As appeared in September 2017 Tablets & Capsules www.tabletscapsules.com liquid-filled capsules Liquid-filled hard capsules help meet today s formulation challenges Jnanadeva Bhat, Fernando Diez, and Justin Kalafat ACG While liquid-filled capsule products are not new, they continue to play an important role in the delivery of poorly bioavailable and highly potent APIs. This article provides an overview and summarizes some recent developments. Drug discovery and development have undergone astounding changes in the last few decades, fueled by advances in many areas. Among the most important are cell and molecular biology, recombinant DNA technology, genomics, proteomics, and biochemical and chemical informatics. Better laboratory instruments and automation have also contributed. Likewise, more efficient manufacturing technologies and processes have led to the creation of purer and more potent active pharmaceutical ingredients (APIs). Figure 1 illustrates how the structural complexity and chemical properties of today s APIs compare to substances discovered decades earlier. The oral absorption of an API is fundamentally dependent on the API s aqueous solubility and gastrointestinal permeability. Extensive research into these fundamental properties led to the Biopharmaceutics Classification Systems (BCS), which categorizes APIs into four groups, Class I to Class IV (Figure 2). The BCS assesses compounds based on factors related to oral absorption and on
Figure 1 Today s APIs are more complex a. Aspirin (approved 1900) Empty capsules loaded and separated by vacuum Figure 3 Liquid filling process (sealing not shown) No-capsule detection Station for liquid filling Segment & cleaning station (by air and vacuum) Filled capsules discharge Optional station for pellet, tablet, or capsule filling b. Interferon (approved 2001) Capsule cap and body closing station Ejection of unopened capsules Station for liquid filling in vitro measurements of permeability and solubility. In this way, the BCS helps formulators predict the in vivo pharmacokinetic performance of drug products. Permeability Class II Low solubility High permeability Class IV Low solubility Low permeability Figure 2 The BCS [4] Solubility Class I High solubility High permeability Class III High solubility Low permeability Because most of the easy molecules have already been discovered only 5 percent of the APIs under development belong to the Class I (high bioavailability) and 70 percent belong to Class II the bioavailability of today s APIs is typically poor. To improve their bioavailability, it is necessary to increase their solubility. R&D scientists have a number of options to do so, and one of them is use to used lipids in the formulation [1-8]. Lipid-based formulations The principle behind lipid-based formulations is not complicated: It involves dissolving the API in a mixture of solvents. The mixture may comprise triglycerides, mixed glycerides, co-solvents (i.e., polyethylene glycol, propylene glycol), water-insoluble surfactants (i.e., Tween 80), water-soluble surfactants (i.e., Cremophor EH 40), solubility enhancers (i.e., Acconon MC 8/2), and other additives, such as α-tocopherol. For formulators, the key goals are developing a mixture that dissolves the API, increases its bioavailability, and can be placed in a compatible container, typically a capsule. The final steps are identifying a suitable capsule and capsule filler to handle the liquid formulation. In addition to improving bioavailability, lipid-based formulations reduce the food effect. This effect in which the co-administration of the drug product and food affects the absorption of the API could lead to a sub-therapeutic concentration of API in blood plasma (C max ). This is a serious problem for APIs that have a narrow therapeutic index, and where increased bioavailability could lead to serious side effects. Table 1 Method of increasing API solubility [6] Class II Class III Class IV Nanoparticles Select more soluble polymorphs Permeability enhancing excipients Efflux inhibitors Solubility and permeability enhancing excipients Pro-drugs Liquid-filled capsules Pro-drugs Gastroretention Solid dispersions and solutions Add surfactant
Figure 4 Capsule suitable for liquid fills Sealing band Liquid medicine because the capsules, after being filled with a liquid, must be sealed and dried. The design of capsules used for liquid encapsulation must also prevent or minimize the formation of bubbles when they are sealed so they do not become banana-shaped. Our company s Flofit capsules are an example of a capsule designed to avoid these problems (page 39). Cap of two-piece hard capsule Body of two-piece hard capsule Filling liquids: Hard versus soft capsules Delivering liquid formulations, including those based on lipids, requires a container, typically either a hard capsule or soft capsule (softgel). Hard capsules have several advantages over softgels, including walls that are typically one-third the thickness of softgel walls. As a result, hard capsules disintegrate faster. And unlike softgels, hard gelatin capsules do not require a plasticizer. Their two main ingredients are gelatin and water, while softgels require glycerin or sorbitol additions to soften the gelatin. Hard capsules are also stable in hot climates, while softgels become tacky and tend to clump. Hard capsules also allow less migration of the fill into the shell, and there is less diffusion of odors. And because hard capsules have fixed dimensions, they are easier to package, especially in blisters, than softgels, whose fill weight can vary throughout a batch, affecting the capsule s size and shape. And while hard capsules accept fills of thermo-stable substances as warm as 80 C, softgel fills are limited to about 35 C, although there is new technology that enables higher-temperature fills in some cases. The important point for formulators to consider when using a hydrophilic carrier is how compatible a hard capsule shell (no plasticizer) would be versus a softgel, which includes plasticizers. Hard capsules are typically made from gelatin or hydroxypropyl methylcellulose (HPMC). While it s beyond the scope of this article to detail the pros and cons of each, their main difference is moisture content. In HPMC capsules, it is lower and as a result, they are more elastic than their gelatin counterparts, which become brittle at low relative humidity. Furthermore, there are two types of HPMC capsules: Those that include a gelling agent and those that do not. Some studies suggest that the absence of gelling agent diminishes the shell s compatibility with liquid solvents, and some scientists have attributed the formation of splits and cracks immediately after banding to these HPMC shells [9-11]. Last, some patients and consumers favor HPMC capsules due to religious beliefs or dietary restrictions that preclude them from consuming a product made from animal parts. To accept liquid fills, hard capsules must have a geometry different from capsules that accept solids. That is Filling machines There is equipment to fill hard capsules with liquids at all scales, from R&D to production. Experimental batches can be filled manually using a hypodermic syringe. This enables formulators to conduct preliminary investigations into the integrity of the capsule shell, its compatibility with excipients, performance in in vitro and in vivo dissolution tests, and its effect on pharmacokinetic properties. Benchtop and production machines operate semi- or fully automatically, and there are few challenges when scaling up for production because increasing the output only requires adding dosing pumps. Look for capsule filling machines that Maintain the product at a constant temperature, up to 80 C, Maintain a homogeneous suspension in the product hopper and filling block, Fill accurate doses at volumes of 0.1 to 1.0 milliliter, Eject the filled capsule body if the cap is missing, 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 purposes: Creation of a leak-proof closure to contain oil, pastes, and other liquids and compliance with the regulatory 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 advantages of banding include a visible seal, easy leak detection, 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
Figure 5 Development of a biological API in capsule using lipid-based formulation (SEDDS) [20] Drug Complex Oily droplet Surfactant Emulsifier Co-emulsifier Capsule Oral administration Gl fluid Mucus barrier Absorbtion barrier that product [18.] Chiasma is developing Octreotide, a growth hormone inhibitor for treating acromegaly. Its formulation is based on the company s transient permeability 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 challenging. 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 technology is expected to grow strongly in the future include highly potent APIs (HPAPIs) for the treatment of cancers, for example and semi-solid formulations. HPAPIs are good candidates for formulation as liquidfilled 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 thought to be one of the fastest growing segments in the pharmaceutical industry. The global HPAPI market is expected to reach $25.86 billion by 2022, with oncology Reproduced with permission of Thiomatrix Table 2 Figure 6 Zeta-potential-changing Flip-Flop system [20] barrier Anionic charge of the mucus therapies the primary driver [21]. Semi-solid formulations are mixtures that take the form of liquids during filling, then solidify in the hard capsule to form a non-porous crystalline plug, or solid dispersion. These formulations can be used to improve not only the dissolution of APIs with low aqueous solubility but also to sustain the release from relatively simple formulations. T&C References 1. Ng R. Drugs: From discovery to approval, 2nd Ed. Wiley-Blackwell. 2009. 2. Custodio JM et al. Predicting drug disposition, absorption/elimination/transporter interplay and the role of food on drug absorption. Adv Drug Deliv Rev 2008. 60(6): 717-733. 3. Timko R. Improving the bioavailability of APIs for delivery in oral dosage form. Tablets & Capsules 2016 14(5): 29-32. 4. Anilkumar. Solubility enhancement of BCS Class 2 drug by novel drug solution drop technique. May 2015. Pharmachitchat.com. Accessed August 11, 2017. 5. Browne J. Improving the odds of success during early development using lipid-based systems. February 2017. Seminar presentation, San Mateo, CA. 6. Holm R. Lipid suspensions An approach to increase oral bioavailability or just greasy business? 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 Reproduced with permission of Thiomatrix
March 2017. DDF Summit, Berlin, Germany. 7. Mueller EA et al. Influence of a fat-rich meal on the pharmacokinetics of a new oral formulation of cyclosporine in a crossover comparison with the market formulation. Pharm Res 1994 11(1): 151-155. 8. Fatouros DG et al. Clinical studies with oral lipid based formulations of poorly soluble compounds. Ther Clin Risk Manag 2007 3(4):591-604. 9. Solaiman A et al. Mechanical properties of capsules shells made of HPMC. April 2008. Poster at 6th World Meeting on Pharmaceutics, Biopharmaceutics, and Pharmaceutical Technology, Barcelona, Spain. 10. Bhat J et al. How to assess and prevent brittleness of hard gelatin capsules. Tablets & Capsules 2017 15(1):15-19. 11. Ware E. et al. Investigation of various lipid vehicles in two piece HPMC capsules. October 2011. Poster at AAPS Annual Meeting and Exposition, Washington, DC. 12. Podczeck F and Jones B (eds). Pharmaceutical Capsules. Pharmaceutical Press. 2014. 13. ACG product development department. Liquid filling and band sealing. Not published. 14. Biyani M. Filling of liquid, semisolids and hotmelts into capsules. Not published. 15. Hauss D (ed). Oral lipid based formulations: Enhancing the bioavailability of poorly water-soluble drugs. Informa Healthcare. 2007. 16. Lightfoot D. An overview of capsule sealing equipment. Tablets & Capsules 2013 11(1):10-16. 17. Evaluation of the use of AZD6244 to induce increased ER expression and anti-estrogen response in ER-negative/low breast cancer. clinicaltrials.gov. Accessed August 11, 2017. 18. Oramed granted European patent for combination oral insulin and GLP-1 analog capsule. Oramed Press Release. April 2017. 19. Melmed S et al. Safety and efficacy of oral octreotide in acromegaly: Results of a multicenter phase III trial. J. Clin Endocrinol Metab 2015 100(4): 1699-1708. 20. Bernkop-Schnürch A. The mucus gel barrier: Industrial applicable strategies to overcome it. March 2017. DDF Summit, Berlin, Germany. 21. Siew A. Liquid encapsulation for HPAPIs. Pharm Tech 2016 40(1):40-41. Jnanadeva Bhat, PhD, is general manager of formulations development, capsules; Fernando Diez is scientific business development manager, capsules; and Justin Kalafat is business development manager, capsules, in North America at ACG. The company operates worldwide. ACG North America is located at 229 Durham Avenue, South Plainfield, NJ 07080. Tel. 908 757 3425. Website: www.acg-northamerica.com.