From Molecule to Dose Form Bioavailability Toolkit to Fast Track Development Introduction

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contents introduction 2 part one: Connecting the 4 Dots in Drug Delivery part two: The Bioavailability 8 Toolbox part three: The Toolbox of 2025 16 part four: Delivering Change 21

from molecule to dose form bioavailability toolkit to fast track development introduction

When it comes to drug formulation challenges, there trend and the key to succeed in this competitive is no one-size-fits-all solution. landscape. The leading evidence of this trend includes more direct-to-consumer advertising and a The 3rd annual drug delivery landscape survey* recent patient focused drug development initiative confirms that bioavailability, safety, efficacy by the FDA to gather the patient’s perspective and solubility are the top challenges faced by on their condition and available treatments. formulation scientists. The pharmaceutical and Interestingly, survey data shows that although biopharmaceutical industries have to overcome not the industry has identified the value of patient- only formulation challenges but also the business centric drug design, it has not been very successful challenges of bringing a product successfully to in applying it. For instance, to successfully apply market. The survey participants, a vast majority of patient-centric design, the drug product should be whom are Formulation Scientists and R&D Managers, adapted as per the patient’s preference at earlier indicated that development time, selecting the stages of drug development to avoid high costs at appropriate drug delivery platform, budget and late stages, a practice which is not very common in choosing the right external partner are the top the industry. Also, when asked to rate the significant business challenges. The survey also shows a major factors in drug development, patient adherence, shift in trend towards “patient-centric” drug design. patient dosing convenience, and impact on patient’s Oral delivery of macromolecules was the trend that likely drug regimen received very low scores. will most influence the drug delivery technology in next five years, followed by improving bioavailability There is a definite need for a drug delivery strategy of BCS Class IV drugs. In a nutshell, Formulation that not only overcomes formulation challenges Scientists have a three-fold challenge; designing a but also meets patient demands. Industry pioneers safe, effective and stable dosage form, ensuring it is in formulation technology have developed a broad patient friendly, and bringing it faster to market. range of advanced drug delivery technologies, which are viable tools to solve formulation challenges, The days of “low-hanging fruit” in the drug discovery improve patient compliance, and bring product faster era when most new chemical entities (NCE) were to market. Here is a brief snapshot of the type of highly permeable and soluble (BCS class I) are over. tools available to formulation scientists. As drug discovery teams dig deeper into compound libraries to identify a NCE, the compounds are softgel technology: For last 80+ years, softgel increasingly becoming less soluble and/or permeable technology has enabled more than 50 poorly soluble than previously developed drugs. It is estimated that drugs to be commercialized, making it one of the ~70% of NCEs are class II or IV, either poorly soluble most successful drug delivery vehicles for BCS class in water, have low cell permeability or both. In II compounds. It is also a proven method to deliver addition, in the midst of the technology and business unstable API, low dose, potent compounds, light and challenges, we cannot afford to lose sight of end oxygen sensitive compounds. Softgel technology users, i.e., the patients. has utilized lipid-based drug delivery systems (LBDDS) in which drug is delivered in a solution Traditionally, the target customers were physicians form and maintained in solution upon dispersion but the survey indicates that the industry has into biological fluids until it reaches GI track. LBDDS realized that patient-centric drug design is a major are used to overcome issues created by API that

2 are practically insoluble in water and spontaneously size range. It is suitable for sensitive API as there emulsify in gastric juices. There are a number of is no heat degradation and the process results technologies that can accommodate a wider range in thermodynamically stable crystalline form of drug molecules and excipients. For instance, one of API. The micronization process has a track technology utilizes a plant polysaccharide based record of improving bioavailability of potent and shell which allows encapsulation of fill formulations thermolabile compounds, such as oncology drugs. at higher temperatures, up to ~70° C for semi-solid This technology is also well known in the industry for and highly viscous fill formulations. bringing orphan drugs faster to market by combining expertise in particle size reduction and efficient Additionally, there is a new tool to improve the manufacturing processes. delivery characteristics of macromolecules including peptides and proteins. Macromolecules delivered fast dissolving technology: Ever-increasing through the intravenous route may result in poor demand for fast dissolving and palatable dosage patient compliance for long term treatment. This forms among pediatric and geriatric population new technology improves the bioavailability of has made it a rapidly growing field. Fast dissolve macromolecules by incorporating permeability technologies have been shown to improve patient enhancers which modulate intestinal membrane compliance by providing a convenient dosage form permeability. The enteric coating provides targeted for allergens and large molecules. It is a unique, delivery of API by preventing gastric degradation of freeze-dried dosage form that is palatable, does macromolecules and releases the macromolecule at not require water, and is resistant to microbial the site of absorption. contamination due to low moisture content. Oral fast dissolve tablets can be tailored to meet various solid dispersion system: Solid dispersion technology dose requirements. At present, it covers seventeen has emerged as an effective way to enhance therapeutic areas in Rx and OTC products. dissolution rate of low solubility API. This versatile technology offers multiple advantages such as To summarize, there are a variety of tools to generating stable and processable product that can overcome bioavailability challenges of poorly soluble be further formulated into the desired dosage form. compounds. It is crucial to select a tool that not only Hot melt extrusion is the process of creating API- solves formulation challenges but also delivers an polymer dispersion by applying heat and shear stress agreeable dosage form for patients. Explore further to create an amorphous dispersion. There is no need chapters to learn how Catalent offers commercially for toxic organic solvents, which means no related viable and faster to market solutions. expense or the environmental hazards associated with removing them. Hot melt extrusion technology *The 3rd annual drug delivery landscape survey can accomodate ~90% of drug loading (the ratio was sponsored by Catalent Applied Drug Delivery of the active drug to the total contents of the dose) Institute. For more information, visit www. which provides reduced pill burden and enhances drugdeliveryinstitute.com patient compliance. Hot melt extrusion processes have been proven to increase bioavailability and decrease time-to-market for multiple compounds including an anti-inflammatory drug and to improve product differentiation and brand performance for analgesic products. particle size reduction: Micronization is an established method of improving oral bioavailability of poorly soluble compounds. The drug particles are accelerated utilizing high velocity compressed gas within a chamber to achieve desired particle 3 But a reduction in bioavailability isn’t the only part one problem. Poor solubility is also often associated Connecting the Dots in with unacceptable variability in blood levels of the drug, both within and between patients Drug Delivery – and it increases the risk of food effects.

Despite the challenges, oral dosage forms The days of “low-hanging fruit” in drug discovery are (read: convenient and non-invasive) remain the a thing of the past. Drug candidates are increasingly preferred route of administration for traditional made up of complex, poorly soluble molecules – and small molecule drugs, making up around 40 that poses a big challenge: how can we continue to percent of all prescription drugs (1). In essence, produce effective medicines that meet patient needs. to deliver the convenient dosage forms that patients want, we must find ways to enhance the bioavailability of poorly soluble drugs. To do that, we need to connect more than a few dots...

Simple Solubility? Improving solubility is simple in theory: we (just!) need to break down the crystal lattice structure before the patient ingests the medicine. In practice though, with the demands of stability and patient acceptability to contend with, it’s a much trickier proposition. Typically, the lattice can be broken down Welcome to the first part of a four-article series by applying heat, shear stress or solvents to the API that will explore the unprecedented challenges and adding suitable excipients. Hot-melt extrusion facing pharmaceutical scientists – in particular, or spray drying to create solid dispersions, self- the ability to offer good bioavailability and patient- emulsifying drug delivery systems and nanocrystal friendly drug delivery for increasingly complex formation are just some of the techniques available new medicines. We will review the current and to aid formulation scientists in rendering the emerging technologies that are likely to play a insoluble soluble. And new advances are being made role, discuss the need for a more collaborative every day (2). However, there is no one-size-fits- approach, and speculate on the future of drug all solution. What is needed is a toolbox approach delivery in an attempt to connect all the dots. – and the more tools at our disposal, the better!

The High Fruit In the midst of all the technological options open “There has been a significant trend over the to us, it’s important that we don’t lose sight of last 10-15 years for more and more lipophilic our end users. Indeed, we must bear them in drug candidates. Up to 70 percent of new drug mind at the earliest stages of development. It’s candidates now belong to what’s called BCS class not just about finding a drug delivery strategy II, meaning low solubility compounds with high that works, but one that works for patients. permeability,” explains Ralph Lipp, a pharma consultant and founding advisory board member “The first step in patient-centered design is to of Catalent’s Applied Drug Delivery Institute. understand that patients are not a homogeneous “These compounds are often difficult to deliver group but made up of many different groups, orally as they do not dissolve fast enough during often with vastly different needs,” says Lipp. “For gastrointestinal passage. In general, a drug that is example, we have an opportunity as an industry not dissolved cannot be absorbed into the body.” to do more to meet the needs of geriatric patients, who make up an increasing proportion of the 4 population.” Those needs could include anything references from developing easily distinguishable tablets 1. R. Lipp, “Major Advances in Oral (to avoid negative drug interactions in this highly Drug Delivery over the Past 15 Years”, medicated population) to improving packaging to Am. Pharm. Rev. 16, 6 (2013). make life easier for those with rheumatoid arthritis. 2. R. Lipp, “The Innovator Pipeline: Bioavailability Age is just one factor to consider – social, cultural Challenges and Advanced Oral Drug Delivery and convenience factors play important roles Opportunities“, Am. Pharm. Rev. 16, 3 (2013). too, and there are subtle differences between 3. S. P. Hertel, G. Winter and W. Friess, “Protein territories. For example, a tablet mass of over Stability in Pulmonary Drug Delivery via 300mg is considered acceptable by most patients Nebulization”, Adv. Drug Delivery Rev., In in Europe, but is too large in Japan. Even biologic Press (2014) doi:10.1016/j.addr.2014.10.003 drugs, which have traditionally been delivered by 4. M-C. Chen et al., “Chitosan Microneedle injection, are moving towards more patient-friendly Patches for Sustained Transdermal Delivery options, with inhalable, topical and oral dosage of Macromolecules”, Biomacromolecules, forms being explored by researchers (3, 4, 5). 13 (12), 4022–4031 (2012). 5. V. K. Pawara et al., “Targeting of Gastrointestinal Team Delivery Tract for Amended Delivery of Protein/ The diverse challenges involved in creating the best peptide Therapeutics: Strategies and Industrial formulations for patients will not be overcome by Perspectives”, J. Control. Rel. 196, 168–183 (2014). single organizations, operating in a vacuum. To fill the gaps in our knowledge – and to get the best results for patients – will require input from industry, academia, and equipment and chemical suppliers.

Life sciences companies are becoming increasingly aware that precompetitive collaboration is good for business – and for patients. PhRMA Executive Vice President William Chin describes it as a “tide that raises all boats.” Companies are already coming together to explore disease mechanisms and identify potential drug targets. To encourage a similar knowledge-sharing approach to speed innovation in drug delivery, Catalent set up the Applied Drug Delivery Institute in 2012. Lipp says his role within the Institute taps into an absolute passion for improving drug delivery for patients. “The Institute’s mission is to bring together scientists from both industry and academia, with a goal of moving the needle for drug delivery as a whole – that very much matches my ambitions.”

In the following three articles, we’ll be exploring some of the most important strategies in the drug delivery toolbox, including the latest advances in existing techniques such as hot melt extrusion lipid-based systems, emerging technologies such as nanotechnology, and cutting-edge research on alternatives to injection for macromolecule drugs. 5 Following initial API and preformulation studies, technology profile Catalent develops the required formulations through Hot Melt Extrusion the application of a range of formulation screening technologies and analytical services, and through Technology: A its clinical development and supply services. The company can perform HME processing from bench Proven Bioavailability through pilot and commercial scale at facilities Enhancement Solution in Somerset, New Jersey, USA and Schorndorf, Germany.

The Challenge: How to OptiMelt HME processing comprises hot melt Enhance Drug Bioavailability extrusion followed by downstream pelletizing/milling to produce the final dose form. OptiMelt HME is Around 40% of currently marketed drugs are used to prepare extrudate of API solid dispersions poorly soluble, and potentially more than 70% of in a polymer/excipient matrix. The formulation may drugs in development are also classified as poorly be processed into a variety of final dosage forms, soluble (BCS Class II/IV), representing an increasing including tablets, capsules, and effervescent ‘Stick industry challenge. The bioavailability of these drugs Packs’. Catalent has extensive dose form capability, can be enhanced by creating a physically stable and including tableting and encapsulation granules, plus processable non-crystalline (amorphous) form of controlled release technologies, co-located with its the API. Hot Melt Extrusion (HME) is a technology HME capabilities. that generates soluble amorphous forms that are physically stable and processable, by combining crystalline API with a suitable polymer, followed Improved Therapeutic Profiles by cooling/precipitation, to produce an extrudate OptiMelt technology improves therapeutic profiles that can be formulated into tablets or granules of new drugs in a number of ways and enables for capsules. Relative to crystalline APIs, these treatment optimization, as follows: amorphous solid dispersions improve bioavailability • Stable formulations give increased development in more than 80% of cases, thus enhancing success rates R&D productivity and enabling effective drug • The wide range of dose functionality means that development. immediate and controlled release formulations deliver more drug when it is needed, where it is ™ OptiMelt : Enabling Holistic needed Bioavailability Enhancement • The wide range of solubilities and dispersion OptiMelt is Catalent Pharma Solutions’ unique concentrations possible gives the flexibility to capability to formulate, develop and commercialize achieve desired efficacy and dosing HME processes and integrate these into • Very high drug loading (up to 90%) gives a differentiated final dosage forms. It enables holistic reduced daily pill burden and enhances patient bioavailability enhancement by broadly addressing compliance multiple bioavailability factors, including: • Patient abuse deterrence formulations give • Optimization of product efficacy, safety and patient safety and compliance release properties • Greater consistency for APIs with high food effect • Increasing development success rates absorption gives enhanced efficacy and reduced • Reducing time to market. patient variability

6 • The tastemasking capability of HME formulations • The wide range of dose forms, including tablets, gives product differentiation and enhanced capsules, and free-flowing granules, results in patient compliance a preferred patient dose form, thus enhancing compliance and differentiating products.

case study: increased case study: enhancing bioavailability of a chronic brand performance of inflammatory disease drug an otc aspirin product

The challenge was that a poorly bioavailable The challenge was that a large company wanted product for treating chronic inflammatory to develop and launch an effervescent aspirin OTC disease required effective formulation for Phase 2 product as a line extension to a very well recognized brand. Catalent partnered with the company for development. Formulation, process development, product formulation, scale-up, and commercial and downstream tableting were all required. manufacturing to provide:

The OptiMelt solution: Catalent developed The OptiMelt solution: Catalent developed and optimized an effective tablet and optimized an effective tablet formulation through the application of: formulation through the application of: • HME polymer screening and selection • An innovative effervescent aspirin formulation • Drug/polymer formulation development • HME process development • Determination of HME processing parameters • Downstream processing in which the product • Scale-up from feasibility to development using a was milled, mixed, and filled into a unique and 10 mm extruder (50 g) to 18 mm extruder (4 kg) distinct single-dose packaging solution ‘Stick • Downstream tableting, including extrudate/ Packs’ tablet formulation and tableting operating • Scale-up and commercial manufacturing parameters selection The result was a successful product launch The result was effective Phase 2 development with a unique formulation, complementing of the customer’s candidate, increasing the the leading analgesic OTC brand. bioavailability and decreasing the time to market.

7 the native active pharmaceutical ingredient (API), a part two much less expensive option than developing complex The Bioavailability Toolbox formulations later on. The ‘go to’ method for acidic or basic compounds is to identify a suitable crystalline salt of the API, but for some of today’s candidate How can we overcome bioavailability challenges drugs even this option is not straightforward. in our increasingly complex drug pipeline? “Molecules are getting progressively bigger and more complex, and this complexity means that There is no ‘one size fits all’ solution salt formation is sometimes not sufficient to overcoming poor solubility and to achieve a meaningful improvement bioavailability, while delivering in solubility,” explains Igo. an oral dosage form preferred by patients, as we discussed An approach that has grown in the first article in the series rapidly in popularity over the (”Connecting the Dots in past decade is the creation of Drug Delivery”). Marrying an amorphous solid dispersion. acceptable solubility with With no crystal structure to break long-term stability is a tough down, amorphous compounds challenge that requires an array of are much more easily dissolved increasingly ingenious formulations. in the GI tract, exhibiting 10,000- fold increases in apparent solubility (1). Since the advent of combinatorial chemistry Amorphous solutions are formed by combining and high-throughput screening in the 1990s, the API with a suitable polymer, by spray drying, bioavailability challenges have become more and hot melt extrusion or co-precipitation, depending more complex. In response, new formulations on the melting point and how easily they can and delivery methods have emerged. The be dissolved in common organic solvents. result? Scientists now have an arsenal of techniques to choose from. “It used to be that The downside of amorphous formulations is that micronization and the particle- forming step the physical form of the compound is generally were all that you had, but now with the different less thermodynamically stable than a crystalline formulation options, scientists have a much form. This can result in a shorter shelf-life due to greater chance of improving bioavailability,” says the potential of the drug to revert to a crystalline David Igo, Director of Product Development and form over time. However, recrystallization can Manufacturing at Catalent Pharma Solutions. be prevented by understanding and carefully managing the product storage condition relative All the patient sees is a simple tablet or to the glass-transition temperature or selection capsule – only a pharmaceutical scientist of the polymeric carrier, incorporating stabilizers knows the years of painstaking work that have into the polymer or controlling pH (2). gone into creating that ideal formulation. Spray Dry Here, we take a whistle-stop tour of the technology Spray drying has been the most widely used method and techniques that enable progress in formulation, to date, with the API–polymer mix dissolved in focusing on the latest and greatest advances. an organic solvent, atomized and then rapidly

dried with hot air or nitrogen into a fine powder. Amorphous APIs Spray drying has allowed commercialization of Early in the drug development process, a process of many drugs that would otherwise have failed, solid-state optimization can increase the solubility of says Filipe Gaspar, Vice President of R&D at

8 Hovione. “It is an enabling technology and we problems, such as recrystallization or high melting have worked on many products that only became point drugs. “Ultimately, our research aims to make bioavailable by adopting it and in many others that hot melt extrusion more efficient and ideally develop became effective drugs at much reduced dose.” platform technologies, so we don’t have to start from scratch for every new chemical entity,” says Repka. So what’s next for spray drying? There has been a lot of progress in process analytical technology, Recently, the group was successful in using according to Gaspar, which allows continuous hot melt extrusion alongside high-pressure monitoring of critical quality attributes such as homogenization to produce solid lipid nanoparticles particle size or solvent content. Other areas of in a continuous process (3). Repka believes innovation include advanced modeling of the process, that capitalizing on the inherent continuous which provides for seamless scale-up and process processing capabilities of hot melt extrusion will optimization with minimum testing, optimization be crucial, as the industry (tentatively) moves in the capture of the powders and more efficient towards continuous manufacturing: “If you can operation and cleaning of the units. Considering develop a continuous rather than batch process, the comparatively gentle nature of the process and that saves a tremendous amount of time and recent advances in sterilization of spray dryers, money and personnel, which means that we Márcio Temtem (group leader, Particle Design & can get the product to the patient faster.” Pharmaceutical Development at Hovione) believes the next logical step will be to apply the technique “It won’t come overnight”, says Repka, “but as in the manufacture of sterile biopharmaceuticals, the equipment becomes better and better, and in place of freeze-drying: “The technology has our understanding of the process grows, more significant advantages over lyophilization in terms and more pharma companies will come to of cost and throughput. I would say it is just a accept hot melt extrusion as a mainstay.” question of time before its use becomes widespread.” Size Matters Hot Topics in Hot Melt Extrusion For a crystalline drug, one way to increase Hot melt extrusion has been underutilized by the bioavailability is to reduce the particle pharmaceutical industry, according to Michael size. Increasing the surface area to volume Repka, Chair and Professor at The University of ratio increases the rate of dissolution in the Mississippi. “Even though hot melt extrusion has gastrointestinal tract. It’s now possible to reliably been in use for years, many pharma companies produce fine particles down to the submicro have not fully accepted it. They have been range in either a ‘top down’ (for example, milling making tablets the same way for 40 years and or micronization) or ‘bottom up’ (for example, can be reluctant to replace older technology.” precipitation) fashion. Micronization is the most common approach, with companies offering ever- But for APIs with the right properties, the faster and more efficient milling techniques. use of hot melt extrusion is rapidly gaining popularity. As the process relies on heat and As well as increasing the surface area to volume shear stress to effect molecular mixing and ratio, nanoparticles have intrinsic properties create an amorphous dispersion, there is no that can help overcome poor bioavailability. The need for toxic organic solvents – or the expense transition from micro- to nano-scale dramatically and environmental hazard of removing them. changes the physicochemical properties of the particles, increasing saturation solubility, Repka’s lab experiments with a variety of different speed of dissolution, and the ability of the APIs, polymers, temperatures and dosage forms particles to adhere to cell membranes (4). to find the optimum process and to troubleshoot

9 Plus, there are special advantages when it comes to be developed using these techniques. Coated targeting cancer. Ronak Savla, a Rutgers University capsules can now delay release of the drug until Research Fellow supporting the Catalent Applied the capsule reaches the lower intestine – useful Drug Delivery Institute, used specially engineered for drugs that might cause gastric side effects or nanoparticles to deliver highly potent cancer where efficacy would be disrupted by the acidic drugs specifically to the tumor site (5). “There is a environment of the stomach. In addition, abuse phenomenon known as the enhanced permeation deterrent coatings are available for products like and retention effect in solid tumors – the blood pseudoephedrine, which can otherwise be converted vessels in the tumor become leaky, allowing the by ‘kitchen chemistry’ to illegal methamphetamine. nanoparticles to exit the blood stream only at the tumor site rather than elsewhere in the body.” Where a solid dosage form is preferred, solid SEDDS have been developed, using Savla also applied cutting edge techniques to create solidification techniques, such as spray nanoparticles for pulmonary (inhaled) delivery drying, to convert the liquid intermediate into (6). Particle size is key for inhaled formulations, a standard solid oral dosage form (7). as Savla explains: “The location where the drug particles deposit is highly dependent on size, so Winning Combinations if you want to reach the alveoli, deep in the lungs, Naturally, these approaches do not operate in you need a smaller particle size, whereas if you isolation – they are all part of the wider drug delivery want to reach the upper airway or bronchus, you toolkit, where advances in one area often trigger need a larger size.” It is likely to be a few years exciting new developments in others. For example, before we see the results of Savla’s work in the amorphous drug nanoparticles have shown a lot of clinic, but experts agree that nanoparticles are promise, combining as they do the high solubility a key drug delivery system for the future. of the amorphous state with the rapid dissolution of nanoparticles (8). In a similar vein, the use of Fat Chance nanoemulsions has previously been limited by issues Lipophilic drugs are often better absorbed when of palatability and formulation, but in combination taken alongside a fatty meal, a fact which gives a with self-emulsification and soft gel technologies, clue to another formulation approach for highly nano-SEDDS are now a hot area for research (9). lipophilic compounds. Self-emulsifying drug delivery systems (SEDDS) are created by dissolving Ralph Lipp, founding advisory board member the API in a mixture of oil, surfactants and other of Catalent’s Applied Drug Delivery Institute, excipients, which results in a liquid or paste believes collaboration is key to addressing intermediate that can be encased in a soft gel or bioavailability challenges. “It is very important hard shell capsule. After ingestion, the coating that there is good communication between the dissolves and the mixture is released into the drug design and formulation teams within an aqueous environment of the gastrointestinal tract. organization. We need a team approach; a more The excipients added earlier cause the mixture to holistic way of developing drugs,” he says. emulsify in the gastrointestinal tract, forming very small, easily absorbed droplets of dissolved API. Collaboration is central to the mission of the Catalent Applied Drug Delivery Institute, which Many poorly soluble drugs also have low brings academic and industrial scientists together to permeability. Lipid-based drug delivery systems address current drug delivery challenges. David Igo, enhance passive transport through the lipophilic cell Michael Repka and Filipe Gaspar have all contributed membrane and tap into the body’s own mechanisms to the Institute’s regular educational symposia. for absorbing fats through the lymphatic system. New developments in soft gel technology have Despite the range of options now available, made it possible for a broad range of drugs to scientists can’t rest on their laurels – they 10 must work continuously to improve and refine references current technologies - and come up with new 1. C. Brough, and R.O. Williams 3rd, “Amorphous ones. Gaspar says, “Today, the vast majority Solid Dispersions And Nano-Crystal Technologies of new drugs are poorly soluble and that is a For Poorly Water-Soluble Drug Delivery”, major challenge, but it also creates opportunities Int J Pharm. 453(1), 157-166 (2013). for new technologies to be developed in the industry.” So innovation is also essential. 2. Y. Huanga and W-G Daib, “Fundamental Aspects Of Solid Dispersion Technology For Poorly Soluble In the next article in the series, we’ll be gazing Drugs”, Acta. Pharm. Sinica B 4(1), 18-25 (2014). into our (amorphous) crystal ball, to see 3. H. Patil et al., “Continuous Manufacturing Of what disruptive technologies will be shaking Solid Lipid Nanoparticles By Hot Melt Extrusion”, up drug delivery in the years to come. Int. J. Pharm. 471(1-2), 153-156 (2014) 4. S. M. Alshahrani et al., “Stability-enhanced Hot- melt Extruded Amorphous Solid Dispersions via Combinations of Soluplus‰ and HPMCAS- HF”, AAPS PharmSciTech (January 2015). 5. R. Savla et al., “Tumor-Targeted Responsive Nanoparticle-Based Systems For Magnetic Resonance Imaging And Therapy”, Pharm. Res. 31(12), 3487- 3502 (2014). 6. R. Savla and T. Minko, “Nanotechnology Approaches For Inhalation Treatment Of Fibrosis”, J Drug Target. 21(10), 914-925 (2013). 7. Tan, S. Rao and C. A. Prestidge, “Transforming Lipid-Based Oral Drug Delivery Systems Into Solid Dosage Forms: An Overview Of Solid Carriers, Physicochemical Properties, And Biopharmaceutical Performance”, Pharm. Res. 30(12), 2993-3017 (2013) 8. W. S. Cheow et al., “Amorphization Strategy Affects the Stability and Supersaturation Profile of Amorphous Drug Nanoparticles“, Mol. Pharmaceutics 11(5), 1611–1620 (2014). 9. A. A. Date et al., “Self-Nanoemulsifying Drug Delivery Systems: Formulation Insights, Applications And Advances”, Nanomedicine (Lond). 5(10), 1595-1616 (2010).

11 range of excipients available which provides good technology profile scope for development. Catalent has 80+ years Softgel Technology: A of expertise to ensure good manufacturability, stability and optimal in-vivo performance. Proven Drug Delivery Solution

The Challenge: Encapsulating and Optimizing Poorly Soluble Molecules Typical challenges presented by APIs in relation to formulation issues include poor aqueous solubility; poor permeability; the occurrence of multiple polymorphic forms; APIs that exist in liquid form; APIs with low melting points; and poor stability.

Typical processing challenges for APIs include Softgel technology offers the following benefits: the formulation of liquid, paste or semi-solid delivery systems; processing of highly potent APIs; • Improved bioavailability for a greater the uniformity of the dose; containment issues; number of poorly water-soluble and handling of cytotoxics; and scalability issues. poorly permeable compounds • Drugs can be released from the shell rapidly upon In the case of solubility being such an issue ingestion, and typically meet the requirements where dry formulations have to be used, this for immediate release dosage forms. can lead to uneven distribution of the API • Modified or controlled release of compounds and excipients before tabletting, leading to can be facilitated with coatings problems with dosing and delivery of drugs. • Improved stability of formulations These challenges slow down, and even • Improved ‘swallowability’ of doses, derail, many development programs. meeting customer preferences and larger dose requirements Softgel Technology: A Proven • Greater dose uniformity and therefore consistent Drug Delivery Solution delivery of, for example, highly potent drugs Catalent’s RP Scherer softgel technology is a • Resistance to tampering through proven drug delivery solution for challenging crushing or breaking down compounds that has helped bring more than 50 • When formulated and packaged with appropriate new drug products (NDAs) to market. Softgel expertise, capsules are able to meet the ICH formulations are typically comprised of a solution requirements for stability up to Zone IVb or suspension of drug in a lipophilic, hydrophilic • Development and screening of formulations or mixed vehicle. Various shell formulations are requires minimal amount of API available depending on the application. Coloring and flavoring can be added to the fill or shell. • Provide a variety of brand differentiation options, such as capsule shape, size, Softgel formulations, and the excipients upon color, and printed outer casings. which these systems are based, are usually liquid or semi-solid in nature. There is a wide

12 OptiShell™ Technology: Advancing Softgel Technology with More case study: catalent Options, for More Molecules softgel solution developed Catalent’s OptiShell capsule technology utilizes for xhale adherence system a patented plant polysaccharide-derived shell which provides a capsule that contains semi- Xhale, Inc., a medical technology company solid matrices for the release of poorly soluble developing patient-centric monitoring solutions and/or poorly permeable drug compounds. for healthcare, needed to develop a breath- based adherence system to verify, monitor, Immediate or controlled release of drugs is and report information about how and when enabled and a wider range of compatible fill participants in research studies were taking study excipients allows enhanced drug bioavailability medications in clinical trials. By working with and stability, and offers more solutions for Catalent Pharma Solutions, Xhale has recently solving unique drug delivery challenges. made available SMART‰ Softgels for clinical OptiShell technology addresses research use with its SMART Adherence System. the following challenges: The SMART Softgels, manufactured by Catalent, are the first solution offered by Xhale to enable • Encapsulation of higher fill temperature integration of breath-detectable adherence (up to 70°C) for semi-solid and markers into a broad range of pharmaceutical highly viscous fill formulations products, and have demonstrated stability, quick • Higher pH fill formulations release of the adherence marker, and favorable • Compounds which exhibit a short half- properties to support their pharmaceutical use. life and require frequent dosing Xhale chose to partner with Catalent because • Drugs that have high peak blood levels of its experience and track record of RP Scherer and unacceptable side effects. Softgel innovation. Working with Xhale, a Catalent RP Scherer Softgel product was developed to feature a special shell to release quickly while still preventing evaporative loss of API during and after manufacturing.

The SMART Adherence System is designed to offer definitive and non-invasive monitoring of medication adherence, utilizing exhaled breath to confirm that medication has been taken by study participants as directed. The SMART Adherence System is now available for research use in the collection and reporting of definitive treatment adherence data in clinical studies. Xhale has filed a Type IV (Excipient) Drug Master File with the FDA that contains comprehensive information supporting the use in clinical studies of the SMART Softgels developed by Catalent.

13 reduction bioavailability enhancement solutions technology profile across a wide customer base, including virtual Particle Size Reduction companies, big pharma, generics and API manufacturers at our state-of-the-art facilities in Technology: A Malvern, PA and Dartford, UK. They are licensed by the DEA to handle and process controlled substances Proven Bioavailability Schedule II to V. Catalent Micron Technologies has over 25 years of expertise with micronization, Enhancement Solution milling and analytical services to manufacture for Crystalline Small high quality cGMP pharmaceutical product. Molecules Catalent Micron Technologies: A Straight-Forward Solution for Oral Bioavailability Enhancement The Challenge: How to Enhance the Benefits of Catalent Micron Technologies Oral Bioavailability of Poorly Soluble particle size reduction services for oral Drugs bioavailability enhancement of poorly Particle size reduction is a conventional, well- soluble small molecules include: proven, and straight forward technology for • Economic Process – Micronization is a high yield improving the oral bioavailability of poorly soluble (>98%), high throughput, non-solvent process small molecules by increasing the surface area resulting in low API (Active Pharmaceutical and hence the dissolution rate of the compound. Ingredient) waste, processing costs, and low It has been used for bioavailability enhancement environmental waste handling and removal of BCS (Biopharmaceutical Classification System) • Heat-Free Process – Due to the high air class IIa, borderline class IIb, and even class IV volumes used during air jet milling, heat small molecules. Air jet micronizers reduce a generation and temperature increase is not drug’s particle size by fluidizing the drug within observed and suitable for thermolabile APIs the chamber resulting in particle to particle impaction at high velocities until it reaches a • Scalable Process – Micronization enables desired particle size range. A coarse fraction optimization and control of particle size from R&D through commercial scale (D90) of less than 5 microns is recommended for bioavailability enhancement. Micronization • Broad Acceptance – Micronization is well is a high energy process with no heat generation understood by regulatory agencies predominantly resulting in thermodynamically • Advanced Processes – Catalent Micron stable crystalline form of the post micronized drug. Technologies have benefited from years of continual improvement and driven to Catalent Micron Technologies: collaborate with pharmaceutical companies to A Versatile Platform Technology improve capabilities and services catered to for Bioavailability Enhancement the ever-evolving pharmaceutical industry Catalent Micron Technologies compliments • Potent Compounds – Catalent Micron the Catalent Pharma Solutions bioavailability Technologies has capabilities for R&D enhancement platform portfolio by providing feasibility studies to commercialization. clients varied tailored solutions from preclinical to commercialization. Catalent Micron Technologies have successfully provided cGMP particle size

14 case study: increased case study: flexibility to oral bioavailability address customers’ needs of orphan drugs for an oncology drug

With the Orphan Drug Act of 1983, there has been Occasionally, micronization of API alone may not a strong drive in the market to treat rare diseases achieve the desired oral bioavailability enhancement (e.g. Parkinson’s disease, Ebola,…). While there are for optimal therapeutic performance. Catalent many challenges in the orphan drug development Micron Technologies is flexible to address our process, accelerated regulatory approval improves customers’ needs with combination technologies, the feasibility to bring the drug to market faster. including the co-micronization of excipient/API However, working with well-respected CMOs blends. Our experts have worked with various blend who can deliver product in a timely fashion for combinations until the customer was able to find the clinical studies has always been a challenge. a blend with the desired therapeutic performance. Catalent Micron Technologies has worked In addition, Catalent Micron Technologies globally with several pharmaceutical companies to launched cryogenic micronization services in address this need and challenges from preclinical 2014 to address the particle size reduction needs to commercialization for many orphan drugs for thermo-sensitive compounds. Our drive to suffering from poor oral bioavailability. Our provide success for our customers has fostered the strong expertise in particle size reduction and continual improvement and growth over the past efficient manufacturing process have provided 25 years and will continue to do so in the future. many customers quick turnaround time to meet their tight timelines for providing high quality product for their preclinical and clinical studies.

15 of scientists and see their enthusiasm. I think part three the field needs more innovation and new minds The Toolbox of 2025 to take it to the next level. In particular, we need more clinician–scientists in our ranks to help translate technologies for the clinic. Previously, in our series – “Connecting the Dots in Drug Delivery” – we examined the current Broad support from the pharma industry is status of drug delivery. We saw how today’s new essential to bridge the gap between academia therapeutics pose tough challenges for formulation and industry, and speed up commercialization. scientists, and how companies are tackling those To that end, the Catalent Applied Drug Delivery challenges with a range of tools, from micronization Institute is reaching out to the broader scientific to hot melt extrusion. But what techniques will community, as well as the younger generation be in the toolbox 10 years from now? We speak with workshops and academic prizes. to academic and industry experts to find out. How Did You Get Into the Field? on target I was really in the right place at the right time. With Hamid Ghandehari, I completed my undergraduate degree at the Professor at University of University of Utah in the late 1980s and stayed on Utah, Director of Utah for my PhD in the early 1990s. At that time, the Center for Nanomedicine university had some of the pioneers in drug delivery, and member of Catalent Applied Drug Delivery including my PhD mentor Jindrich Kopecek – one Institute Advisory Boards of the world leaders in polymer therapeutics. I was inspired to continue this great work. What do you To deliver the drug to the right site at the right time think will be the is so important – it really impacts on patient’s lives most important by reducing side effects and improving efficacy. future trends in drug delivery? For one thing, we are going to continue to see What Are You Working on Right Now? the approval of targeted drug delivery systems, A lot of drugs, such as cancer chemotherapies, are including polymeric systems. There are several fabulous at what they do, but have devastating micellar polymer structures that are in various off-target side effects, so can only be used in small stages of clinical trials, and I expect to see doses – or not at all. We aim to confine the delivery those in the clinic in the next few years. of those drugs to the target tissue, for example cancer cells, by using novel drug delivery systems. In the next decade, we are going to see local triggered-release drug delivery. Here, the drug In our lab, we tailor-make recombinant polymers delivery system is delivered to the target site for gene delivery applications. These polymers are and activated by local or external triggers to made using genetic engineering, which gives us enhance the delivery of the active agent. a high degree of control over the sequence and length. In particular, we use them to deliver genes What is Needed to Drive to accessible head and neck solid tumors. The Continued Innovation? particular polymers we use are made of silk and elastin blocks. They are liquid at room temperature Two decades ago this was a very specialty field, and when mixed with viral gene carriers and but now a lot more research is going on. It is very injected they solidify at body temperature and satisfying to work with a younger generation improve localization and duration of gene transfer.

16 In another project, we use local hyperthermia to target delivery of polymer–drug conjugates to dissolving delivery prostate tumors. We use plasmonic photothermal challenges therapy or other means of hyperthermia, such With Rosie McLaughlin, as ultrasound, to maximize the delivery of the Director, Scientific Affairs at polymeric systems to the site of action. This Catalent Pharma Solutions improves blood flow in the tumor and enhances cellular uptake of the cytotoxic agents. What’s the focus of your work? Where Have You Seen the Right now, I’m looking at Most Promising Results? innovative ways to expand There are a couple of areas where I think we have on the Zydis‰ drug delivery had particular impact. By using recombinant platform – a freeze-dried, techniques we have been able to sustain the orally dispersible tablet. We start with a dispersion expression of adenoviral systems locally in head of active pharmaceutical ingredient (API) in the and neck tumors. More recently, we have developed formulation matrix, and freeze-dry it to create a recombinant polymer systems that are responsive very porous, lightweight product, which dissolves to local enzymes, such as matrix metalloproteinases, in the mouth in around three seconds and without that are overexpressed in tumors. This allows gene the need for water. The drug can enter the body therapy to be delivered primarily in the tumor. either by standard gastrointestinal absorption or through the oral mucosa, depending on the In the area of targeted delivery using API. The sublingual area (under the tongue) is hyperthermia, we have shown that by carefully highly vascularized so certain APIs can be quickly controlling local temperature we can magnify transported through the oral mucosa and into the the so-called enhanced permeability and bloodstream, bypassing first-pass metabolism retention (EPR) effect, whereby certain sizes of and potentially improving bioavailability. molecules tend to accumulate in tumor cells. What are your most exciting projects at the moment? There’s always something new and exciting! The best thing is when we push the boundaries. At the moment I’m working on two new developments - one is a new API coating process developed exclusively for Catalent by the New Jersey Institute of Technology. The process involves a Resonance Acoustic Mixer, which uses sound energy to generate vibrations for dry-coating very fine particles, increasing drug loading and improving taste masking. Previously, we haven’t been able to use coated APIs in Zydis, so this expands the number of drugs we can develop in the platform. We’ve also been doing proof-of-concept work on oral delivery of vaccines, starting with influenza.

17 An oral flu vaccine could be quite a breakthrough… We’re using influenza in our proof-of-concept preclinical trials because it is so well characterized, but we hope the technology may be applicable to a whole range of vaccines. The availability of a noninjectable, room temperature-stable vaccine delivery system could certainly transform the whole field. This is particularly true of the developing world, where the logistics of cold chain storage are a big challenge, causing significant wastage, and where trained healthcare workers may not always be available to administer injections.

What approach are you taking? Vaccines, except for some live attenuated viruses like polio, are generally destroyed in the gastrointestinal tract if swallowed. Using Zydis Bio, we’re administering the vaccine sublingually, to bypass the acidic environment of the stomach and enzymes of the digestive system and go directly into the bloodstream via the oral mucosa.

Proteins, being large molecules, have less tendency to cross the oral mucosa. But we know it is possible because we have already used Zydis Bio to deliver an allergy vaccine. The active ingredient is a protein extract, which is delivered sublingually and induces tolerance in hay fever sufferers. Our work on oral vaccines is a natural continuation – the difference is that we’re now trying to trigger an immune response, rather than immune tolerance. The results so far have been encouraging, although it may be several years before we see clinical trials.

What challenges will tomorrow’s drug development scientists face? Bioavailability challenges will continue to be a problem for drug manufacturers. As more and more biologics become available, the Holy Grail is to find new routes of administration to improve the patient experience – whether that’s oral, inhalation or microneedle delivery.

18 Catalent supports 6 of the top 10 largest technology profile pharmaceutical companies with Zydis fast dissolve Zydis‰ Fast Dissolve formulations. Seventeen distinct therapeutic areas are covered in both Rx and OTC products, with Technology more than 1 billion tablets manufactured each year.

Zydis Fast Dissolve Solutions The Challenge: Finding Convenient Meet Dosing Challenges Dosage Forms to Improve Patient Compliance Catalent’s Zydis best-in-class family of fastdissolve technologies can satisfy a Difficulties in ensuring patient compliance with range of dosing requirements: drug dosage regimes may not always be the • Zydis ODT is a unique, freeze-dried oral solid fault of the patient. For example, many patients dosage form, providing almost instant oral suffer difficulties in swallowing, particularly those dispersion, typically in less than 3 seconds in aging and pediatric populations. Psychiatric illnesses are often linked to poor compliance and • Zydis Ultra has a functional coating patients may ‘cheek’ medications, causing issues that provides greater tastemasking for caregivers and the potential for patient relapse. capabilities and allows increased doses Related to patient compliance is speed-of-onset • Zydis Granules enable the highest dose and of treatments, for example, some conditions, such provides more tastemasking options as migraines, require a rapid onset of action (the • Zydis Bio enables dosing of large molecules, symptoms of migraines, however, often include including allergens, peptides and viral nausea, which makes taking normal solid oral doses vaccines, in fast dissolve formulations. difficult.). Convenient dosage forms improve patient compliance, while also providing the means to treat Benefits of Zydis fast dissolve technology include: acute conditions, such as pain, cough and cold, • Almost instantaneous dispersion allergy, gastric discomfort and more, that require in the mouth, allowing for potential immediate relief in out-of-home environments. buccal or sublingual absorption Zydis Fast Dissolve Technology: • Improved compliance in many therapeutic markets A Convenient Dosing Solution • High suitability for treating children, the elderly, Catalent Pharma Solutions, the leading global pets, and anyone having trouble swallowing provider of advanced delivery technologies • Almost instant dosing without the need for water and development solutions for drugs, biologics, consumer health products, vitamins, and minerals, • More efficient delivery offers Zydis fast dissolve technology which provides • Possible faster onset of action and a unique, freeze-dried ,solid, orally disintegrating reduction of metabolites tablet (ODT) dosage form that disperses almost • High suitability for certain indications instantly in the mouth with no water required. With more than 20 products launched in 50 countries, • High suitability for treating pain and Zydis is the leading best-in-class ODT technology. other conditions where rapid dosing Catalent’s Zydis team offers feasibility evaluations and absorption are required, including as well as support across the entire lifecycle of allergies and travel-related illnesses products to provide solutions that can have the • The possibility of reduced and potential to enhance pharmacokinetics through less frequent dosage pregastric absorption, improve patient compliance, • Enhanced marketing appeal or provide a marketing advantage for a valued brand. 19 • Consumer satisfaction, as Zydis fast • Protection from counterfeiting dissolve formulations are easier to • Provision of tamper evidence. swallow and faster-acting

case study: zydis bio technology and grazax®: revolutionizing allergy therapy

ALK-Abelló is a global research-driven pharmaceutical company that focuses on the prevention,

diagnosis and treatment of allergies. Before ALK-Abelló partnered with Catalent, marketed allergen immunotherapies were delivered by injection or drops, resulting in a limited patient population and reduced patient adherence. Catalent worked with ALK-Abelló to apply Zydis fast dissolve technology to one of these therapies, Grazax‰, to bring a vastly superior product to market. The overall result was a marked improvement in patient tolerability, preference, product stability and compliance. This new technology has allowed ALK-Abelló to deliver on its promise to improve the quality of life for allergy patients.

ALK-Abelló approached Catalent with challenges similar to others in the industry. Allergy injection- based therapy had been essentially unchanged for the past 100 years. These therapies required lengthy patient-specific dose-titration phases and required patients to go to specialist clinics for monthly subcutaneous injections, which contributed significantly to patient time spent as well as out- of-pocket medical cost. Additionally, patients needed to undergo successful completion of therapy for 3 years (3 seasons, for seasonal allergies) if they were to expect long-term protection. Potential patients were subject to stringent criteria for specialist therapies, which limited treatment to only the most severe cases. Finally, potentially dangerous systemic adverse events had occurred with this class of therapeutics, requiring risk/benefit assessments and availability of rescue facilities.

Catalent scientists partnered with ALK-Abelló to develop a superior alternative drug delivery solution using Zydis Bio technology. This unique technology not only enables administration by sublingual doses, but also offers a number of unique benefits that differentiate it from other orally-disintegrating tablet technologies on the market, including fast dispersion (< 3 seconds) and smooth mouth feel .

As a result of its partnership with Catalent, ALK-Abelló was able to launch Grazax, the first patient-friendly allergen immunotherapy using Zydis Bio technology. • Patients can administer a daily sublingual dose themselves, which has led to increased patient adherence. • The reduction in clinical visits and elimination of complex dose titrations has further improved the patient experience. • ALK-Abelló was also able to improve its market position by increasing the patient reach of this immunotherapy to pediatrics and primary care patients.

The US Biologics Application was approved in 2014 and Grastek‰ is now marketed in the US, EU and Canada. Many additional allergens for allergic rhinitis and asthma are currently in development using Zydis Bio technology.

20 part four What are your main research areas? My group is focused on overcoming the Delivering Change barriers that limit macromolecular uptake of pharmaceuticals. The body’s barriers have a series of endogenous mechanisms that Alternative delivery routes for large- prevent the casual uptake of large molecules to molecule drugs are sorely needed – could protect us from environmental intoxication. By a new consortium lead the way? looking at how certain pathogens successfully overcome these endogenous mechanisms and Welcome to the fourth and final part of our series, enter the body, my group hopes to find ways to “Connecting the Dots in Drug Delivery”. So far, we manipulate them for macromolecule delivery. have examined the challenges facing formulation scientists, explored the options for improving bioavailability, and caught a glimpse of the toolbox What did you set out to of 2025. A common thread has been the need achieve with the NMDC? for greater collaboration between industry and When I was first contacted by Catalent Applied academic partners. Here, we take a closer look at Drug Delivery Institute, I immediately thought it an example of this collaboration in action – the was a very interesting approach that could do a Non-invasive Macromolecule Delivery Consortium lot to help advance the field. We decided early on (NMDC), spearheaded by the Catalent Applied that a key goal was to get industry and academics Drug Delivery Institute. To find out more, we working together. Having worked in both sectors, I spoke with two key figures in the consortium. know that we need academics that think outside of the box and who can bring new ideas to the better biologics table, but just as importantly, we need industry Randy Mrsny is a Professor people to assess whether those ideas are practical at The University of Bath, and to mold them into something that can be and Chair of the NMDC. successfully developed. The goal of the consortium is to get this ‘golden dialogue’ to happen. How did you get into drug No easy task… delivery? Over the years, big pharma companies have become more cautious about claims made regarding My training ‘breakthroughs’ in non-invasive macromolecular drug was all over the delivery - they have seen a lot of snake oil in the map – I studied past. By getting open dialogue going at a very early biochemistry and biophysics, and embarked on stage to address the potential and the limitations of the path to a medical degree, but then decided to various technologies under development, we hope to get my PhD in anatomy and cell biology instead, avoid anyone getting burned. This dialogue has so far before returning to biophysics for my post doc. included a series of conferences and presentations, I then put my multidisciplinary skills to good and the formation of four working groups in oral, use in the pharmaceutical industry, optimizing transdermal, respiratory and ocular delivery. biopharmaceutical drug delivery systems for ALZA and Genentech. After that, I got involved with several biotech start-ups, before returning What are some of the most exciting to academia in the UK, first at Cardiff University projects underway in this area? and now the University of Bath, to search for answers to more fundamental questions. There are some very interesting projects going on in ocular delivery. In recent years, advances in ocular delivery have really changed people’s lives – before, 21 conditions like macular degeneration invariably led to blindness, but now we have drugs that can stop that breathing it in progression and even reverse it. However, current Craig Davies-Cutting is treatments typically require an injection into the eye Director of R&D for Inhaled every month, which is obviously not much fun for the Products & Technologies at patient. Researchers are now looking at controlled- Catalent and Co-Chair of the release systems and other technologies to take that Pulmonary and Nasal Delivery frequency down to once every 6 months or so. working group of the NMDC.

Are you optimistic about the How did you get future for noninvasive delivery? involved with The pharma industry is traditionally cautious about the NMDC? taking a new path. They feel most confident using Since completing my PhD on metered-dose inhalers, established models and strategies to bring new I’ve spent my career working with inhaled therapies. products to market. Drug delivery approaches Over the years, there has been a lot of interest that might overcome endogenous barriers of from pharma in the lung or nasal cavity as a portal the body, however, are novel and thus there is for the delivery of macromolecules, and since no established regulatory path for developing joining Catalent I have been involved in a few early these approaches. But from my conversations development programs involving large-molecule with the FDA, I understand that regulators are drugs. When the Catalent Institute set up the very interested in and supportive of new drug NMDC, I was in a good position to get involved in delivery techniques, which will be encouraging to the Pulmonary and Nasal Delivery working group. companies. We want to bring representatives of regulators into the NMDC to get these conversations What makes inhalation an attractive out in the open. Getting the regulatory bodies involved on board will be crucial; fortunately, delivery route for biopharma? the leadership within these agencies appears The lungs represent a very large surface area for enthusiastic about the added patient value and delivery and so could offer a route for enhanced societal impact that non-invasive macromolecular bioavailability and rapid-onset action. There drug delivery can potentially achieve. are also commercial and regulatory precedents after the approval of two inhalable insulin products – Exubera in 2006 and Afrezza in 2014 – although Exubera was not a commercial success and was later discontinued.

How does the consortium work to advance research? One of the best things about the Institute is that it is agnostic – the goal is to promote dialogue between industrialists and academics to highlight the key challenges within the drug delivery space. To that end, the NMDC held an inaugural meeting last year in San Diego, bringing together industrialists, academics and key opinion leaders,

22 with interests in a wide range of delivery methods for What are the research opportunities macromolecules, from ocular to oral to pulmonary. for inhaled delivery? It was a great meeting that got a lot of the questions out on the table. Since then, the various For the pulmonary and nasal delivery working working groups have pulled together a synopsis group, the most immediate priorities are: of the key attributes and challenges associated • Evaluating excipients for large- molecule with that mode of administration and begun to delivery. There are no established excipients identify opportunities for advanced research. specifically for use with large molecules. • Establishing appropriate clinical biomarkers. • Developing in vitro models to clarify the mechanism behind clearance of large molecules from the lungs.

non-invasive macromolecule consortium working group co-chair

delivery method academic co-chair industry co-chair(s) catalent scientific lead oral Dr. Edith Mathiowitz, Dr. Siddhesh Patil, Takeda Julien Meissonnier, Brown University Executive Board, Catalent Institute pulmonary/nasal Dr. Claus-Michael Lehr, Dr. Ralph Niven, Novartis Dr. Craig Davies-Cutting, University of Saarland Executive Board, Catalent Institute transdermal Dr. Bo Michniak-Kohn, Dr. Steven M. Wick, 3M Dr. Ralph Lipp, Advisory Rutgers University Board, Catalent Institute

ocular Dr. Justin Hanes, Johns Dr. Jim Cunningham, Hopkins University Allergan; Dr. Thierry Nivaggioli, Genentech overall chair Randy Mrsny, University of Bath

23 technology profile OptiGel Bio Technology: An Oral Drug Delivery Solution for Macromolecules ™ OptiGel Bio Technology: OptiGel Bio technology is a lipid-based formulation that incorporates enteric coating and targeted Meeting Formulation and permeation enhancement to increase the Delivery Challenges for bioavailability of macromolecules without absorbing other unwanted toxic molecules, and therefore Macromolecular Drugs potentially enabling oral delivery of macromolecules. Whereas traditional Catalent’s RP Scherer softgel technologies enable improved delivery of BCS The Challenge: Producing Oral Class II and IV drugs, OptiGel Bio is a new softgel Formulations of Macromolecular technology to potentially enable the non-invasive Drugs delivery of biomolecules (BCS Class III drugs).

Macromolecule therapies have traditionally OptiGel Bio is the result of years of research been limited to injectable and infused dose into a non-invasive delivery method for biologic forms, due to a number of challenges that drugs and provides a versatile solution to the limit their bioavailability including: development challenges traditionally associated • Poor absorption due to rigid molecular with the oral delivery of macromolecules. Lipid- geometry and flexibility based drug delivery systems (LBDDS) not only • Permeation limitations with tight junctions overcome the solubility limitations of some and limited transcellular pathways APIs, but often also provide some benefits in modulating the membrane permeability of drugs. • Degradation by proteolytic enzymes of the stomach and lumen When a macromolecule is delivered to the stomach, • Harsh acidic gastric conditions. the API degrades or denatures upon exposure Oral dosing of drugs is preferred by innovators, to the acidic environment (pH 1~3). The enteric health care professionals and patients, as it offers coating of the OptiGel Bio softgel helps the numerous advantages over injectable and infused macromolecule pass the stomach and deliver the dose forms. These advantages include convenience API to the intestine allowing for targeted delivery. and adherence, self-administration and painless dosing, dosing flexibility, access to frequent dosing In the small intestine, the macromolecules cannot to maintain or extend therapeutic efficacy, lower permeate through tight junctions in the intestinal manufacturing and treatment wall due to their size and steric hindrance. They costs, and a more efficient are then vulnerable to further degradation by clinical path. The various pathways. OptiGel Bio technology dissolves challenge, therefore, the macromolecule in a lipid-based formulation is to produce oral in a softgel. The softgel capsule dissolves after formulations of reaching the intestine and only then releases locally poorly soluble high concentrations of permeation enhancers at macromolecular the same time as releasing API. The permeation drugs such as enhancer molecules open up the tight junctions, peptides and biologics allowing the macromolecules to pass through into the bloodstream. After 30 minutes, the tight junctions close again and therefore, absorption of unwanted toxic molecules is avoided.

24 OptiGel Bio technology employs the same well as peptides and some proteins, and Catalent targeted co-delivery of permeation-enhancing is conducting research to further expand its formulations that have been safely applied to application to the more complex delivery challenges already marketed, poorly water soluble drugs, to associated with larger and less stable molecules. the delivery of macromolecules or peptides. Such localized delivery allows for higher transient To learn more, watch a 90-second concentrations of permeation-enhancing excipients video on our website. alongside the active pharmaceutical ingredient. www.catalent.com/optigelbio The technology is applicable to various classes of macromolecules, including oligosaccharides, as

case study: optigel bio technology enables iv to oral therapy conversion

An early-stage biotechnology company had developed a novel macromolecular intravenous (IV) therapy for a thrombolytic post-surgical indication and approached Catalent to enable conversion of the dose form to oral delivery. The aim was to reduce manufacturing costs and improve both patient compliance and the clinical path efficiency.

The macromolecule was soluble, however it had a high molecular weight (>2500 Da), a strong negative charge and a rigid, inflexible geometry which challenged the desired delivery across the walls of the small intestine into the blood.

Catalent’s formulation expertize and OptiGel Bio technology achieved an optimized oral therapy which combined both the desired permeability enhancement and targeted delivery.

A stepwise screening approach utilizing both in vitro and in vivo models was adopted to evaluate formulation candidates to overcome the permeability challenge of the macromolecule. These studies showed that formulations with higher levels of lipid digestion products had enhanced but variable permeability.

Despite the improvements in bioavailability, the pharmacokinetic variability highlighted the need for targeted delivery utilizing an enteric coating. Screening was again undertaken to optimize the coating formulation, percentage of coating, plasticizer, and solvent.

The final formulation was optimized and confirmed by imaging/pharmacokinetic profiling in which iodine-tagged capsules were orally dosed and imaged with PK samples using a canine model. The studies proved that enteric capsule batches were delivered in active form to the small intestine with reduced variability and enhanced bioavailability.

25 more products. better treatments. reliably supplied.™

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Zydis is a registered trademark of Catalent Pharma Solutions

OptiGel, OptiMelt and OptiShell are trademarks of Catalent Pharma Solutions

GRASTEK is a registered trademark of Merck & Co., Inc.

Grazax is a registered trademark of ALK-Abelló A/S Corp

SMART is a registered trademark of Xhale, Inc.