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• Control specific dosing when the cap and body are not separated, • Fill liquids over a wide range of viscosity values, and • Are compatible with a band sealing machine [12-14]. Sealing Sealing two-piece hard capsules serves two basic pur- poses: Creation of a leak-proof closure to contain oil, pastes, and other liquids and compliance with the regula- tory requirement that over-the-counter capsule products sold in the USA include a tamper-evident feature (FDA's compliance Policy Guide 450.500). The two main sealing methods are application of a gelatin or HPMC band to the cap-body junction and micro-spraying aqueous ethanol into void where the cap and body meet, which fuses the two halves. The advan- tages of banding include a visible seal, easy leak detec- tion, tamper evidence, and suitability for subsequent coating. Our company's band-sealing machines handle as many as 70,000 capsules per hour [15, 16]. Liquid-filled capsules, today and in the future Liquid-filled capsule products are not new, and there are many on the market. Table 2 lists some of them. Yet the technology is also vital to the success of future drug products. Astra Zeneca, for example, is using hard HPMC capsules for developing AZ6244 (selumetinib) [17]. This API is being developed for the treatment of various cancers. Oramed is developing an oral insulin product that will be delivered in liquid-filled capsules. In April 2017, it was granted a European patent related to that product [18.] Chiasma is developing Octreotide, a growth hormone inhibitor for treating acromegaly. Its formulation is based on the company's transient perme- ability enhancer system, which combines excipients to form an oily suspension of solid hydrophilic particles in a hydrophobic medium. This protects the API and allows it to permeate the gut wall [19]. Much of the work in this area is innovative and chal- lenging. One example is the University of Innsbruck's development of "Flip-Flop" systems to increase the bioavailability of APIs by changing the zeta potential of the formulation in situ [20]. See Figure 6. Two other areas where liquid-filled capsule technol- ogy is expected to grow strongly in the future include highly potent APIs (HPAPIs)—for the treatment of can- cers, for example—and semi-solid formulations. HPAPIs are good candidates for formulation as liquid- filled hard capsules because that format improves safety by lowering the risk of exposure to the HPAPI and the risk of cross contamination. Although HPAPIs constitute a relatively small portion of the API market, they are 42 September 2017 Tablets & Capsules Figure 6 Zeta-potential-changing "Flip-Flop" system [20] Figure 5 Development of a biological API in capsule using lipid-based formulation (SEDDS) [20] Complex Emulsifier Co-emulsifier Oral administration Oily droplet Drug Absorbtion barrier Mucus barrier Gl fluid Surfactant Capsule Reproduced with permission of Thiomatrix – – – – – – – – – – – – – – – – + + + + + + + + + + + + + + + + + + + + + + + + Anionic of the mucus charge barrier Reproduced with permission of Thiomatrix Table 2 Examples of marketed drug products formulated using liquid-filled capsules Active Brand Dosage Form License holder Danthron Co-danthramer Hard capsule Napp Captopril Captopril-R Hard capsule Daiichi Sankyo Pepperment oil Colpermin Hard capsule Janssen Isotretinoin Claravis Hard capsule Teva Mebeverine Mebeverine Hard capsule Mylan Dutasteride/Tamsulosin Combodart Hard and softgel capsule GSK Cyclosporin Neoral Softgel capsule Novartis Ritonavir Norvir Softgel capsule Actavis