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release for periods of 10-12 hours and beyond. This poses a challenge as the polymers get dissolved before the drug reaches the desired site in colon or large intestine. Thus, the targeted delivery remains challenging, but it offers significant benefits as to avoid the multiple dosing and reduce the pill burden for treatment of same therapeutic indications.

Kyle Kyburz, PhD, Senior Research Chemical Engineer, Bend Research, a division of Capsugel Dosage Form Solutions: Oral controlled release dosage forms provide tunable platforms to modify and adjust critical drug release characteristics – such as the time scale of release, reduction of Cmax, and GI site targeting (such as gastro-retentive or colonic delivery) – with the potential of reducing dosing frequency to increase patient compliance. While some new technologies exist, evolution of proven oral solid technologies remains the mainstay. When considering controlled release, formulation scientists should select a dosage form and technology based on the specific characteristics of the drug substance – including solubility, pharmacokinetics and drug loading – and the desired release profile. For example, these may include hydrophilic or lipophilic matrix tablets, typically for first-order release; osmotic systems for zero-order or consistent release; gastroretentive tablets for targeting the upper GI; and multiparticulates (MP) such as lipid, spray-layered, extrusion/spheronized and mini-tablets for tailored release profiles including delayed, pulsed or multiphase. Additionally, specialized approaches for fixed-dose combinations or dual release profiles can be achieved by implementing variably coated MPs, bi/tri layered tablets, and capsule-in-capsule technology.

MP systems hold distinct drug release advantages, specifically being highly-tunable and versatile platforms that can be coated with multiple drug and polymeric layers, and blended at encapsulation, to afford targeted release rates with consistent GI transit and absorption characteristics. MPs are also amenable to combinations of controlled release and solubilization technologies, which is a challenging combination. Spray- layered dispersions can be applied by spraying a solution of drug and polymer to an amorphous form, or a micronized or nanomilled form. MPs tend to provide flexibility for pediatrics, including flexible dosing from six- months of age forward, and are suitable for taste-masking, palatability and controlled release, in the form of sachets, capsules, or capsules that can be opened and the contents sprinkled into liquids or soft foods.

At Capsugel, one newer technology focus is lipid MPs created by a melt-spray-congeal, which uses a continuous process spinning-disk to produce smooth, tunable (often 200-400um) microspheres. These can be used as-is or fluid-bed coated for immediate and modified release and/ or taste-masking.

Additionally, osmotically controlled systems such as EOP, PPOP, SCT and AMT have the advantage of consistent drug release over a variety of physiologically relevant conditions, including fed and fasted states, and do not dose-dump in the presence of alcohol. SCT and PPOP technology can further be combined with solubilized forms for improved absorption across the entire GI tract.

Shrikant N. Khot, Ph.D., Sr. R&D Manager, Dow Pharma & Food Solutions: Whether it is for immediate release or for controlled release applications, there is an overarching need to improve manufacturing efficiencies without sacrificing the quality of the end product.

For the multiparticulate market, Dow has developed a new ethylcellulose grade, ETHOCEL™ HP, with a particle size distribution which has been optimized for use with high productivity dry powder coating processes. These processes are capable of offering drug release profiles similar to traditional fluid bed coatings in a fraction of the time and without the use of expensive solvents and solvent handling requirements.

Additionally, in traditional matrix modified release, Dow recently introduced METHOCEL™ DC2, a pure hypromellose designed to offer similar controlled release performance of hypromellose, but with improved powder flow properties, thus helping streamline tablet manufacture and helping avoid costly and time-consuming granulation processing steps.

Jasmine Musakhanian, Scientific and Marketing Director – Pharmaceutical Division, Gattefosse: Among processing technologies, melt extrusion, melt congealing, and spray atomization may be the biggest accelerators for the development of novel and sophisticated compositions for developing controlled release (CR) drug delivery systems. Also on the development list are solid lipid nanoparticles (SLN/NLC), orally administered floating particles, and muco-adhesive formulations. Meanwhile, devices such as implants, topical patches, and vaginal rings are among the technologies that are amenable to CR delivery.

Whether administered orally as a tablet or delivered by a patch on the skin, the goal of a CR formulation is to offer a predictable, constant plasma concentration of the drug, over a fixed period of time. Controlling the drug release rate is beneficial for improving the drug efficacy, safety, and simultaneously reducing its undesirable side effects. Moreover, it is desirable for improving acceptance and patient compliance.

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?

Dürig: Formulators face challenges in the rate controlled oral delivery of high dose drugs. Both highly soluble and low solubility high dose drugs represent a tremendous challenge as these drugs typically necessitate the use of large amounts of excipients to modulate their release or render them soluble, which combined with a large amount of drugs then leads to large, difficult to swallow dosage forms. Fixed dose combination drugs are also very challenging as again the combination of drugs may represent a considerable payload, but also in this case two distinctly different release profiles may have to be reliably achieved. Lastly drugs with poor bioavailability such as limited colonic absorption, low water solubility or peptides and proteins which have virtually no permeability in the GIT represent major challenges. Pediatric and geriatric treatments in oral liquid form also are challenging.

The best candidates are drugs that can be administered orally at effective doses of 1-250mg with a dose/ solubility ratio of 1-100ml and no ionization in the physiological pH range. They should have at least 30% colonic absorption, a half- life of 2 to 10 hours.

Ali: Polymeric excipients are the key components in the design and development of a controlled release dosage. With the advent of new polymers and a better understanding of formulation technologies, the industry is aiming for targeted delivery to avoid side effects, and using safe and pharmaceutically accepted polymers to yield certain release profiles. These polymers possess unique characteristics ranging from pH dependent to independent solubility, (e.g. enteric and reverse enteric polymers), bearing functional groups that are prone to self-healing and semipermeable in nature. All these characteristics aid in the design of a dosage for effective delivery of an API. For instance, polyvinyl acetate polymer (e.g. Kollicoat® SR30D, a 30% dispersion) has been effectively used to deliver the drugs in a controlled manner while maintaining the semipermeable characteristics without any dose dumping. Such flexibility | | 59


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