delivery.

Khot: Liquid dosage forms are gaining popularity with geriatric and pediatric applications, but have traditionally been difficult to formulate into CR dosage forms. Ion exchange resins have successfully been used to impart CR performance into oral liquids and syrups.

In tablets, the complexity and robustness of the final formulation is API- dependent. For certain APIs it’s critical to understand how the excipient attributes play a role in final formulation. A science-driven approach, based on a comprehensive understanding of the excipient characteristics is needed to develop a robust tablet formulation.

Musakhanian: Studies confirm that a large proportion of patients do not take drugs as prescribed. As such, CR delivery is ideal for treatments that require chronic and multiple daily doses, notably when patient compliance or lack thereof critically compromises the efficacy of the therapy. Examples include chronic administration of blood pressure, glaucoma, and pain management medicines.

Whereas drug candidates that are absorbed in the gut by diffusion mechanisms, and which have acceptable solubility and short half-life are generally good candidates for CR development. Water soluble but poorly absorbed potent drugs which rely on carrier mediated transport mechanisms for absorption are deemed to be poor candidates for CR.

Meanwhile, drugs requiring high administration doses, having poor solubility, and very long half-life which have historically been dismissed, may now face new opportunities – thanks to emerging developments and new formulation technologies.

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?

60 | | May/June 2016

Dürig: Controlled release technologies have huge potential to add value to existing and more mature therapies. However today’s regulatory and third party payer environment discourages the traditional, life cycle extension plays. In order to gain regulatory approval and adoption in third party payer formularies, a controlled release dosage form needs to demonstrate patient benefit that the marketed, conventional dosage form cannot provide. Increasingly these benefits are not just convenience of reduced dosing frequency, but improved therapeutic and economic patient outcomes. An example is the wide spread adoption of controlled release metformin HCl as the standard treatment for type II diabetes. In contrast to the conventional immediate release metformin, the controlled release version allows not just for reduced dosing but also significantly reduced gastric side effects and better compliance and glycemic control. Additionally recent advances in this therapy have led to the adoption of manufacturing technologies that allow for tablet size reduction, an important aspect of metformin controlled release therapy in the largely middle aged and older patient population. The Metsmall brand of metformin HCl marketed by Dr Reddy’s is an example of this innovative approach. Further examples of older therapies that can be enhanced with advanced controlled release technologies are opioid analgesics which have been increasingly reformulated as controlled release dosage forms for both enhanced pain management but also improved abuse deterrence.

Ali: OROS® technology, which delivers an immediate release and a controlled release mechanism of a drug through a tiny laser drilled hole, has been used in over 17 marketed drugs. The OROS® patent, set to expire in July 2017, with pediatric exclusivity until January 2018, has generated tremendous interest in the industry for use in both generic and innovative drugs as well. Polyvinyl acetate based excipients such as Kollicoat® SR30D and Kollidon® SR have been used in controlled and sustained release drugs due to their profile and ease of use in coated and matrix tablets, respectively. Requiring no laser drilling in the tablets, as required in OROS®, these excipients carry a pore forming ingredient such as Povidone K30 (Kollidon® 30), that controls the release via a diffusion process, thereby avoiding dose dumping. The unique properties of these polymers offer further advantages such as the ability to adjust release profiles in bioequivalent media by incorporating other hydrophilic polymers compatible to a drug and/or polymer in formulation dosages.

Kyburz: An increasing number of new drug applications are following the FDA NDA 505(b)2 pathway, due to the relatively short development times and economic incentives (3-7 years dependent upon reformulation complexity). Products pursuing the 505(b)2 pathway include new indications and improvements to existing products’ bioavailability. These often include solubility enhancement technologies; reduced Cmax and more consistent drug levels in the blood plasma resulting in reduced side effects; dosing convenience and therefore improved patient compliance; and new fixed dose combinations, among others. Controlled release technologies play a critical role in formulating an improved product via 505(b)2 pathway and plays a continuing role in life cycle management (LCM), including CR versions for pediatric and geriatric patient populations. Additionally, there is an increasing number of products being developed as CR for initial filing, rather than for LCM.

Khot: Yes. Controlled release technologies continue to be the preferred life-cycle management (LCM) approach by pharmaceutical companies, as they provide tangible benefits like improving patient compliance. There is also a clear interest in the industry to try unique polymers and technologies as a way to achieve performance-driven differentiation in the market and to produce high quality drug products costs-effectively.

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