Oral Drug Delivery & Advanced Excipients

ORAL DRUG DELIVERY & ADVANCED EXCIPIENTS

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OORALRAL AAprpr 22010.indd010.indd 1 330/4/100/4/10 08:39:4608:39:46 “Oral Drug Delivery & Advanced Excipients” CONTENTS

This edition is one in the ONdrugDelivery series of publications from Frederick Furness Publishing. Each issue focuses on a specific topic within the Introduction field of drug delivery, and is supported by industry Oral Drug Delivery: the Numbers behind leaders in that field. the Business Josef Bossart PhD, Managing Director Full contact information appears alongside each article. Pharmanumbers, LLC 4-6 Contributing companies would be delighted to hear from interested readers directly. Frederick Furness Specialised Techniques for Developing Publishing would also be very pleased to pass on to ODT Dosage Forms authors, or answer as appropriate, any queries you Michelle K. Papp, PhD, Formulation Scientist, might have in relation to this publication or others in Gopi Venkatesh, PhD, R&D Director, and the series. Troy Harmon, MS, MBA, Vice-President

Business Development SUBSCRIPTIONS: To arrange your FREE subscription (pdf or print) to Eurand, Inc 8-10 ONdrugDelivery, contact: Guy Furness, Publisher Company Profile T: +44 (0) 1273 78 24 24 Mayne Pharma International 12-13 E: [email protected]

Advances in Solid Dose Oral Drug Delivery SPONSORSHIP/ADVERTISING: To find out more about how your company can become Gurvinder Singh Rekhi, PhD, Senior Director, a participant in ONdrugDelivery, contact: Oral Controlled Release Product Development Guy Furness, Publisher Elan Drug Technologies 14-18 T: +44 (0) 1273 78 24 24 E: [email protected] The Right Formulation – and how to get there Gita Shankar, PhD, Director of Formulations R&D, MAILING ADDRESS: Pharmaceutical Sciences Frederick Furness Publishing SRI International 21-24 48, Albany Villas, Hove, East Sussex, BN3 2RW United Kingdom SoluBest‘s Solumer™ Solubilising Platform: PRODUCTION/DESIGN: an “all in one” technology Mark Frost Amir Zalcenstein, PhD, MBA, Senior Director, www.frostmark.co.uk Business Development & Planning SoluBest, Ltd 27-30 “Oral Drug Delivery & Advanced Excipients” is published by Frederick Furness Publishing. Orally Disintegrating Extended Release (ODT-ER) Dosage Forms Copyright © 2010 Frederick Furness Publishing. Woubalem Birmachu, PhD, Senior Manager All rights reserved of New Technology CIMA Labs, Inc 33-34

The views and opinions expressed in this issue are those of the authors. Due care has been used in producing this publication, but the publisher makes no claim that it is free of error. Nor does the publisher acceptliability for the consequences of any decision or action taken (or not taken) as a result of any information contained in this publication.

OORALRAL AAprpr 22010.indd010.indd 2 330/4/100/4/10 08:39:5008:39:50 OORALRAL AAprpr 22010.indd010.indd 3 330/4/100/4/10 08:39:5108:39:51 INTRODUCTION

ORAL DRUG DELIVERY: THE NUMBERS BEHIND THE BUSINESS

For the pharmaceutical industry, extended pharmaceutical active. The acronym (DDEP) lion sales in 2006; Toprol XL (metoprolol; release oral dosage forms provide multiple refers to these drug delivery enhanced and/ AstraZeneca) with $1.5 billion sales in 2006; commercial benefits. Reduced dosing fre- or enabled products. Our definition will not and Adderall XR (mixed amphetamines; Shire) quency improves compliance, which translates include commonly available formulations con- which had $1.4 billion of sales in 2008. into higher unit sales. And better therapeu- sidered to be part of a standard toolbox. This It is worth noting that the majority of these tic outcomes due to improved efficacy and includes simple enteric coated products such as products address chronic central nervous system improved tolerability can lead to fewer medi- proton pump inhibitors. Extended release psue- indications. All of these top selling oral DDEPs cation switches and greater physician loyalty. doephedrine, ephedrine and antihistamines are are reformulations of previously approved, and New formulations can also extend market also excluded because of the formulation tool- very successful, immediate-release products. exclusivity. box nature of the technologies. All other oral The top products in terms of peak annual sales With oral drug delivery becoming an sustained release and quick dissolve technol- are all reformulations of previously approved and increasingly mature technology it’s worth ogy products are included. marketed actives. Only when you get to the 29th looking at some of the numbers and parameters product, Invega (paliperidone; J&J), do you find that impact the business of oral drug delivery. ORAL DRUG DELIVERY a new molecular oral DDEP. Sales of Invega What was once a novel and high value tech- PRODUCTS SALES were reported as $246 million in 2008. nology has increasingly become a commodity The top selling non-SR oral DDEP was platform. Is there still value to be found in Table 1 provides a summary of the annual Claritin RediTabs (loratidine; Schering-Plough/ developing novel oral drug delivery platforms? sales of oral drug delivery products in the US Merck) at the 17th position with sales of $383 Perhaps the numbers can give us a sense of the for the years 2000 to 2008. This list is limited million in 2002. Other notable ODT formulation past, present and future. to prescription oral drug delivery products (oral products include: Zofran ODT (ondansetron; DDEPs) that were among the Top 200 Retail GlaxoSmithKline) with sales of $214 million BACKGROUND Products in terms of sales. These Top 200 prod- in 2005; and Maxalt MLT (rizatriptan; Merck ucts accounted for about 85% of all retail sales & Co) with sales of $192 million in 2008. The numbers in this article focus on the US in the US. Tussionex (hydrocodone/chlorpheniramine; market. The US represents the largest global Overall, oral DDEPs accounted for between UCB), a liquid SR product for the treatment of market controlled by a single, remarkably six and 11% of the sales of all pharmaceutical cough, was in at the 28th position with sales of transparent, regulatory process. This permits products in the Top 200. The sharp increase in $247 million in 2008. trends and values to be more easily analysed. sales of oral DDEPs between 2000 and 2003 is accounted for by the strong ORAL DRUG DELIVERY PRODUCT growth of new sustained release DEVELOPMENT PARAMETERS “COMPANIES PROVIDING ORAL formulations of antidepressant, DRUG DELIVERY TECHNOLOGIES incontinence and ADHD medi- What about the development parameters cations. Oral sustained-release associated with oral DDEP? How long does it WILL NEED TO EVOLVE THEIR (SR) product sales accounted for take to develop these formulations? What are OFFERINGS AND BENEFITS IF THEY 96.6% of all oral DDEP sales, the expected success rates? with ODT formulations account- The figures from the recent Bionumbers HOPE TO AVOID COMPETING IN A ing for 2.2% and Liquid SR the report, DD09 – Drug Delivery Product remaining 1.2%. Success Rates, Development Times, Costs and COMMODITY MARKET” The top-selling oral DDEPs Marketing Exclusivity, provide a good idea of are all SR formulations with development parameters for oral DDEP. The And what happens in the US doesn’t just stay Effexor XR (venlafaxine; Wyeth/Pfizer) hold- report looked at DDEP developed and approved in the US; products and ideas often move over- ing the number one spot with peak sales of over the last 13 years in the US. These numbers seas. While there are great oral drug delivery almost $2.7 billion in 2008. The second-place should be considered optimistic; products devel- ideas coming from Europe and Asia, compa- product was OxyContin (oxycodone; Purdue) oped and approved in the last few years require nies almost always look to the US as the most with reported sales of $2.5 billion in 2008. longer development times and have lower suc- important market. Other top products included: Wellbutrin SR cess rates. The report provides detailed guidance We will define “drug delivery” for the (bupropion; GlaxoSmithKline), which had sales on these trends. purpose of this article as a formulation technol- of $1.7 billion in 2003; Wellbutrin XL (bupro- For the period 1996 to 2008, it has taken ogy that enables and/or enhances the use of a pion; Biovail/GlaxoSmithKline), with $1.7 bil- on average 5.8 years to move a DDEP through

OORALRAL AAprpr 22010.indd010.indd 4 330/4/100/4/10 08:39:5208:39:52 clinical development and approval. This is In the marketplace this means DDEPs enjoy The third approach to securing exclusivity exclusive of any earlier formulation or preclini- market exclusivity from generics for the longer involves developing novel delivery systems cal activities. The average clinical development of the two FDA exclusivity periods, or any pat- that cannot be duplicated. This is difficult success rate for this period is 34% (see table 2). ent protection existing for the pharmaceutical with oral drug delivery systems. As is the These figures now stand close to 6.2 years and active. But this does not prevent the introduc- case within the electronic products market 24% respectively. tion of functionally equivalent DDEPs where (computers, smart phones, televisions), once The corresponding 1996 to 2008 average there are numerous technologies available and a company introduces a new technology com- development time for oral DDEPs is 4.9 years, there is no parent molecule patent protection. petitors are quick to offer a comparable tech- with an average of 2.7 years for ODT formula- In the generic scenario a good example nology that does not infringe the originator tions and 5.6 years for oral SR products. These of the three year exclusivity period is seen company patents. can be compared with the 5.8 year average noted in the previous paragraph (see table 2). Year Top 200 Product Top 200 Oral Drug Proportion of Oral It is reasonable to expect that these times have Sales (US$ billions) Delivery Product Drug Delivery increased by at least 10% in the past few years. Sales (US$ billions) Products (%) The overall development and approval suc- 2000 90.0 5.5 6.1% cess rate for oral DDEPs is 43%, with a 47% success rate for oral SR DDEPs (table 2). This 2001 103.2 7.3 7.1% is about a third higher than the overall rate for 2002 111.0 9.9 9.0% DDEPs (34%). Current success rates for oral 2003 117.5 12.2 10.4% DDEPs are probably lower, but most likely 2004 117.3 12.3 10.5% above 33% (1 in 3). It is interesting to speculate why the devel- 2005 119.7 11.6 9.7% opment and approval times for oral DDEPs are 2006 126.4 12.9 10.2% shorter than the average for all DDEPs and why 2007 130.6 13.6 10.1% the success rate is higher. The reason may be 2008 133.2 14.5 10.9% that oral DDEPs are targeted to enhance convenience. SR provides once-a-day dosing versus Source: SDI/Verispan thrice daily, for example. And ODT gives the Table 1: Top 200 Retail Product Sales – US convenience of ‘melt in the mouth’ tablets. These product benefits often require little more with Wellbutrin XL. A once-daily formulation In general one can expect to have no more than demonstrating bioequivalence with cur- of bupropion, this product was developed by than three to five years’ exclusivity with a new rently approved immediate-release products. Biovail and licensed to GlaxoSmithKline. With oral drug delivery product unless one also has Even if efficacy endpoints are required, the the underlying active having lost its patent patent protection on the underlying pharma- development program is often quite simple. And protection long ago, the first generics appeared ceutical active, has defined a unique product if the drug delivery platform is validated, the a little over three years after the approval of profile, or has a unique technology. regulatory review period can be short. Wellbutrin XL, despite Biovail having issued patents that extended through 2018. FUTURE OF ORAL DRUG DELIVERY MARKET EXCLUSIVITY In the functional-equivalent scenario, there PRODUCTS are two approved oral SR formulations of The attractive development parameters asso- Tramadol, each of which was approved on the There remains an important therapeutic role ciated with oral DDEPs are offset to some basis of its own technologies and studies. for sustained-release and quick-dissolve drug extent by the relatively short market exclusiv- There are at least three strategies for secur- delivery products. Unfortunately commercial ity periods for these products. The US FDA ing extended market exclusivity with oral drug benefits are more limited than has been seen provides regulatory exclusivity of three or five delivery products. The first, as noted earlier, in the past with billion dollar products like years depending on whether a product incor- relates to having a patent on the underlying Procardia XL, OxyContin, Wellbutrin XL and porates a previously approved active (three pharmaceutical active. This is often the basis Effexor XR. Product exclusivity is limited and years) or a new molecular entity (five years). for the exclusivity enjoyed by big pharma’s pricing flexibility will be limited. This regulatory exclusivity is with regard to products and for which oral drug delivery for- Nonetheless there remain pressing oral deliv- generic products approved solely on the basis mulations represent a lifecycle strategy. ery needs that can be exploited therapeutically of bioequivalence data (the ANDA process) The second strategy involves securing patent and commercially. The first of these, sustained and exclusivity runs in parallel with any patent protection on non technology-related performance release liquids, is poorly served by current exclusivity the product may possess. parameters of the DDEPs; for example, drug plas- technologies. While products based on UCB’s In the case of products incorporating previ- ma levels. This strategy has been used effectively Pennkinetic delivery system have been avail- ously approved actives, the three year exclusiv- by Purdue Pharma with their OxyContin product able for more than two decades, the delivery ity provides no protection from functionally line. First approved in 1995, this product enjoys technology is crude and unlikely to meet current equivalent DDEPs. These functionally equiva- market exclusivity until at least 2011, solely on the FDA standards for new products. However, the lent DDEPs incorporate the same active, but use basis of patents related to serum levels of the active. promise of new liquid SR platforms is starting a non-patent infringing drug delivery system. Attempts to invalidate these patents, while initially to be realised with the recent approval of an These products are approved on the basis on successful, have failed and OxyContin continues to extended release liquid formulation of clonidine their own clinical data. generate sales of more than $2 billion annually. by Tris Pharma.

OORALRAL AAprpr 22010.indd010.indd 5 330/4/100/4/10 08:39:5208:39:52 principles that make today’s computer or Average Development Product Type Average Success Rate Time* (years) mobile phone obsolete within a couple of years applies to drug delivery technologies. DDEP 5.8 34% While these technologies are still useful and Oral DDEP 4.9 43% pharmaceutically valuable, they do not sup- Oral SR DDEP 5.6 47% port the attractive margins they used to com- ODT DDEP 2.7 data not available mand even a few years ago. An important test for the drug delivery * time from initiation of clinical development to approval industry will be whether it can rise to the chal- Source: Bionumbers lenge of true innovation. The numbers suggest Table 2: Comparison of average development times and success rates for DDEPs, oral drug delivery remains as relevant today as it Oral DDEPs, Oral SR DDEPs and ODT DDEPs for the period 1996-2008. did a decade ago. Who will lead the way to new technologies and products? The most exciting oral drug delivery oppor- Additional abuse-deterrent strategies are tunity may be in the area of abuse deterrent in development ranging from the use of nar- Josef Bossart PhD formulations for opioids and stimulants. There cotic antagonists, to the inclusion of aversive Managing Director, Pharmanumbers, LLC exists in the US a significant regulatory interest agents, to the use of physical methods to make ([email protected]) in reducing the levels of misuse and abuse of crushing and solubilisation difficult. If these these products. technologies can match the efficacy and safety Embeda, from King Pharmaceuticals, is the of current opioids and stimulants, but with lit- first of the abuse deterrent formulations to be tle abuse potential, they will find significant The report, DD09 - Drug Delivery approved by the FDA. An oral SR morphine market acceptance. Product Success Rates, Development combined with naltrexone, Embeda provides Times, Costs and Marketing Exclusivity, sustained-release analgesia when taken orally as REFLECTIONS is available from Bionumbers. directed. But when crushed, the narcotic antago- Contact: nist naltrexone is released antagonising both pain Companies providing oral drug delivery T: +1 (512) 535-3613 relief and opioid high. This should limit success- technologies will need to evolve their offer- E: [email protected] ful attempts to get a rapid high by crushing and ings and benefits if they hope to avoid com- www.bionumbers.com swallowing, injecting or insufflating the product. peting in a commodity market. The same

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OORALRAL AAprpr 22010.indd010.indd 6 330/4/100/4/10 08:39:5208:39:52 Making good drugs better GeoclockTM Chronotherapy Focused Real-Time Oral Drug Delivery A new clinically validated oral drug delivery technology which allows, with a high degree of precision, the timed delivery of drugs using press-coating technology.

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OORALRAL AAprpr 22010.indd010.indd 7 330/4/100/4/10 08:39:5208:39:52 SPECIALISED TECHNIQUES FOR DEVELOPING ODT DOSAGE FORMS

Orally disintegrating tablets (ODTs) are unique dosage forms that facilitate improved patient convenience and compliance. However, they also come with unique formulation and manufacturing challenges, requiring specialised expertise, in order to create a product that appeals to customers while improving on disintegration and dissolution rates. Eurand employs a proprietary external lubrication tabletting system to manufacture its AdvaTab® ODT. This is often used in combination with its Microcaps® technology for masking the bitter drug taste and rapidly dispersing microgranule technology. In this article, Dr Michelle Papp, Formulation Scientist, Dr Gopi Venkatesh, R&D Director, and Troy Harmon, Vice-President Business Development, all of Eurand, describe how, by removing lubricants from within the tablet Michelle K. Papp, PhD Formulation Scientist formulation, an AdvaTab ODT provides important patient advantages through increased dissolution and disintegration rates. External lubrication also creates manufacturing advantages for partners, such as decreased overall production time and harder, more robust tablets that can be packaged in bottles or blisters. Eurand’s recent commercialised AdvaTab products include Lamictal® ODT with GlaxoSmithKline and Unisom® SleepMelts with Chattem.

Tablets are still the pharmaceutical dosage form disintegrating tablets, which are required to of choice for oral administration. During their disintegrate within 30 seconds when tested manufacture, an extensive amount of friction for DT by United States Pharmacopeia (USP) between the tablet and the surfaces of the die Disintegration Test Method <701>. Gopi Venkatesh, PhD and punch is generated as the tablet is ejected. To reduce the negative aspects, a new R&D Director This can impart considerable amounts of strain approach has been developed that localises and shear to a tablet resulting in tablet defects the application of lubricants to the interface such as sticking, capping and lamination.1-3 between tablet and tooling. This method is The tablet defects arising as a consequence known as external lubrication. of these adhesion and frictional forces are There are different techniques for applying generally reduced by the incorporation of a an external lubricant during tableting. Manual hydrophobic lubricant such as magnesium stea- application methods, such as gentle blending rate, stearic acid, or sodium stearyl fumarate of the tooling with the powdered lubricant4 or (Pruv®) in the final blending step prior to tablet- swabbing the lubricant in suspension onto the Troy Harmon, MS, MBA ing. However, this internal lubrication process punches and die wall5, have long been known Vice President Business Development imparts a hydrophobic film on the surface of the and are still used in compaction studies utilis- powdered or granulated formulation which can ing a single station tablet press or a compaction Contact: negatively impact the performance properties of simulator. Although useful for small-scale stud- Dr Michelle Papp Formulation Scientist the resultant tablets. ies, this method is not practical for production T: +1 937 415 0433 Depending on the formulation, choice of scale. Therefore, a second automated method F: +1 937 898 9529 lubricant and its concentration, this method involves the direct application of lubricant E: [email protected] may result in a longer disintegration time powders to tooling on rotary presses. Recent (DT) and slower dissolution due to reduced demonstrations5-16 highlighting the advantages Eurand, Inc water penetration rate, as well as lower tab- of external lubrication by automated systems 845 Center Drive let strengths due to decreased interparticu- have stimulated interest in its use and a variety Vandalia, OH 45377 United States late bonding. These negative effects from of equipment is available. internally incorporated lubricants can become Kyowa Hakko Kogyo (Tokyo, Japan) has www.eurand.com problematic, especially in the case of orally developed a powder material spraying device

OORALRAL AAprpr 22010.indd010.indd 8 330/4/100/4/10 08:39:5308:39:53 for use in combination with an industrial-scale decreased dissolution. The use of an external rotary tablet press called the ExLub system. It is lubricant for the tableting of calcium hydrogen extensively used by both Kyowa Hakko Kogyo phosphate/starch granules showed a 20-second and Eurand for the development and commer- faster dissolution compared with the same gran- cialisation of several ODT products. ules blended with magnesium stearate.6 A second system, the Fette Tablet Press- Otsuka et al reported the immediate release PKB-1 (Press-Kammer-Beshichtung) external of trypsin (100% in approximately seven min- lubrication system manufactured by Fette utes) when tableted using external lubrication, GmbH (Schwarzenbek, Gemany), was first compared with less than 20% release of the described by Gruber et al.6 Currently, PKB- drug in 20 minutes when an internal lubricant 1, -2, and -3 external lubrication systems are was used. In this case, the disintegration of available from Fette and magnesium stearate the external lubricated tablets was immediate and sodium stearyl fumarate as external lubri- whereas the internally lubricated tablets failed cants on this system have been evaluated.6,10 to disintegrate.4 This was attributed to the exter- A Kikusui (Yokohama, Japan) tablet press nal lubricant method producing a tablet with equipped with an external lubrication system, Figure 1: Schematic of external higher porosity and increased wettablity. ELS-P1 or P214,15,16 has also been described in the lubrication system showing lubricant The advantage of increased dissolution and application to tablet tooling system literature for the external application of magnesium disintegration without impacting negatively on surface stearate. Other external lubrication systems17,18,19 tablet strength makes external lubrication an exist, such as Die Wall Lubrication System and unlubricated surfaces needed for the formation ideal choice for ODT development. Figure 2 Punch Face Lubrication System offered by GEA of strong intermolecular bonds. provides a summary of ODT products manu- Pharma Systems (Courtoy; Halle, Belgium) and With external lubrication, lubricants are not factured by Eurand for commercialisation or to Lubrication System offered by Sejong Pharmatech coating the particles to be compressed, instead support phase III clinical development. Co Limited (Incheon, South Korea), which uses a the lubricant is directed to the tooling. Therefore All of these products take advantage of US FDA-approved edible oil as the lubricant. the generation of new surfaces is not neces- the benefits provided by utilising external However these are not described in the literature. sary. External lubrication methods require less lubrication in their manufacture. For example, Bayer Aktiengesellschaft (Leverkusen, Germany) force to produce tablets of comparable strength, diphenhydramine HCl, an antihistamine, the has an approved US patent (US6,079,968) for an in contrast to those formulated with internal active ingredient in the OTC brand product, external lubrication system. lubricants.4,5 In some cases, tablets are 10-30% Unisom® is indicated to induce sleep, typically The above external lubrication systems stronger at comparable compression forces taken at bedtime. The ODT product comprising involve the spraying of the lubricant by an air when external lubrication is employed.4 Diffucaps® beads taste-masked using Eurand’s nozzle directly onto a tablet tooling similar to that Surprisingly, the increased tablet strengths Microcaps® technology, AdvaTab® microgran- represented in figure 1. However, the individual associated with externally lubricated tablets, ules (rapidly dispersing microgranules), shows systems differ in the details of achieving/monitor- compared with internal lubricants, does not superior oral disintegration results as well as ing the lubricant spray rate and its adherence to result in an increased disintegration time nor better taste/flavour results, while providing a the punches and die wall. For example, the robust dosage form. ExLub system has a penetrating aperture Although it is desirable to opti- and a dispersion chamber with a pulsat- mise and control the quantity of the ing vibration air supply to control the lubricant sprayed onto die wall and spray rate precisely. For the ELS-P1 or punch surfaces during the production ELS-P2 the use of the electrostatic charge of such ODTs, Jahn and Steffens, and function on the spray nozzle improves the Yamamura et al, make the following adherence and hence increases the amount observations regarding such: of the lubricant deposited on the punch surfaces and die wall. • Lubricant spray rate is optimised by In all cases, these external lubrication determining the threshold lubricant methods concentrate the lubricant at the concentration on the tablet or the interface between the formulation and spray rate that is characterised by the the stainless steel tooling where friction lowest ejection force observed during is at a maximum. The main advantage is tablet ejection.9 that it leaves the powder surfaces on the • Higher spray rates above the optimised interior of the tablet lubricant free. level had no significant enhancement With traditional dry-blended lubri- but lubricant concentration on the cants, the surface morphology of the tablet continued to increase.9 excipients can become hydrophobic3 • Based on the compaction data for lac- potentially compromising the strength tose, mannitol, sorbitol and pregelati- of the compacts. This necessitates addi- nised starch, a nearly linear depend- tional energy, in the form of higher ency between spray rate and lubricant compaction forces, in order to fracture Figure 2: Summary table of products using Eurand’s (magnesium stearate) concentration lubricated particles to create the clean, AdvaTab® technology of tablet was evident.9

OORALRAL AAprpr 22010.indd010.indd 9 330/4/100/4/10 08:39:5308:39:53 • Tensile strength has been observed to be nearly REFERENCES 12. E. Hayakawa, M. Ohta, H. Morimoto, K. constant, despite the lubricant concentration Morimoto, Y. Watanabe, K. Ito, and S. increased up to ten-fold from 0.12% to 1.27%9 1. G. Moody, M.H. Rubinstein, and R.A. Tokuno. US 6,464,737 B1: “Process for the in contrast with conventional internal lubrica- FitzSimmons. “Tablet lubricants 1: Theory production of tablets”, assigned to Kyowa tion, where variations in the lubricant concen- and modes of action”, Int. J. Pharm., 9 Hakko Kogyo Co. tration or modifications in the blending dynam- (1981) 75-80. 13. Y. Watanabe, K. Hayakawa, and K. ics of the lubricant prior to compression cause 2. T.A. Miller and P. York. “Pharmaceutical Morimoto. US 6,776,361 B1: “Powder significant variations in the resultant tablet ten- tablet lubrication”, Int. J. Pharm., 41 (1988) material spraying device”, assigned to sile strengths, thereby necessitating continued 1-19. Kyowa Hakko Kogyo Co. optimisation whenever the blending dynamics 3. G.K. Bolhuis, C.F. Lerk, H.T. Zijlstra, and 14. H. Takeuchi, S. Nagira, M. Aikkawa, and of the lubricant change due to changes in the A.H. De Boer. “Film formation by magne- H. Yamamoto, Y. Kawashima. “Effect of composition , equipment, or both. sium stearate during mixing and its effect on lubrication on the compaction properties • Evaluation by scanning elecron microscope tableting”, Pharmaceutisch Weekblad, 110 of pharmaceutical excipients as measured (SEM) observation by focused ion beam (1975) 317-325. by die wall pressure”, J. Drug Deliv. Sci. showed the thickness of the magnesium stear- 4. M. Otsuka, M. Sato and Y. Matsuda. Technol., 15 (2005) 177-182 ate layer on the central part of the tablets be “Comparative evaluation tableting compres- 15. S. Bell, M.C. Roy, and J. Nelson. relatively uniform and thinner than at the sion behaviors by methods of internal and “Equivalence determination of magnesium edges for two different spray rates.16 external lubricant addition: Inhibition of stearate levels using the Fette external enzymatic activity of trypsin preparation lubrication system”, Abstract R6263. AAPS As an added benefit, external lubrication has by using external lubricant addition during Annual Meeting and Exposition, Atlanta, been shown to increase the stability of certain the tableting compression process”, AAPS Georgia (2008). APIs, such as those that are incompatible with Pharm. Sci., 3:3 (2001) 1-11. 16. T. Yamamura, T. Ohta, T. Taira, Y. Ogawa, magnesium stearate. Eprazinone hydrochloride 5. E. Sjokvist and C. Nystrom. Y. Sakai, K. Moribe and K. Yamamoto. is one such compound. Compressed tablets of “Physicochemical aspects of drug release. “Effects of automated external lubrication eprazinone hydrochloride with 0.12% external XI. Tableting properties of solid dispersions, on tablet properties and the stability of magnesium stearate had a higher percentage of using Xylitol as carrier material”, Int. J. eprazinone hydrochloride”, Int. J. Pharm., the API remaining after four weeks at 40°C and Pharm., 67 (1991) 139-153. 370 (2009) 1-7. 75% RH compared with the internally lubri- 6. P. Gruber, VI. Glasel, W. Klingelholler and 17. GEA Pharma Systems. “Die Wall cated formulation containing 1.06% magnesium T. Liske. “Direct lubrication of tablet tools, Lubrication System and Punch Face stearate. The lower amount of magnesium stear- a contribution to the optimisation of tablet Lubrication System”, at www.gea-ps.com ate required by the formulation utilising external manufacture”, Drugs Made in Germany, 34 18. Sejong Pharmatech Co. Limited. lubrication resulted in the increased stability of (1991) 24-30. “Lubrication System”, at www.sejong- eprazinone hydrochloride.16 7. T. Laich, and T. Kissel. “Experimental char- trading.com Increased stability of the enzymatic drug acterization of an external lubrication sys- 19. G. Schmitz, H-D Schmitz, P. Kurka, and trypsin has also been reported from an external tem (Presskammerbeschichtung) on rotary J. Maasz. US 6,079,968: “Device for lubrication technique.1 In this case, the lower presses.” Pharm. Ind., 59:3 (1997) 265-272. the controlled spraying of pulverulent compression forces required to produce a tablet 8. J. Hinzpeter, U. Zeuschner, H-J Pierags, lubricants onto punches and dies of of corresponding strength to that of internally P. Luneburg, E. Wittenberg, and U. Arndt, tableting presses”, assigned to Bayer included magnesium stearate resulted in expos- US 5,643,630: “Method and device for Aktiengesellschaft. ing the API to less heat or pressure. As a result, depositing pulverized lubricants or parting 20. G. Venkatesh, N.H. Vyas, M. Gosselin, and less loss of activity of the API was reported. compounds the pressing tools of tablet- J-W Lai. US 2009/0092672 A1: “Orally ing machines”, assigned to Wilhelm Fetti disintegrating tablet compositions of lamot- CONCLUSION GmbH rigine”, assigned to Eurand, Inc. 9. T Jahn and KJ Steffens. “Press chamber 21. G. Venkatesh, J-W Lai, P. Percel, and C. Although the advantage of a stronger tablet coating as external lubrication for high Kramer. US 2009/0155360 A1: “Orally with faster dissolution and disintegration times speed roatary presses: Lubrication spray disintegrating tablets comprising diphenhy- might not be obvious for a conventional tablet, it rate optimization”, Drug Dev. Ind. Pharm., dramine”, assigned to Eurand, Inc. can provide a critical advantage in the develop- 31 (2005) 951-957. 22. G. Venkatesh, J. Clevenger, J-W Lai, and ment of orally disintegrating tablets. Likewise, 10. K. Hoffman, KJ. Steffens and RF. V. Purohit. US 2009/0169620 A1: “Orally utilisation of this technology can eliminate an Lammens. “Comparing Pruv® and mag- disintegrating tablet compositions of additional manufacturing step, decreasing the nesium stearate for external and internal temazepam”, assigned to Eurand, Inc. overall production time. lubrication during rotary tableting”, 23. G. Venkatesh, C. Kramer, J.D. King, and Taken as a whole, external lubrication tech- 6th World Meeting on Pharmaceutics, B.L. Young. US 2009/0202630 A1: “Orally niques can provide many benefits over tradi- Biopharmaceutics and Pharmaceutical disintegrating tablet compositions of tional tablet manufacturing methods that incor- Technology; Barcelona, Spain (2008). ranitidine and methods of manufacture”, porate a lubricant in the blend. 11. K. Morimoto, Y. Watanabe, Y. Sanada, assigned to Eurand, Inc. T. Milwa, and T Masada. US 5,700,492: 24. G. Venkatesh, P.Stevens, J-W Lai. US Editorial support for this article was provided “Rotary type tableting machine with lubri- Utility Application Ser. No. 12/639,496: by Corinth Group Communications, New York, cant spraying means”, assigned to Kyowa “Compositions comprising melperone”, NY, USA. Hakko Kogyo Co. filed on 16 December, 2009.

OORALRAL AAprpr 22010.indd010.indd 1010 330/4/100/4/10 08:39:5408:39:54 OORALRAL AAprpr 22010.indd010.indd 1111 330/4/100/4/10 08:39:5808:39:58 COMPANY PROFILE - MAYNE PHARMA INTERNATIONAL

DRUG DELIVERY SYSTEMS to the outside of a seed core (typically a sugar sphere). This process provides Mayne Pharma International’s drug deliv- a very tight size distribution of pellets. ery systems include: Drug potencies up to 60% are possible.

A leading pharmaceutical organisation, Technology to control drug release For both of the processes above, the desired built on a heritage of 160 years of industry To enable pulsed release; sustained release; drug release profile is achieved by coating excellence, Mayne Pharma International is modified release; and delayed release pro- particles with the appropriate polymer. a technology-driven, drug delivery, contract files (pellet/bead formulations produced development and manufacturing company using extrusion and marumerisation, or SUBA™ for oral and topical pharmaceutical products. spheronisation processes). SUBATM is a novel technology for enhanc- Mayne Pharma International has comprehen- Technology to improve oral bioavailability ing the bioavailability of poorly water solu- sive experience in the solid oral Drug Delivery Particularly for insoluble drugs (SUBA™ ble drugs utilising a solid dispersion of drug System (DDS) market, encompassing develop- technology). in polymers having acidic functional groups. ment and manufacture of these products. Technology to taste mask liquids and tablets SUBATM has been shown to increase the oral The company has: To improve palatability and aid swallowing bioavailability of itraconazole (our lead can- (Cleantaste™ technology). didate) when compared with the innovator • more than 30 years’ experience in suc- product (Sporanox®). cessfully developing DDS products for the TECHNOLOGY TO CONTROL global market DRUG RELEASE CLEANTASTE™ • a dedicated product development facility which meets cGMP standards, and includes Pellet (or bead) technology allows a vari- Cleantaste™ technology allows a polymer pilot-scale plant equipment. This allows a ety of different drug delivery profiles to be coat to be applied to produce particles scale-up pathway from small clinical trial achieved by coating drug and excipient with (25-150 μm diameter) to improve taste. It batches to full commercial manufacture various polymers. The drug cores are gener- is also possible to use this technology to • proven ability to develop and successfully ally spheroidal in shape and have a diameter improve stability or to deliver sustained transfer manufactured product and technol- in the range of 300-1,700 μm. release characteristics. The fine, non-gritty ogy to other sites around the world texture of product produced by this tech- • formulation capababilities to help with Two types of process are used to generate nology lends itself to being used in orally product life cycle management. the spheroidal particles (see diagram): dispersible tablet and liquid formulations, as well as encapsulated products. Cleantaste™ Mayne Pharma International has been grant- • The first of these processes, which allows acetaminophen (paracetamol) and ambroxol ed, or applied for, patents that protect its vari- potencies up to 90%, utilises extrusion and have been commercialised and launched in ous drug delivery technologies. The in-market marumerisation to form a drug core with a Australia, the USA and Japan. sales of products developed at the Salisbury, polymer coat. Australia facility using its technologies are in • The second process is known as spheroni- SERVICES SUMMARY excess of US$500 million per year. sation, where the drug particles are fixed Mayne Pharma International can develop and manufacture oral and topical formulations for clinical trials and has the ability to deliver to sites anywhere in the world. Mayne Pharma International can provide:

• Tablets (immediate, modified, sustained, delayed or pulse release and taste masked) • Capsules (powder, pellets/beads) • Liquids and Creams

Placebo formulations can be provided to match client specifications or innovator product. Packaging and labelling to suit cus- Pellet technology used for controlled release formulations tomer requirements.

OORALRAL AAprpr 22010.indd010.indd 1212 330/4/100/4/10 08:40:0008:40:00 In addition to its drug delivery technologies, Annual production capacity: Mayne Pharma International is located in Mayne Pharma International offers a number Salisbury, South Australia, approximately of specialty services: • Approximately 2,500 million capsules and 19 km from the capital city of Adelaide on a tablets 19-hectare site. There is 12,000 m2 of manu- • Formulation Development • 100 tonnes of bulk product facturing space located on the site. • 16 million units of liquids and creams Provide solutions to a range of common Mayne Pharma International is a wholly formulation challenges such as poor solubil- The site is approved by major regulatory owned subsidiary of HalcyGen Ltd, an ity, poor bioavailability, short half life, low authorities: Australian public company listed on the ASX. Cmax, poor powder flow, non-uniform crys- tal size and scale-up issues. • FDA: United States • MHRA: UK Mayne Pharma International • Analytical Services • TGA: Australia PO Box 700 • Regulatory Services • TPD: Canada Salisbury South Australia 5108, Australia ABOUT MAYNE PHARMA Mayne Pharma International has generated a substantial worldwide patent estate in the Mayne Pharma International competes in drug delivery field, comprising:. T: +61 8 8209 2604 F: +61 8 8281 6998 the oral drug delivery, branded, generic and E: [email protected] value-added API markets. The oral pharma- • 11 patent families ceutical business at Salisbury, Australia, is a • 38 pending applications www.maynepharma.com GMP facility. • 76 granted

maynepharma

OORALRAL AAprpr 22010.indd010.indd 1313 330/4/100/4/10 08:40:0008:40:00 ADVANCES IN SOLID DOSE ORAL DRUG DELIVERY

Oral drug delivery still remains the preferred route of drug administration by physicians and patients alike. Here, Gurvinder Singh Rekhi, PhD, Senior Director, Oral Controlled Release Product Development at Elan Drug Technologies, describes novel technologies which provide improved performance, patient compliance and enhanced delivery. These technologies will advance further differentiation in the oral delivery market.

Oral delivery continues to be the most popular systems some 60% of the market.3 The intro- route of administration due to its versatil- duction of widely prescribed proprietary medi- ity, ease of administration and probably most cines in new oral controlled-release forms will importantly patient compliance. In a recent be the driver of market gains. New England Healthcare Institute report, the Generally, controlled-release medicines can cost of non-compliance in the US alone was be categorised into two groups based on actions. estimated to be as much as $290 billion, or Extended-release formulations deliver a portion 13% of total annual health care expenditure.1 of the total dose shortly after ingestion and the Providing patients with simplified, convenient remainder over an extended time frame. For example, Avinza® is a once-daily, rapid-onset, extended-release “ADVANCES IN NANOTECHNOLOGY morphine product. Delayed- HAVE IN RECENT TIMES PROVIDED release systems provide steady dosing after passage through the ONE OF THE MOST SIGNIFICANT stomach, such as with Bayer Healthcare’s Safety Coated OPPORTUNITIES FOR GROWTH, Bayer Aspirin product. ADDRESSING THE ESTIMATED 40% Two of the most widely commercialised controlled-release OF DRUGS LEAVING THE CLINIC THAT technologies are OROS® (developed by J&J’s Alza), and the HAVE POOR WATER SOLUBILITY ISSUES” SODAS® technology developed by Elan Drug Technologies (see Gurvinder Singh Rekhi, PhD oral medications that improve compliance and figure 1). Other successfully commercialised Senior Director, Oral Controlled Release Product Development thus result in more effective treatment has been technologies include SkyePharma’s Geomatrix®, T: +1 770 538 6321 ® ® one of the major drivers of innovation in the Eurand’s Diffucaps and Flamel’s Micropump . F: +1 770 538 6421 oral drug delivery market. E: [email protected] Within the oral drug delivery market, con- RECENT DEVELOPMENTS trolled-release tablets and capsules will contin- Elan Drug Technologies ue to create the largest demand. Adaptations of Since the development of those technologies 1300 Gould Drive these technologies, including chewable, orally described above, both they and other technologies Gainesville GA 30504 disintegrating, nanoparticle and combined tech- have evolved to address specific therapeutic needs United States nology formulations, are expected to broaden such as in the treatment of pain and blood pres- applications and revenues. The total market for sure. A number of companies are engaged in the General Contact details: oral medications adapted to delivery systems is development of pulsatile release systems where T: +353 1 709 4068 (Europe & ROW) T: +1 610 313 7045 (US) forecast to reach $56.7 billion in 2012, up 7.1% drug is released in pulses, separated by defined E: [email protected] annually from 20072 for the US alone. Oral time intervals. Ritalin® LA and Focalin® XR, products represent about 70% of the value of both used to treat Attention Deficit Hyperactivity www.elandrugtechnologies.com pharmaceutical sales and among drug delivery Disorder (ADHD), mimic the twice-daily dos-

OORALRAL AAprpr 22010.indd010.indd 1414 330/4/100/4/10 08:40:0108:40:01 While there are a number of other delivery Rapamune®. In-market sales for these three prod- systems being developed, such as chewables ucts in 2008 were over US$1.8 billion. Other and transmucosals, advances in nanotechnology technologies designed to overcome problems have in recent times provided one of the most associated with poor water solubility include significant opportunities for growth, addressing Skyepharma’s IDD® solubilisation technology the estimated 40% of drugs leaving the clinic which has been used to launch Triglide® (Shionogi that have poor water solubility issues.4 Elan Pharma Inc), and LifeCycle Pharma’s Meltdose® Drug Technologies’ NanoCrystal® technology is technology which was used in Fenoglide® (also ® SODAS (Spheroidal Oral Drug Absorption seen as leader in this area and recently received marketed by Shionogi in the US). Over the System) is Elan Drug Technologies’ the Technology Innovation Award at the 14th coming years, many more poorly water soluble multiparticulate drug delivery system. Based on the production of controlled- Annual Drug Delivery Partnership Meeting in products are expected to be launched aided by release beads, the SODAS® technology Orlando, Florida, USA.5,6 these and similar technologies. is characterised by its inherent flexibility, Figure 2 summarises some of the most com- enabling the production of customised mon problems encountered in the development FUTURE OPPORTUNITIES dosage forms that respond directly to of poorly soluble products. Oral formulations individual drug candidates’ needs. developed using the NanoCrystal® technology, While oral bioavailability is now considered compared with conventional forms, can over- an important feature of optimising the drug3 Figure 1: Pictorial representation of Elan come many of these obstacles. Specifically, there are many more advances underway that Drug Technologies’ SODAS® technology NanoCrystal® can enhance bioavailability and will provide even further opportunity. thereby reduce dose and size of dosage form, ing of a conventional immediate release tablet. provide for rapid absorption and hence rapid Mini-tablets in one system for greater These once-daily pulsed profiles offer the patient onset, extend the range of dose proportionality flexibility efficacy throughout the day negating the need allowing for more drug to be delivered to the The launch of new drugs which incorpo- for children to take a second dose during school body, and reduce fed/fasted variability thereby rate a number of mini-tablets provides a very hours. Ritalin® LA and Focalin® XR both utilise enhancing safety and efficacy. flexible oral dosage option which can incorpo- Elan’s SODAS® technology. Several of these benefits are embodied in rate different mini-tablets, each one formulated Further manipulation of delivery systems marketed solid oral products including Abbott’s individually and designed to release drug at has lead to the development of chronothera- TriCor® 145mg, Merck’s Emend® and Pfizer’s different sites so that higher dose loading is peutic systems, where release enables a drug to take advantage of the natural biorhythms of the human body. Cardiovascular procucts such as Biovail’s Cardizem® XL and UCB’s Verelan® PM provide therapeutic concentrations to correlate with normal circadian rises in blood pressure when patients are most at risk from hypertension and a possible heart attack. Orally disintegrating tablets (ODTs) are evolving into an important delivery system for drugs that treat medical conditions vulnerable to a sudden onset of symptoms. Such conditions include allergies, nausea, migraine headaches and schizophrenia. Among the available ODT technologies are Catalent Pharma Solutions’ Zydis®, CIMA Labs’ (Cephalon) Durasolv® and Orasolv®, and SPI Pharma’s Pharmafreeze™ systems. Catalent’s Zydis® technology has been the most commercially successful, and has numerous products launched through licensees. Eli Lilly’s Zyprexa® is one of the most widely prescribed drugs that have been adapted to ODT delivery. GSK’s Lamictal® ODT product is the A significant percentage of active pharmaceutical ingredients identified through discovery most recently approved by the FDA in this class screening programs are poorly soluble in water. These molecules are difficult to formulate using of products. It used Eurand’s technology, and is conventional approaches, and are associated with innumerable formulation-related performance issues: poor oral bioavailability; lack of dose proportionality; and slow onset of action. the first antiepileptic treatment available in an orally disintegrating formulation. Figure 2: Delivery of poorly soluble drugs: the problem

OORALRAL AAprpr 22010.indd010.indd 1515 330/4/100/4/10 08:40:0108:40:01 Alpharma’s morphine-based abuse-resistant SABER™ technology, SOLIQS’ Meltrex® tech- opioid, Embeda™, which was licensed to King nology and Banner’s Versatrol™ controlled Pharmaceuticals, has become the first prod- release softgel technology. uct of its type to gain approval. It contains morphine and a sequestered naltrexone core Combination approaches in an extended-release formulation. Launched Advances in the oral controlled release in mid September 2009, a black box warning (OCR) market have seen companies looking and a REMS program were conditions of the to combine products and/or technologies to approval. In February 2010, analysts Cowen and achieve better therapeutic effects. The develop- Company estimated 2009 sales of $15 million ment of drug combinations designed to help and expect the product to achieve sales of $250 improve patient compliance has been a signifi- Programmable Oral Drug Absorption million by 2012. cant driver of the pharmaceutical industry for ® System (PRODAS technology) is Elan Other drug delivery programs such as many years. The combination of approaches Drug Technologies’ multiparticulate tablet Remoxy and Acura’s Acurox™ are still not to overcome delivery problems of certain drug technology, which combines the benefits of 10 tabletting technology within a capsule. approved by the FDA. The most recent expec- candidates will become more prevalent as tation is that Acurox™ will be launched in the companies push further the limits of their tech- Figure 3: Pictorial representation of Elan third quarter of 2010, with Remoxy® follow- nologies. Combining the NanoCrystal® technol- Drug Technologies’ PRODAS® technology ing in 2011. It is estimated that the market for ogy with its Oral Controlled Release Platform, possible within the gastro-intestinal tract. It is abuse-resistant products, which will be driven Elan Drug Technologies seeks to overcome also possible to incorporate mini-tablets of dif- by oxycodone and morphine abuse-resistant for- problems associated with poorly water soluble ferent sizes so that high drug loading is possi- mulations, will be worth $1.2 billion by 2017.11 candidates, while applying any one of its OCR ble. The Trilipix® fenofibrate product launched technology platforms to offer the additional by Abbott in January 2009 is comprised of Alcohol dose dumping benefits of modified or controlled release prop- a number of mini-tablets. Another technol- Another challenge for the controlled release erties and allow the drug to be processed into a ogy using a similar approach is the PRODAS® market is that of alcohol dose dumping. In 2005, solid oral dosage form. delivery system by Elan Drug Technologies.7 A Palladone® capsules were withdrawn from the PRODAS® capsule is shown in figure 3. market in the US and Canada due to dose-dump- Other delivery approaches with potential ing when co-ingested with alcohol. Work to Other approaches that also have significant Abuse-resistant delivery systems resolve this problem is being addressed by a sig- potential include the targeting of drug directly to At present there are a number of initiatives to nificant number of companies including Flamel the colon and also the stomach.12,13 Colonic drug minimise the risk associated with abuse of drugs; with its Trigger-Lock® Micropump technology. delivery has attracted interest primarily for local in particular strong pain medications. A record The Trigger-lock® formulation of an opioid anal- delivery in diseases of the colon such as Crohn’s 36 million Americans have abused prescription gesic is being studied in two clinical trials. disease, ulcerative colitis and colorectal cancer. drugs at least once in their lifetime, a US govern- Egalet’s key technology is an oral drug Furthermore, it has been proposed that the colon ment study found.8 Pain Therapeutics was con- delivery system of capsules comprising a coat is a better site than the small intestine to promote sidered the front runner with its abuse-resistant and a drug release matrix. The drug is distrib- oral macromolecule uptake. The colon is also formulation of oxycodone, which was formu- uted throughout the drug release matrix, and typically a site of drug absorption from extend- lated with DURECT’s sustained-release gel-cap is released over time as the coat and matrix ed-release preparations where a substantial por- ORADUR® technology. In December 2008, Pain are eroded within the gastrointestinal tract. tion of the drug is delivered to the colon. Therapeutics received a complete response letter Egalet’s technology claims to be abuse resist- One approach is XenoPort’s proprietary from the US FDA for its NDA (submitted in June ant (neither crushable nor injectable, resistant Transported Prodrug™ technology, which uti- 2008) for REMOXY®. To date, REMOXY® has to fast extraction) and does not experience lises the body’s natural mechanisms for actively not been approved for marketing, with the FDA alcohol-induced dumping. transporting nutrients through cellular barriers to believing additional non-clinical data will be Other technologies designed to avoid/ gain efficient absorption into the bloodstream. required to support its approval.9 reduce alcohol dose dumping include Durect’s XenoPort’s approach typically relies on a drug’s ability to diffuse passively through the intestinal Year Reformulations NCEs Total wall to enter the bloodstream and reach the 2002 55 17 72 targeted tissue. Its most advanced project is currently in Phase III clinical trials. Other approach- 2003 49 21 70 es being investigated include Alizyme’s Colal 2004 69 31 100 delivery system (also in Phase III) and Cosmo’s 2005 64 18 82 MMX technology, which is in Phase II. 2006 77 18 95 Research around gastro-retentive delivery, where dosage forms are retained in the stomach 2007 50 16 66 to achieve a prolonged and predictable drug deliv- 2008 73 25 98 ery profile in the GI tract continues. One example 2009 75 26 101 is Depomed’s AcuForm® – a multi-hour, gastro- retentive, controlled-release drug delivery system, Source: Compiled by Elan Drug Technologies using US FDA website (www.fda.gov). which allows for targeted, controlled delivery of Figure 4: FDA approvals 2002-2009: reformulations and NCEs pharmaceuticals to the upper GI tract.

OORALRAL AAprpr 22010.indd010.indd 1616 330/4/100/4/10 08:40:0208:40:02 Elan A4.indd 1 9/4/10 12:41:10 LdgaYAZVY^c\ 9gj\9Za^kZgnIZX]cdad\^Zh

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OORALElanRA LA4.indd AAprpr 22010.indd0 1 01.indd 1717 330/4/109/4/100/4/10 12:41:1008:40:0308:40:03 “SINCE 2001, 11 ORAL DRUG DELIVERY PRODUCTS 7. US Patent 6,110,494, Article Butler et al. Pharm. Tech. 1998, 22(3), 122-138 HAVE BEEN LAUNCHED THROUGH LICENSEES/PARTNERS 8. Associated Press. Scientists explore abuse- resistant painkillers, Associated Press, IN THE US ALONE, MAKING ELAN DRUG TECHNOLOGIES March 12, 2007. Available at http://www. THE MOST SUCCESSFUL DRUG DELIVERY SERVICE PROVIDER msnbc.msn.com/id/17581544/ 9. Pain Therapeutics Receives Complete WORLDWIDE OVER THAT PERIOD” Response Letter From FDA for REMOXY® - Press release, 11 December 2008. Available at http://investor.paintrials.com/releasede- SUCCESSFUL BUSINESS MODEL Elan Drug Technologies is a world leading tail.cfm?ReleaseID=354003 BUILT ON DEMAND drug delivery company which has provided oral 10. R&D Focus, IMS Portal, accessed controlled release solutions for dozens of prod- April 2009. Available at http:// Reviewing the number of US FDA approv- ucts which have been subsequently launched www1.imshealth.com/web/prod- als over the past years, new chemical entities worldwide. Over 1,900 patents/patent applica- uct/0,3155,64576068_63872702_712 have accounted for only 25% of all products tions support its technologies. 63548_71480111,00.html approved, with the majority of approvals being Since 2001, 11 oral drug delivery products 11. Wheeler H. Short acting and anti-abuse reformulations or combinations of previously have been launched through licensees/partners technologies set to fragment and grow the approved products (see figure 4).14 With a new in the US alone, making Elan the most success- market , Datamonitor Report Reference formulation costing approximately $40 million15 ful drug delivery service provider worldwide Code: DMHC2377, March 2008 and taking four to five years to develop com- over that period. Elan’s most recent oral con- 12. Dubin C, Discussing Gastro-retentive pared with the average cost of a next-generation trolled release product approval in the US uses drug delivery systems, Drug Delivery product (in the region of $330 million16), the its internally developed MXDAS™ technology. Technology, June 2007 Vol 7 no 6, pp26-29 potential of reformulation using OCR technolo- This technology was used in the development 13. Touitou E, Barry BW, Enhancement in gies cannot be emphasised enough. Moreover, of Ampyra™ (dalfampridine), which received Drug Delivery, Enhancement in Drug the development of an NCE has been estimated US FDA approval in January 2010 and was Delivery, CRC Press, 2006, pp 77-80 to cost between US$1.3-1.7 billion.17 subsequently launched in March 2010. 14. United States Food and Drug In the face of financial pressures, it is not Administration website. Available at surprising that more pharmaceutical compa- REFERENCES: http://www.fda.gov/ nies are turning to drug delivery companies to 15. Business Insights. Lifecycle management optimise their marketed products. Analysts at 1. 2010 report from New England Healthcare strategies: maximizing ROI through indica- PricewaterouseCoopers believe that an extra Institute tion expansion, reformulation and Rx-to- five years’ of patent life could generate 50-100% 2. The Freedonia Group. Drug Delivery OTC switching. Business Insights report. more revenue for a product.18 Systems to 2012—Demand and Sales February 2006. There are now many drug delivery com- Forecasts, Market Share, Market Size, 16. Grudzinskas C, Balster R L, Gorodetzky C panies that offer a range of OCR solutions, Market Leaders. Study # 2294. Cleveland, W, Griffiths R, Henningfield J , Johanson plenty of which have been validated by product Ohio: The Freedonia Group, March 2008 C-E, Mansbach R S, McCormick C G, launches. Ongoing developments as noted here 3. Colombo P, Sonvico F, Colombo G, et al. Schnoll S G, Strain E, Wright C. Impact of will ensure the OCR market will continue to Novel platforms for oral drug delivery. formulation on the abuse liability, safety grow in order to satisfy demand of pharmaceuti- Pharm Res. 2009;26(3):601-611. and regulation of medications: The expert cal companies and patients alike. 4. Merisko-Liversidge EM, Liversidge GG. panel report. Drug and alcohol depend- Drug nanoparticles: formulating poorly ence, June 2006 vol 83, (Supp 1):S77-S82. ABOUT THE AUTHOR AND ELAN water-soluble compounds. Toxicol Pathol. 17. Collier R, Drug development cost estimates DRUG TECHNOLOGIES: 2008;36(1)43-48. hard to swallow, CMAJ. 2009 February 3; 5. Technology Innovation Award at 14th 180(3): 279–280. Dr Gurvinder Singh Rekhi is based at Elan Annual Drug Delivery Partnership 18. PriceWaterhouseCooper Report, Pharma Drug Technologies’ Gainesville, Georgia facil- Meeting, Orlando, Florida January 26th, 2020, The Vision. PWC Publication , ity. He has been instrumental in the develop- 2010 2007June 2007. Available at: ment of a number of products that have since 6. Bottomley K, NanoTechnology for Drug www.pwc.com/extweb/pwcpublications.nsf/ been commercialised – both in the US and Delivery: a Validated Technology? Drug docid/91BF330647FFA402852572F2005 internationally. Delivery Report. 2006:20-21 ECC22.

IN WHICH EDITION SHOULD YOUR COMPANY APPEAR? WWW.ONDRUGDELIVERY.COM

OORALRAL AAprpr 22010.indd010.indd 1818 330/4/100/4/10 08:40:0308:40:03 advantagesthe of multi-phase, multi-compartment capsules are clear

INNERCAP® Technologies Granted US Patent No. 7,670,612 on multi-phase, multi-compartment capsular delivery apparatus and methods for using the same.

March 23, 2010, Saint Petersburg, Florida USA, INNERCAP Technologies, Inc., an international drug delivery and specialty pharmaceutical company, recently announced the grant of US Patent No. 7,670,612 entitled “Multi-Phase, Multi-Compartment Capsular Delivery Apparatus and Methods for Using Same.” The delivery system has uses for bio-pharmaceutical, pharmaceutical, medical foods and nutraceutical products. In addition to the existing New Zealand patent, this patent covers the company’s multiphase multi- compartment delivery system used to enable the development of multicompartment, multi-phase delivery forms (two piece capsule based) of combination products that have compatibility, formulation or targeted delivery obstacles. “This is a significant development for INNERCAP Technologies NOVACAP technology,” said Fred H. Miller, Chief Executive Officer at INNERCAP. “The continued growth of our patent portfolio establishes INNERCAP as one of the leading companies in this space.” The delivery system and combinations covered by the patent have the ability to deliver therapeutic entities that have never been combined previously and now can be administered together, via an oral, implanted, or suppository capsule, in the most advantageous pharmacokinetic profile, utilizing different physical phases. This technology can therefore be used to enable capsule administration of compounds that are not normally administered as a combination product. The efficacy, safety, and side-effect profiles of drugs can be substantially improved using this delivery technology. It will also provide very significant quality-of-life improvements for patients and substantial economic savings for hard-pressed healthcare systems. “INNERCAP’s multi-phase, multi-compartment technology has been commercially manufactured and validated in several products, demonstrating that INNERCAP’s delivery system creates real value to consumers and branded manufacturers,” added Mr. Miller. INNERCAP was represented by Cliff Davidson, Esq. of the patent firm Davidson, Davidson & Kappel, LLC (www.ddkpatent.com) based in New York City.

United States Patent No. 7,670,612 For more information contact us at the telephone number and email address below: US and International Patents Pending

OORALRAL AAprpr 22010.indd010.indd 1919 330/4/100/4/10 08:40:0508:40:05 15th Annual

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OORALRAL AAprpr 22010.indd010.indd 2020 330/4/100/4/10 08:40:0708:40:07 THE RIGHT FORMULATION – AND HOW TO GET THERE

The objective of drug formulation is to develop a product with the correct amount of drug in the right form, and to maintain its chemical and biological integrity for delivery at or over the proper time, at the proper rate, and in the desired location. SRI International’s approach to drug formulation is customised according to the client’s needs and the stage of development. This article by Gita Shankar, PhD, Director of Formulations R&D, Pharmaceutical Sciences at SRI, describes the strategy that the company uses to develop an appropriate formulation.

Formulators start their task by gaining an under- substances based on their aqueous solubility standing of the bulk drug’s physical and chemi- and intestinal permeability.1 cal properties. Once the pharmaceutical profile The biopharmaceutical classification sys- of the drug has been determined, the appropriate tem was developed primarily in the context of route of administration can be identified and immediate release (IR) solid oral dosage forms. designed. Next we develop preclinical for- It is a drug development tool that allows estima- mulations, which overcome the drug’s innate tion of the contributions of three major factors deficiencies. For example, a poorly soluble – dissolution, solubility and intestinal perme- drug might require solubilising additives, and a ability – that affect oral drug absorption from poorly bioavailable drug might require a perme- IR solid oral dosage forms. The classification is Figure 1: High Throughput Liquid ability enhancer. associated with a drug dissolution and absorp- Handling System. Additional excipients are selected to over- tion model that identifies the key parameters come potential problems in processing, manufac- controlling drug absorption as a set of dimen- turing and stability. Bench studies are performed sionless numbers: the absorption number, the on pilot batches to establish the efficacy, manu- dissolution number and the dose number. facturability and stability of dosage forms. The According to the BCS, there are four classes final formulation design is optimised to take into of drug substances based solely on their solubil- account the pharmacokinetic properties of absorp- ity and intestinal permeability: tion, distribution, metabolism, and excretion. These steps in the drug development proc- Class I: High Solubility – High Permeability ess are common to all routes of administration. Class II: Low Solubility – High Permeability However, this article covers only the develop- Class III: High Solubility – Low Permeability ment of oral dosage formulations. Class IV: Low Solubility – Low Permeability Oral formulation has been the preferred and most common route of delivery around the globe Class I drugs exhibit a high absorption owing to its ease of administration and good number and a high dissolution number. The Gita Shankar, PhD patient compliance. And from a drug develop- rate-limiting step is drug dissolution; if dissolu- Director of Formulations R&D, ment and manufacturing perspective, an oral tion is very rapid, then the gastric emptying rate Pharmaceutical Sciences T: +1 650 859 2000 formulation offers superior stability compared becomes the rate-determining step. Metoprolol, F: +1 650 859 3041 with intravenous formulations. Developing an diltiazem, verapamil, and propranolol are exam- E: [email protected] oral formulation is by no means an easy task ples of Class I drugs. because each drug substance is a different entity Class II drugs have a high absorption number SRI International with different characteristics. but a low dissolution number. In vivo drug dis- 333 Ravenswood Avenue To standardise oral formulation develop- solution is then a rate-limiting step for absorption Menlo Park ment, the US FDA published the biopharma- except at a very high dose number. The absorp- CA 94025 United States ceutical classification system (BCS) guidance tion rate for Class II drugs is usually slower in 2000, which formed the basis of the sci- than the rate for Class I drugs and absorption www.sri.com/biosciences entific framework used for classifying drug occurs over a longer period. Phenytoin, danazol,

OORALRAL AAprpr 22010.indd010.indd 2121 330/4/100/4/10 08:40:0808:40:08 one-third of the drugs listed in the Binary Combinations (1:1) Ternary Combinations (1:1:1) US Pharmacopoeia are poorly water Solvent Combination Abbreviation Solvent Combination Abbreviation soluble. Poor solubility leads to sig- Ethanol / Water Eth Wat Ethanol / Water / PEG400 Eth Wat PEG nificant hurdles in the oral absorption Ethanol / PEG400 Eth PEG Ethanol / Water / Propylene Glycol Eth Wat PG and bioavailability of the drug candi- Ethanol / Propylene Glycol Eth PG Ethanol / Water / Tween80 Eth Wat Twe date by decreasing its dissolution rate and membrane permeation. Ethanol / Tween80 Eth Twe Ethanol / Water / Glycerin Eth Wat Gly SRI has developed its own pro- Ethanol / Glycerin Eth Gly Ethanol / PEG400 / Propylene Glycol Eth PEG PG prietary solvent screening system, Water / PEG400 Wat PEG Ethanol / PEG400 / Tween80 Eth PEG Twe which is both economical and fast. Water / Propylene Glycol Wat PG Ethanol / PEG400 / Glycerin Eth PEG Gly This system, which we call the High- Throughput Solubility Screening Water / Tween80 Wat Twe Ethanol / Propylene Glycol / Tween80 Eth PG Twe (HTSS) system, uses minimal drug Water / Glycerin Wat Gly Ethanol / Propylene Glycol / Glycerin Eth PG Gly quantities, since in its early devel- PEG400 / Propylene Glycol PEG PG Ethanol / Tween80 / Glycerin Eth Twe Gly opment stages, availability of the PEG400 / Tween80 PEG Twe Water / PEG400 / Propylene Glycol Wat PEG PG drug is limited. Our proprietary screening sys- PEG400 / Glycerin PEG Gly Water / PEG400 / Tween80 Wat PEG Twe tem is based on a High-Throughput Propylene / Glycol / Tween80 PG Twe Water / PEG400 / Glycerin Wat PEG Gly Liquid Handling Instrument (see Propylene Glycol / Glycerin PG Gly Water / Propylene Glycol / Tween80 Wat PG Twe figure 1) which is used to prepare Tween80 / Glycerin Twe Gly Water / Propylene Glycol / Glycerin Wat PG Gly the excipient combinations. This instrument is programmed for aspi- Water / Tween80 / Glycerin Wat Twe Gly rating and dispensing the solvents/ PEG400 / Propylene Glycol / Tween80 PEG PG Twe excipients. A predetermined volume PEG400 / Propylene Glycol / Glycerin PEG PG Gly of the cosolvent combinations are PEG400 / Tween80 / Glycerin PEG Twe Gly dispensed into each well in a micro- titer plate. After solvent addition, Propylene Glycol / Tween80 / Glycerin PG Twe Gly the plates are shaken in a controlled Figure 2: Solvent combinations (SRI’s Level 1 screen) used for the paclitaxel solubility study. environment for an extended period. (Concentrations: ethanol X%v/v in water; water 100%; PEG400 100%; propylene glycol Y%v/v in Levels of solubility are read using water; Tween80 Z%v/v in water, and glycerin A%v/v in water). the baseline turbidity of the excipi- ketoconazole, mefenamic acid, and nifedipine IV compounds were an exception rather than the ent. A software program is used to control are examples of Class II drugs. In vitro-in vivo rule, yet today about 10% of the drug candidates the solvent combinations and the analytical correlation (IVIVC) is usually expected for Class under development fall into this category. A well- outputs. Different level screens of solvent I and Class II drugs. known example of a Class IV drug is paclitaxel. combinations are available to address different For Class III drugs, permeability is the rate-lim- formulation options. A stock solution of the iting step for drug absorption. These drugs exhibit PROPRIETARY HIGH-THROUGHPUT drug is prepared either in absolute alcohol or a high variation in the rate and extent of drug SOLUBILITY SCREENING SYSTEM DMSO and added into plates prefilled with the absorption. Cimetidine, acyclovir, neomycin B premixed cosolvent combinations. The plates and captopril are examples of Class III drugs. In recent years, there has been an increase in are again shaken and analysed using the turbid- Class IV drugs exhibit a many characteristics the drugs that fall into BCS Classes II, III and ity reader. Solubility is assessed by the change that are problematic for effective oral administra- IV. Of these, Class II and IV pertain to drugs that in turbidity before and after addition of the drug tion. A decade back, extreme examples of Class are poorly water soluble. Currently, more than in the solvent system.

Figure 3: Solubility of paclitaxel (3 and 4mg/mL) with binary Figure 4: Solubility of paclitaxel (3 and 4 mg/mL) with ternary combinations of six solvents combinations of six solvents

OORALRAL AAprpr 22010.indd010.indd 2222 330/4/100/4/10 08:40:1008:40:10 soluble, but they do not have the appropriate hydrophobic-hydrophilic balance to be absorbed by the intestinal epithelium. Developing an oral formulation for these compounds sometimes requires imparting the right hydrophobic-hydrophilic balance to improve the GI-permeation of the drug. In this step in the drug development process, SRI uses an in vitro screen known as the Ussing Permeation System to rank-order formulations Figure 6: Drug transport in the on the basis of their permeability. mucosal-to-serosal direction, across The system at SRI is a modified Ussing different segments of rat intestine and system (shown at the top of figure 5) that has colon, from buffer. multiple sets of side-by-side chambers and is used for in vitro studies. Each set consists of two side-by-side diffusion chambers, a heating block for temperature control, needle valves for gas flow adjustment and gas mixing, and Ag/AgCl voltage and current electrodes for measuring transepithelial voltage and for passing current. Harvested segments of small intestine or colon are mounted on sliders placed between the Figure 5: Top: Ussing absorption unit; two horizontal chambers of the modified Ussing Bottom: Slider with the intestinal tissues being mounted between the side-by-side system (bottom of figure 5). One of the chambers Figure 7: Effect of drug concentration compartmental unit of the Ussing system. is exposed to the mucosal side of the intestinal on transport in the mucosal-to-serosal segment and the other to the serosal side. direction across rat jejunum, from buffer. The following is an example of the strategy For drug transport across epithelial mem- employed in developing a formulation for a branes of harvested rat small intestine and colon model drug substance, in this case, paclitaxel. segments in the mucosal-to-serosal (M-to-S) direction, aliquots of buffer are added to both the SRI EXAMPLE mucosal and serosal chambers. The buffer in the mucosal chamber is replaced with a solution of A total of 35 solvent combinations (listed in the drug formulation. Aliquots of buffer solutions figure 2) were generated by the software using are removed periodically from the serosal cham- the six solubilising excipients in binary and bers and are replaced with equal volumes of fresh

ternary combinations at a 1:1 and 1:1:1 ratio, warm buffer previously saturated with 100% O2. respectively. Paclitaxel stock solutions were Changes in transepithelial short-circuit cur- prepared in absolute ethanol and dispensed rent (in micro-Amps) and membrane resistance into each of the micro-titer plates containing (in Ohms) as a function of time are monitored Figure 8: Effect of a known Pgp inhibitor solvent combinations to obtain the desired final continuously during in vitro studies to serve as on drug transport in the mucosal-to- concentrations of 3 and 4 mg/mL. Turbidity was indicators of tissue viability and drug perme- serosal direction across rat jejunum. measured using the plate reader. ability, respectively. Figures 3 and 4 show the solubility profiles The buffer samples from the receptor cham- tial solute concentration in the donor compart- of paclitaxel in both binary and ternary combi- bers are analysed for drug content on a high ment, and A is the surface area.2 nations as obtained from the HTSS. In these fig- pressure liquid chromatograph (HPLC). Owing The following is an example of the strategy ures, the longer bars represent more turbidity in to the expected variation for in vitro test condi- employed in developing a formulation for a the formulation. Based on this analysis, we were tions and harvested rat intestinal segments, four model BCS Class III drug substance. able to narrow down a few cosolvent-based replicates are used per experimental condition. formulations options for paclitaxel, which were SRI EXAMPLE

then tested in a pharmacokinetic study. Apparent Permeability Coefficient (Papp) Calculation: Figures 6, 7 and 8 illustrate this strategy PROPRIETARY IN VITRO To compare data obtained from different in vitro for a poorly permeable drug substance. The PERMEATION SYSTEM experiments, the apparent permeability coeffi- plot between the amount of drug transported cients are calculated using the equation: through the different regions of the intestine Although Class III and Class IV drugs are from the mucosal to the serosal side for the

poorly absorbed substances, in recent times Papp = dQ / dt drug at a given concentration and formulation is

there has been an increase in drug products C0 × A presented in figure 6. falling into these categories owing to newer The cumulative amount of drug trans- formulation options. Class III compounds are where dQ/dt is the linear appearance rate of ported through jejunum fragments of the

drug substances that are sometimes highly water mass in the receiver compartment, C0 is the ini- intestine from the mucosal to the serosal side

OORALRAL AAprpr 22010.indd010.indd 2323 330/4/100/4/10 08:40:1108:40:11 at increasing drug dose concentrations CONCLUSION (in the same formulation), is shown in figure 7. Now is the time for integrating high- Figure 8 presents data obtained from throughput experimental techniques into using a Pgp (permeability glycoprotein) the preformulation and formulation steps inhibitor, which was placed either on in the drug discovery process. Companies the mucosal side or on the serosal side, are screening larger numbers of drug can- compared with that without at inhibitor. didates than ever before, and the decision In this figure, the dose, formulation, to choose one drug candidate over anoth- and kind of intestinal segment used er has become more complicated because are constant. Similar data compilation increasing numbers of these drugs fall continues until all conditions and for- into BCS Classes II to IV. mulation options are covered. The decision to choose a poorly solu- Figure 9: AUC versus Papp values obtained for different Based on calculated P values ble drug over a more soluble counterpart app drug formulations (data not shown) obtained from in vitro may be required for improved efficacy data, the rate of M-to-S transport of drug was in rats. The in situ absorption of the drug in the and safety, if the formulation can address the found to be highest in jejunum, followed by presence of the various additives and enhanc- solubility issues. In drug discovery, time is of colon and ileum, and lowest in duodenum (fig- ers and upon intra-intestinal administration is essence, and a fast in vitro method is required ure 6). Increasing the concentration of drug evaluated in healthy rats. The rats are fasted to screen the drug in the formulation alongside in the mucosal (donor) chamber increased overnight and anaesthetised so that the abdo- the drug itself. M-to-S transport of drug in a dose-dependent men can be opened for isolation of GI tract. No longer is it the drug alone, but the drug manner (figure 7). Increased M-to-S transport Ligatures are placed above the mid-duodenum in combination with its formulation additives, of drug was observed in vitro, when a known and below the mid-jejunum, and an intestinal that determine the probability of success for that Pgp inhibitor was added to the mucosal or dosing receptacle is created; the drug is then molecule. SRI International has successfully used serosal chambers. Addition of a known Pgp administered into the lumen of intestine by the above strategy for many client companies, inhibitor to the serosal chamber caused a dra- injecting formulation compositions at mid- helping these companies screen out many poten- matic (three-fold) increase in M-to-S transport duodenum level. Blood samples are collected tial drug candidates at a faster rate. We anticipate of drug. Addition of inhibitor to the mucosal pre- and post-dose, processed for collection of that the next few years will see many such time- chamber also increased M-to-S transport of plasma, and analysed by LC-MS. and resource-saving revolutions in the way we drug, but to a lesser extent (figure 8). Selection of formulation additive combina- attempt to develop these formulations.

The above observations are indicative of tions is based on the Papp values obtained from the significant role of presystemic elimina- comparative in vitro studies. The absorption ACKNOWLEDGEMENTS tion processes in poor permeation of drug of the drug is determined by calculating across the GI tract. The secretory transport- the area under the plasma drug concentra- The author wishes to thank the research- ers involved may include Pgp, the family tion versus time curve (AUC). Based on ers of the Formulations Laboratory for con- of multi-drug-resistance-associated proteins the results from in vitro and in situ studies, stantly striving to improve our experimental (MRP), and possibly other transporters operat- AUC values obtained are compared with the techniques. Special thanks to Helen J. Parish

ing across the GI tract. corresponding Papp values calculated using (Senior Director, Pharmaceutical Sciences, SRI’s strategy is to study the permeation in vitro experimental data. Figure 9 is a bar Biosciences Division) and Dr Walter H. Moos properties of the drug substance in vitro with graph comparing the AUC values with their (Vice-President, Biosciences Division) for

and without added permeation and solubility corresponding Papp values for the different discussions and critical input in the strat- enhancers. Experiments are also conducted in compositions studied. egy presented in this article. Thanks also the presence and absence of inhibitors of efflux In vitro studies using the Ussing system to Janice Schindler-Horvat (Senior Director, proteins (glycoproteins that pump out the may be useful for determining the preferen- Marketing, Biosciences Division) for helping absorbed drugs through independent pathways, tial site of drug absorption for BCS Class III/ with this article. resulting in a net decrease in the amount of IV drugs, and for screening and selection of drug in the serosal side). If the drug substance formulation additives as permeation enhanc- REFERENCES: is found to be influenced by the efflux proteins, ers. In situ studies would further facilitate the formulation strategy will include inhibition optimising the concentrations and ratios of 1. Amidon GL, Lennernas H, Shah VP, of those proteins. additives used, therefore reducing the cost Crison JRA. “A Theoretical Basis for a and number of in vivo evaluations for for- Biopharmaceutic Drug Classification: IN SITU PHARMACOKINETIC mulation optimisation. In vitro-in situ cor- The Correlation of In Vitro Drug Product DATA BY INTRA-DUODENAL relations performed in our laboratories have Dissolution and In Vivo Bioavailability.” ADMINISTRATION IN RATS indicated that it is difficult to predict the Pharm Res. 1995;12: 413-420. in vivo performance of different formulation 2 Luo FR, Paranjpe PV, Guo A, Rubin E, Once the in vitro permeation data has additives solely based on in vitro transport Sinko P. “Intestinal transport of irinote- been obtained, we determine the pharmacoki- studies using isolated intestinal segments at can in Caco-2 cells and MDCK II cells netic parameters of the drug in the presence higher concentrations of permeation enhanc- overexpressing efflux transporters Pgp, of various formulation additives/permeation ers or when paracellular transport is the mode cMOAT, and MRP1.” Drug Metab Dispos enhancers upon intra-duodenal administration of drug absorption. 2002;30(7):763-770.

OORALRAL AAprpr 22010.indd010.indd 2424 330/4/100/4/10 08:40:1208:40:12 SRI International Biosciences

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OORALRAL AAprpr 22010.indd010.indd 2525 330/4/100/4/10 08:40:1608:40:16 Combination Products Regulatory & Compliance Summit Ensure Compliance & Master Partnering to Achieve Long – Term Proﬁtability in the Global Marketplace

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OORALRAL AAprpr 22010.indd010.indd 2626 330/4/100/4/10 08:40:1708:40:17 SOLUBEST‘S SOLUMER™ SOLUBILISING PLATFORM: AN “ALL IN ONE” TECHNOLOGY

Recently SoluBest has implemented a significant strategy shift: from developing proprietary pipeline products that would compete in the nano-generic space, to a licensing-based model where its unique solubilisation platform, Solumer™, is used by clients to formulate their pipeline molecules, both for discovery and marketed products. The platform is currently being tested by multiple companies, from CMOs/CROs to drug delivery/specialty pharma companies and large pharmas. In this article, Amir Zalcenstein PhD, MBA, Senior Director, Business Development and Planning at Solubest, describes Solumer, its applications and reports proof of-concept study data.

Solubility, or the lack of it, is one of the most SoluBest has taken on this challenge and in prevalent problems in drug development. A the last four years has developed a proprietary number of non-proprietary solubilisation meth- platform for the creation of solid dispersions ods exist – for example, salt creation and solu- which effectively and reproducibly improves the bilisation by co-solvents, amongst others – but bioavailability of insoluble drugs. The platform, these are often suboptimal. Furthermore, recent referred to as Solumer™, is robust, versatile, years have seen high-throughput discovery and is readily and cost effectively implementa- technologies uncover vast numbers of insoluble ble towards a wide range of molecules. compounds demanding both more versatile and friendly solubilisation solutions. THE TECHNOLOGY The advent of nanotechnology, most significantly Elan’s NanoCrystal technology, pio- Solumerisation is based on the self assembly neered the first generation of solubilisation of select components, enabling the design and technologies which affected solubility through production of new polymer-drug constructs particle size reduction to a nano-scale, employ- with well defined physico-chemical proper- ing sophisticated milling methodologies. ties. Leveraging the thermodynamic behavior Solid dispersions have been repeatedly of amphiphilic and hydrophilic polymers in noted as a most promising approach for for- mixed solvents, SoluBest’s platform creates mulation development as they have inherent drug-polymer solid dispersions in which the advantages over other approaches: namely lipophilic drug is interwoven within a multi- straightforward processing of an API into a polymer entity. The drug in this solid dispersion molecular or nanoparticle dispersion which is homogeneously dispersed in the polymer shows enhanced bioavailability. matrix. In addition, due to the interaction with Amir Zalcenstein, PhD, MBA However, only a very small number of the amphiphilic polymer, Solumerised drugs Senior Director. Business products on the market incorporate solid exhibit modified physico-chemical properties Development & Planning dispersions as they present a number of (for example, decreased enthalpy and tempera- T: +972 8 940 3023 x102 significant problems, including: laborious ture of melting) compared with the crystalline F: +972 8 930 2878 E: [email protected] methodologies; difficulties in particle charac- lipophilic APIs. terisation; limited in vivo proofs of concept; Candidate molecules’ solubility parameters complications in conversion into suitable are used as a semi-empirical tool to predict SoluBest Ltd Weizmann Science Park dosage forms; batch reproducibility issues; component interactions, facilitating their selec- POB 4053 problems in process scale-up and manufactur- tion and accelerating the development process. 18 Einstein Street ing; and, perhaps most significantly, inherent Once selected, the optimal ratios of specific Ness Ziona 74140 instability. It is recognised that a technology amphiphilic and hydrophilic polymers yield Israel able to overcome these challenges would be solid dispersions with a unique built-in hydro- www.solubest.com highly desirable. phobic-hydrophilic gradient. This gradient ena-

OORALRAL AAprpr 22010.indd010.indd 2727 330/4/100/4/10 08:40:1708:40:17 bles the rapid disintegration of the powder in aqueous media generating easily measurable colloidal nanodispersions. For our purposes, amphiphilic polymers are those soluble both in organic solvents and in water (PEG and Poloxamer, for example), while hydrophilic polymers are those soluble in water or in a mixture of organic solvent and water, but not in organic solvent alone (sodium carboxymethylcellulose and chitosan, for example). Significantly, SoluBest formulations utilise only US FDA-approved polymers in the amounts appropriately noted in the Inactive Ingredients List. STEP 1 The Solumer process is an easily scalable two-step methodology (see figure 1). In step one, a liquid feed is prepared which is a homogeneous solution of the lipophilic drug and at least two polymers in a mixed solvent (organic solvent–water). In step two, the solution is spray-dried to obtain a well characterised powder. There are no additional inter- mediate steps, nor post-drying steps required. The simplicity of the methodology eliminates the drawbacks associated with other nanoparticle platforms (such as agglomeration of nanoparticles or degradation under shear STEP 2 force) as it does not necessitate isolation of nanoparticles during processing. It is in fact exactly the simplicity of the process that makes it readily amenable in an industrial setting. Spray drying is an inherently flexible, continuous and automatic process. Moreover, spray dryers are common in pharmaceutical plants; as the process requires no equipment modification it can be easily implemented without increasing the manufacturing footprint. The resultant spray-dried powder is well- defined and exhibits the collective unique “fin- gerprints” of a Solumer solid dispersion:

• Solubilised drug homogeneously interwoven Figure 1: A brief overview of the Solumer process and the resulting formulations into a polymer matrix unique characteristics • Modified thermal behaviour: depressed melting temperature and enthalpy of melting products); b) reproducible on a batch-to-batch PROOF OF CONCEPT 1: • Spontaneous formation of nano-colloidal dis- basis; c) stable (measured up to two years in ALBENDAZOLE persions upon contact with aqueous media accelerated conditions); and d) amenable to • Enhanced dissolution rate/solubility of the industrial scale-up. The results of SoluBest’s Albendazole is an insoluble anti-helmintic drug as well as the ability to achieve pro- preclinical and exploratory clinical trials are medication. The Solumer formulation of this drug longed supersaturation in dissolution media discussed below. yielded a composition with decreased temperature and model biological fluids Finally, and perhaps most significantly from and enthalpy of melting (161oC from 215oC and a commercial point of view, the Solumer plat- 31 J/g from 210 J/g respectively, DSC). X-ray Validated with multiple proofs of concept, form has a clear advantage in terms of project analysis indicated that the active compound in the the Solumer platform has been shown to “turnaround time”. The elegantly simple meth- SoluBest formulation has a crystalline structure avoid pitfalls common with other solid disper- odology allows SoluBest to generate initial with effective crystallite size of 33 nm. Laser sion techniques. Namely, Solumer has been formulations in as little as 2-3 weeks, while diffraction and dynamic light scattering analysis shown to generate formulations which are: a) progressing from feasibility studies to pilot showed that upon disintegration in water the for- clinically proven to enhance bioavailability clinical formulations and industrial scale-up can mulated powder forms a colloidal dispersion with (or show bioequivalence to marketed nano- be achieved in as little as six months. a mean particle size of 419 nm.

OORALRAL AAprpr 22010.indd010.indd 2828 330/4/100/4/10 08:40:1708:40:17 Together, these properties result in a high dissolution rate of Solumerised albendazole in sodium lauryl sulfate (SLS) (see figure 2a) and its ability to reach supersaturation solubility in physiological media, exemplified by fasted state simulating intestinal fluid (FaSSIF) (see figure 2b). Subsequent in vivo studies in pigs validated the correlation between the formulation’s physico-chemical properties and its bioavailability. A comparative study between SoluBest’s formulation and commercially available albendazole (Albazen) showed that oral absorption of albendazole administred as Solu-Albendazole is significantly higher than its absorption from Albazen suspension. Solu-Albendazole exhibits a clear dose dependence, while Albazen does not. A comparison of both formulations’ anti- helminitic activity (figure 2d) clearly favours Solu-Albendazole, achieving complete dehelmintisation within 10 days at the lowest dose, a result not obtained with even the highest dose of Albazene. Thus, this study demonstrated good correlation between the in vitro and in vivo behavior of Solumerised albendazole, as well as a correlation between improved bioavailability Figure 2: a) Dissolution of SoluAlbendazole vs raw bulk material in SLS; b) supersaturation in physiological media, fasted state simulating intestinal fluid and efficacy. (FaSSIF); c) a comparative evaluation of bioavailability of Solu-Albendazole and a commercial formulation (Albazen). A total of 40 spontaneously infected pigs were PROOF OF CONCEPT STUDY 2: treated with oral suspensions at doses of 5 and 10 mg/kg; d) therapeutic efficacy was FENOFIBRATE estimated through coproscopy on days 0, 1, 3, 5, 10 and 15. Fenofibrate, a cardiovascular drug used to lower triglyceride and cholesterol levels, is practically insoluble in water. When Solumerised, the composition yields a formulation with decreased temperature and enthalpy of fenofibrate melting (64.4oC down from 82oC and 9.3 J/g down from 74.3 J/g, DSC). X-ray analysis indicated the effective crystalline size of formulated fenofibrate at about 40 nm. Disintegration of formulated powder in water results in a colloidal dispersion with a mean particle size of 774 nm as measured by dynamic light scattering. These collective properties result in a higher dissolution rate of solubilised fenofibrate when compared with the Figure 3: a) Dissolution rate of Solumerised fenofibrate compared with raw API, raw API and commercially available micronised commercial micronised Fenofibrate, and TriCor 145; b) results of a randomised fenofibrate. Indeed, the formulation’s dissolu- crossover study on 12 healthy volunteers comparing a single 145mg dose of tion was shown to be virtually identical to the Solumerised fenofibrate with TriCor 145 under fasted conditions. market leading nano-formulation of this drug, Abbot’s TriCor 145 (figure 3a). To determine Solu-Fenofibrate’s bioavail- Mean pharmacokinetic parameters ability in comparison with a reference product Formulation (TriCor 145) a randomised crossover study C (µg/ml) AUC (µg·hr/ml) T (hr) max t max was conducted in 12 healthy volunteers. The TriCor 145 8.10 ± 1.63 113.9 ± 38.70 2.0 ± 0.8 results of this pharmacokinetic study are pre- SoluFeno 7.06 ± 1.16 109.20 ± 37.45 3.0 ± 0.8 sented in figures 3b and 4. The geometric SoluFeno / TriCor 145 0.87 0.98 - mean of test/reference ratios for AUC and C values fall well within the accepted limits 90 % Conﬁ dence intervals 0.76 – 1.01 0.91 – 1.01 - max for bioequivalence, while some subject values

Figure 4: Summary table of Tricor 145 pharmacokinetics compared with for Cmax fell outside the accepted confidence Solu-Fenofibrate interval. It is expected that a larger study

OORALRAL AAprpr 22010.indd010.indd 2929 330/4/100/4/10 08:40:1908:40:19 Figure 5: a) Saturation solubility for Solumerised Resveratrol vs raw API in a fast state simulating intestinal fluid; b,c) an exploratory clinical study comparing Solumerised Resveratrol with the raw API.

would ameliorate this problem. There is some decreased temperature and enthalpy of melting significantly higher bioavailability was dem- o o potential for increasing the Cmax in the course (199 C from 267 C and 14 J/g from 254 J/g, onstrated using Solumerised resveratrol, not of tablet development with the appropriate respectively, as measured by DSC). X-ray analy- only for the total resveratrol metabolites but excipients. Notably, the administration of the sis indicated that the effective crystallite size of also for intact resveratrol. Solu-Fenofibrate formulation did not result in formulated resveratrol is 45 nm. Disintegration any adverse effects or abnormal changes of the of the formulated powder in water results in SOLUBEST’S COMMERCIAL blood and urine parameters. a colloidal dispersion with a mean particle DIRECTION & VALUE size of 1244 nm as shown by laser diffraction PROPOSITION PROOF OF CONCEPT 3: analysis. These collective properties impact a RESVERATROL significantly increased saturation solubility for SoluBest intends to become a major player Solumerised resveratrol versus raw API in a in the field of oral nano-formulations for solu- Resveratrol is a small-molecule activator of FaSSIF (figure 5a). bility-compromised drugs. As such, SoluBest’s sirtuins, enzymes which may control age-related The above in vitro data correlates well with general strategy calls for the inclusion of the disorders in various organisms and in humans. the enhanced bioavailability of Solu-Resveratrol technology in as many drug products as possi- Resveratrol is practically insoluble in aqueous demonstrated in an exploratory clinical study. ble. Thus, our first milestone is to gain industry media, demonstrates very low bioavailability The two-way crossover randomised trial in 12 validation, and to this end SoluBest has engaged and rapid, extensive metabolism resulting in healthy volunteers was carried out with a single multiple parties in its “Formulate-it-Free” ini- only trace amounts of unchanged resveratrol in oral administration resveratrol 500mg under tiative which took place during the first quarter the systemic circulation. fasting conditions. Solumerised resveratrol of 2010. Interested parties were welcomed to The physico-chemical characteristics of res- (test) and raw API (control) were administered formulate their selected drugs using the Solumer veratrol are similar to other lipophilic small as a powder dispersed in water. Plasma concen- platform with no commitment. molecules, which are appropriate candidates trations of resveratrol and its metabolites were SoluBest is confident that this approach, for Solumerisation. The Solumer formulation analysed by HPLC-UV with complementary designed to demonstrate the platform’s capa- of resveratrol yields a composition including LC-MS analysis. bilities, will encourage participants to progress only the active form of the compound – trans- The results of these pharmacokinetic stud- towards development and licensing while con- resveratrol. As demonstrated with other for- ies are depicted in figures 5b, 5c and 6. As vincing other clients to come aboard with mulations, Solumerised resveratrol possesses can be clearly seen from the data presented, a their solubility-compromised drug candidates. This thus reflects SoluBest’s pri- orities: first to gain recognition of Resveratrol Resveratrol Total Metabolites our solubilisation solution, and then Formulation Mean Mean Median Mean Mean Mean Median leverage this recognition in order AUCt Cmax Tmax AUCinf AUCt Cmax Tmax to secure multiple partnership deals (ng·hr/ml) (ng/ml) (hr) (ng·hr/ml) (ng·hr/ml) (ng/ml) (hr) with drug developers. SoluResveratrol 504 330 0.50 28410 27600 8820 1.00 We both welcome and encour- Raw Resveratrol 331 111 2.00 23960 22430 4160 1.50 age interested parties to approach SoluBest and inquire about the Test / 1.52 2.97 - 1.19 1.23 2.12 - Reference suitability of their molecules to our platform. Our strength lies in 90% Conﬁ dence 0.90- 1.95-4.54 - 0.95- 0.97- 1.58- - Intervals 2.58 1.48 1.56 2.83 our ability to turn around projects quickly and cost effectively, allow- Statistical NS* <0.00009 <0.0013 NS* NS* <0.0009 <0.003 ing clients to evaluate the technol- Signiﬁ cant ogy rapidly, with minimum risk and * NS = No statistically significant difference commitment – both in the feasibility Figure 6: Summary table of resveratrol and metabolite pharmacokinetics – test compound stage, and throughout the develop- (Solu-Resveratrol) compared with reference compound (raw resveratrol API) ment process.

OORALRAL AAprpr 22010.indd010.indd 3030 330/4/100/4/10 08:40:1908:40:19 solubest ad.indd 1 8/4/10 10:45:10 How far could you go with a Nanotechnology platform that’s simple, reliable, and cost effective?

SoluBest’s Solumer technology: A Robust, 2-step process for solubilization of insoluble API’s using FDA approved polymers. Easily and rapidly scalable, using standard spray dryers. Clinically proven to enhance bio-performance.

Performance through Nanotechnology

solubestOORALRAL AApr pad.inddr 22010.indd010. i n 1dd 3131 330/4/108/4/100/4/10 10:45:1008:40:3208:40:32 ONdrugDelivery EDITORIAL CALENDAR

Publication Month Issue Topic Materials Deadline

May 2010 Delivering Injectables: formulation focus n/a

June 2010 Delivering Injectables: device focus June 4th

July 2010 Targeted Drug Delivery July 2nd

September 2010 Needle-Free Injection Devices August 7th

October 2010 Preﬁ lled Syringes September 3rd

November 2010 OINDP (Pulmonary & Nasal Delivery) October 1st

December 2010 Delivering Biologics: proteins, peptides & nucleotides November 5th

January 2011 Preﬁ lled Syringes December 6th

February 2011 Oral Drug Delivery & Advanced Excipients January 3rd

March 2011 Transdermal Delivery February 7th

IN WHICH EDITION SHOULD YOUR COMPANY APPEAR? WWW.ONDRUGDELIVERY.COM

OORALRAL AAprpr 22010.indd010.indd 3232 330/4/100/4/10 08:40:3208:40:32 ORALLY DISINTEGRATING EXTENDED RELEASE (ODT-ER) DOSAGE FORMS

In this article, Woubalem Birmachu, PhD, Senior Manager of New Technology at CIMA Labs, summarises CIMA’s ability to combine orally disintigrating tablet technology with extended release delivery systems, providing all of the benefits of these two drug delivery technologies in a single pharmaceutical product.

The goal of controlled-release drug delivery (GERD) and inflammation of the oesophagus, systems is to provide the optimum dosage oesophagitis as well as oesophageal cancer. In of a drug so as to increase efficacy, reduce these cases, rapidly disintegrating dosage forms side effects and increase patient compliance. which melt in the mouth add great clinical value. Extended release (ER) formulations enable less CIMA builds on its expertise in taste-masking frequent dosing of drugs with short half lives and orally disintegrating tablet technology to devel- and avoid the ‘peaks and troughs’ of drug plas- op orally disintegrating extended release (ODT- ER) dosage forms. A variety of “CIMA BUILDS ON ITS EXPERTISE different solvents and polymer IN TASTE-MASKING AND systems are utilised to encapsulate the drug, resulting in polymer- ORALLY DISINTEGRATING TABLET coated fine particles. These particles are then incorporated into an TECHNOLOGY TO DEVELOP ORALLY ODT matrix. The resulting ODTs DISINTEGRATING EXTENDED RELEASE are capable of providing a variety of custom release profiles rang- (ODT-ER) DOSAGE FORMS” ing from immediate-release to enteric-coated, delayed release to ma concentrations associated with rapid release extended-release, once-daily formulations. drugs and the resulting time variant efficacy. The drug plasma concentrations remain inside EXTENDED RELEASE ORALLY the therapeutic range for a longer period of time DISINTEGRATING TABLET compared with conventional rapid-release for- TECHNOLOGY mulations. Once-a-day extended-release formulations provide an additional advantage for the Using its OraSolv®, DuraSolv® and Lyoc™ paediatric population and adult patient popula- technologies CIMA has been successful in tions where compliance is an issue. the formulation of orally disintegrating tablets Orally disintegrating tablets (ODT) which (ODT) with extended-release profiles. Woubalem Birmachu, PhD melt fast in the mouth are easy to swallow and These ODT technologies meet the CDER Senior Manager of New Technology easy to administer to paediatric populations and definition of an ODT: “A solid dosage form T: +1 763 488 4700 F: +1 763 488 4800 increase patient compliance in this population. containing medicinal substances, which dis- E: [email protected] These dosage forms also provide additional integrates rapidly, usually within a matter of advantages for patients who experience dysphagia seconds, when placed upon the tongue”. CIMA Labs, Inc (difficulty swallowing). Dysphagia may result as ODTs are popular because they offer many 7325 Aspen Lane a consequence of neurological disorders such as advantages to patients and physicians, such as: Brooklyn Park stroke, brain or spinal cord injury, multiple scle- • Convenience – can be taken with or without MN 55428 rosis, muscular dystrophy, or Parkinson’s disease. water. United States Dysphagia may also result from gastro-intestinal • Great taste – bitter drugs can be taste-masked www.cimalabs.com disorders such as gastro-esophageal reflux disease and many flavour options are available.

OORALRAL AAprpr 22010.indd010.indd 3333 330/4/100/4/10 08:40:3208:40:32 “DRUG PLASMA CONCENTRATIONS REMAIN INSIDE THE THER- OraGuard™ extended release / tamper deterrent technology. This technology provides APEUTIC RANGE FOR A LONGER PERIOD OF TIME COMPARED robust extended-release PK profile, even during co-administration with alcohol. It is also resist- WITH CONVENTIONAL RAPID-RELEASE FORMULATIONS” ant against various tampering methods including crushing and ingestion, injection or snorting, • Ease of administration – disintegration of the ABOUT CIMA chewing, aqueous extraction for IV dosing and dosage form in the mouth makes swallowing alcohol extraction. the dosage form an easy task. CIMA Labs, a world leader in the drug For insoluble drug candidates, CIMA has • Discreet – taken whenever and wherever delivery partnering business, specialises in developed a solubilisation technology known patients want. Quick disintegration of tablet, the formulation, taste-masking and manu- as MicroSolv™. It is a solid self emulsifying convenient unit dose blister packaging. facturing of pharmaceuticals utilising its drug delivery system (S-SEDDS). The drug is • Safety – blisters can be made to meet many orally disintegrating tablet (ODT), oral emulsified and adsorbed onto a powder that can child-resistant packaging requirements. transmucosal (OTM), tamper deterrent, solubiliza- be manufactured as a tablet, capsule or ODT. tion and oral powder drug delivery technologies. Finally, CIMA offers a granules / oral powder The combination of ODT technology with Orally Disintegrating Tablets disintegrate formulation system, comprised of drug granules, ER technology results in ODT-ER dosage in the mouth and can be taken without water. packaged in a sachet. It can accommodate high forms, which provide additional clinical value CIMA offers compressed (OraSolv® and doses (>1 g) of drug product. Customised gran- to patients, including: DuraSolv®) and lyophilized (Lyoc™) tablets ule size, release profile, enteric coating, flavour- with customised release profile, enteric coating, ing and colouring options are available. • Extended release – reduction in dosing fre- flavouring and colouring options. CIMA Labs has proven commercialisation quency, better compliance. The Oravescent®, oral transmucosal buccal success with more than 20 products marketed in • Better maintenance of therapeutic levels. tablet technology delivers drugs directly through more than 70 countries around the world. Our • For patients who experience dysphagia the oral mucosa rather than in the gastro-intestinal expertise includes R&D, formulation, manufac- due to stroke, brain or spinal cord injury, tract. Transmucosal drug delivery can result in a turing and packaging. We put these capabilities multiple sclerosis, muscular dystrophy, greater rate and extent of drug uptake into the sys- to work for our partners to commercialise their Parkinson’s disease, GERD, oesophagitis temic circulation, which may also reduce the dose products and bring them to doctors and patients and oesophageal cancer. of drug required to produce a therapeutic effect. around the world. ecv Changing World of APIs

New! Join the growing market of biotech-based proteins

Protein Pharmaceuticals Hanns-Christian Mahler, Gerrit Borchard, Henrik L. Luessen

ISBN 978-3-87193-382-0 • € 126.00 • 1st edition 2010 • 15,3 x 23 cm, 464 pages, paperback

The book covers principal topics on the basics in protein glycolation of proteins, targeting aspects and still evol- Target groups chemistry in order to understand the particular behavior ving technologies to modify delivery of such protein the- • Scientists in Research & Development of such molecules and their analytical characterization. rapeutics by depot formulations or lipid complexation. • Scientists in Preclinical and Clinical R&D Particular issues related to stability aspects and aggrega- Considering its importance of safety and efficacy, also im- • Scientists in Drug Metabolism and tion have been addressed as well. munogenicity and considerations for product development Pharmacokinetics have been addressed. • Engineers in Production As a second area the book then discusses the formulation • Manager in Quality Control / of biopharmaceuticals and drying techniques to stabilize Last but not least, two chapters address regulatory Quality Assurance proteins, as well as further specific areas such as highly aspects that pharmaceutical and biopharmaceutical scien- • Formulation Scientists concentrated protein formulations, primary packaging ma- tists should keep in mind when being involved in the de- • Packaging Development Experts terials, and manufacturing challenges. velopment of biopharmaceuticals. • Qualified Persons

In addition, the in vivo fate of biopharmaceuticals considering their pharmacokinetic/pharmacodynamic behavior is addressed in this section. Tel. +49 (0)7525-940 135, Fax: +49 (0)7525-940 147, eMail: [email protected] Since a second generation of biopharmaceutical products Visit www.ecv.de for our online shop, book extracts and tables of contents are facing market authorization or are already launched, some chapters were also dedicated to the polyethylene ECV · Editio Cantor Verlag

OORALRAL AAprpr 22010.indd010.indd 3434 330/4/100/4/10 08:40:3308:40:33 OORALRAL AAprpr 22010.indd010.indd 3535 330/4/100/4/10 08:40:3608:40:36 Extraordinary not Ordinary Zydis® Fast-Dissolve Technology

Zydis® fast-dissolve technology is a unique, freeze-dried oral solid dosage form that disperses instantaneously in the mouth in as little as three seconds.

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Whether you are considering an ODT to enhance pharmacokinetics through pre-gastric absorption, looking for a way to improve patient compliance, or seeking a marketing advantage for a valued brand, Zydis technology can help to enhance the value of your investment – and accelerate your product’s potential.

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OORALRAL AAprpr 22010.indd010.indd 3636 330/4/100/4/10 08:40:4308:40:43