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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 multilayer tablets.

nanotechnologies for controlled delivery of biologics for oral, injectable and topical products.

Kyburz: The recent emergence of continuous processing for oral solid immediate release products is expected to be quickly adopted for certain controlled release dosage forms, such as matrix tablets, with additional processing technologies to follow, including functional coating and coupled extrusion. Along with the many benefits of continuous processing, adhering to regulatory guidelines such as QbD becomes easier with the implementation of real-time process monitoring of the operational space utilizing process analytical techniques (PATs) and potential reduction of the scale-up API and resource burdens during development and manufacture.

New encapsulation technologies will likely see expanded use in enabling the oral delivery of sensitive molecules, including proteins, peptides, and live biological products. Microbiome and live biotherapeutics, such as using a living microorganism that is applicable in the prevention, treatment, and cure of a disease, represents exciting new fields. An oral controlled- release/delivery of microbial flora to ileum and colon for disease treatment is an unmet medical need and has significant challenges. One focus of current research is delayed release capsule technology to provide enteric protection and site delivery for targeted release applications such as fecal microbiota transplantation (FMT) to treat relapsing clostridium difficile infection. The use of oral DRcap®-in-DRcap® technology obviates the need for invasive procedures for administration and significantly reducing cost.

The new enTRinsic™ drug delivery technology platform offers full enteric protection without the use of functional coatings. This utilizes cellulosic enteric derivatives and a standard single capsule manufacturing processes. Thus, biomolecules (proteins and peptides) and live organisms (bacteria and viruses) that require gastric protection can be formulated with common encapsulation equipment and avoid heat and moisture liability from functional coating and drying. Such sensitive applications have previously relied on non-oral delivery mechanisms.

Khot: We continue to see a higher need for productivity enhancement in the development of solid oral dosage forms. Excipient offerings which allow faster, streamlined processing with fewer steps help our customers see reduction in costs without sacrificing quality or performance.

62 | | May/June 2016


Another market trend we see is the environmental push towards more sustainable operations. New technologies combined with new excipient offerings could help reduce or eliminate the use of solvents.

In addition, most new chemical entities have poor bioavailability and thus are more difficult to formulate into CR dosage forms. Improving solubility with solid dispersions manufactured via spray drying, employing lower molecular weight polymers for their spray-ability, does not impart controlled release. Additional formulation steps are required to impart the desired release performance. On the other hand, hot melt extrusion is also gaining popularity for its ability to continuously produce solubilized products, but high molecular weight controlled release polymers are very challenging to process via HME. We believe that new developments, such as the extrudable HPMC grades available from Dow, will continue to emerge in this area, enabling both solubilization and controlled release performance in fewer processing steps.

Musakhanian: Technology-driven changes such as new devices and continuous process technologies are expected to dramatically accelerate. Solvent free technologies such as extrusion and spray congealing, atomization and granulation will facilitate the development of novel dosage forms with safe and stable combinations of enhanced, immediate, and extended delivery systems.

Launching of new excipients is time consuming and costly and quite expectedly new raw materials are subject of rigorous scrutiny for safety and functional attributes. Therefore, innovative use of existing well known excipients is the safest and shortest path to development of new CR dosage forms. For these reasons, at Gattefossé we focus on the novel applications of well characterized and fully understood excipients.

As indicated previously (in question 4) polymeric matrices are susceptible to rapid disintegration in alcoholic media, leading to dose dumping. In contrast, lipid excipients are insoluble in ethanol and offer a pH independent modulation of the drug release. In addition to being safe alternative to polymers, due to their low melting point and low melt viscosities, lipids do not require solvents during granulation, extrusion or other matrix preparations.

A great example of lipid matrix for CR is that of an azithromycin oral suspension prescribed as antibiotic for pediatrics. Azithromycin is characterized for its very rapid absorption, extensive distribution into tissues, and serum half-life of ~68 hours which make it an ideal candidate for a single dose controlled release therapy. The formulation consists primarily of microspheres obtained by melt congealing of the drug with two different lipid excipients: a hydrophobic excipient to provide a water- insoluble matrix and a hydrophilic surfactive lipid within the matrix serving as pore former.

Another trend in CR development relates to amorphous solid dispersions which are increasingly used for addressing solubility limitations of BCS Class II and IV drugs. For poorly soluble drugs that have short half-life however, it may be beneficial if not crucial to enhance drug dissolution reducing the drug release rate in the gastrointestinal tract. For example, CR tablets of carbamazepine and itraconazole have been successfully developed with a hydrophobic excipient like Compritol® combined with high MW polyvinylpyrrolidones (PVP) to produce extrudates prior to compression. In this example, Compritol® created an insoluble matrix exhibiting near zero order release while also serving as binder / processing aid by reducing the undesirably high melt viscosity of PVP.

Used alone or in combination with polymers, lipid excipients therefore have key roles to play in the development of future CR dosage forms.

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