Oral Delivery Oct 06 18/1/07 20:19 Page 1
Oral Delivery Oct 06 18/1/07 20:19 Page 1
ORAL DRUG DELIVERY WHEN YOU FIND THE HOLY GRAIL
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“Oral drug delivery: when you find the Holy Grail” CONTENTS
This edition is one in a series of sponsored themed publications from ONdrugDelivery Ltd. Each issue focuses on a specific topic within the field of drug delivery, and contain up to eight articles contributed Introductory comment by leaders in that field. Guy Furness 3
Full contact information appears alongside each article. Contributing companies would be delighted to hear Growing sales and new opportunities for oral from interested readers directly. ONdrugDelivery fast dissolve would also be very pleased to pass on to authors, or Dr Ian Muir answer as appropriate, any queries you might have in relation to this publication or others in the series. Cardinal Health 4-6
During 2007 ONdrugDelivery will be covering the following topics: From oral drug delivery technology to proprietary February: Transdermal delivery product development April: Pulmonary delivery Dr Anand Baichwal, Thomas Sciascia, MD June: Prefilled syringes Penwest Pharmaceuticals 7-10 August: Oral drug delivery October: Delivering injectables December: Nanotechnology in drug delivery Combination oral products: the time is now! Fred H. Miller To start a FREE subscription (pdf or print) to INNERCAP Technologies 12-15 ONdrugDelivery’s sponsored series, please contact ONdrugDelivery directly (details below) Combining technologies without compromise: taste masking + ODT + modified release Steve Ellul Eurand 16-19
Oral drug delivery: the Holy Grail To find out more about how your company can Ms Bavani Shankar participate in 2007, please contact ONdrugDelivery Emisphere Technologies 20-21 directly (details below).
Contact: More than just fast-dissolve: Guy Furness, Publisher CIMA’s broad oral delivery technology offering T: +44 1273 32 02 79 Dr Richard J. Welter, Dr Derek Moe E: [email protected] CIMA R&D 22-23
Oral drug delivery: when you find the Holy Grail. Company profile Published by ONdrugDelivery Ltd, Cedar Cottage, SkyePharma 25 Newtimber Place Lane, Newtimber, West Sussex, BN6 9BU, United Kingdom. Registered in England: No 05314696.
Copyright © 2007 ONdrugDelivery Ltd
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 accept liability for the consequences of any decision or action taken (or not taken) as a result of any information contained in this publication.
Front cover image reproduced with kind permission from InnerCap Technologies, Inc, whose article appears on page 12 of this issue
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INTRODUCTION
Despite phenomenal advances in the inhalable, The message that pharmaceutical companies The increasing injectable, transdermal, nasal and other routes usually send to would-be oral technology number of oral fixed- of administration, the unavoidable truth is that partners is: only those with technologies that are dose combinations oral drug delivery remains well ahead of the highly differentiated, fulfil needs that are near reaching the market and their growing acceptance pack as the preferred delivery route. There are impossible to meet elsewhere, and are proven in by the medical and regulatory communities is of course many applications and large markets the market place, need apply. highlighted by InnerCap Technologies. The for non-oral products and the technologies that company’s multiphase, compartmentalised capsule deliver them. However, if it is a viable option, Nevertheless, although the environment is technology, NovaCaps, both meets the existing oral drug delivery will be chosen in all but the tough, success is possible. Indeed, a thriving oral needs for developing oral combinations, and most exceptional circumstances. Moreover, if drug delivery sector does exist and it is expands the potential application of combinations the oral route is not immediately viable, populated by innovative companies involved in into areas not previously considered possible. pharmaceutical companies will often invest fruitful collaborations with pharma and biotech resources in making it viable, rather than partners. I will divide these successful oral drug Finally, we are pleased to include here a piece plumping for an alternative delivery method. delivery technologies into two broad categories: from Emisphere Technologies. Its eligen drug carrier technology for delivering fragile In a presentation last year, John Lynch, Chief 1. technologies which represent the crème de la macromolecules via the oral route has the Operating Officer of Merrion Pharmaceuticals crème among many available systems addressing potential to bring the Holy Grail, oral drug said that the oral drugs market generated US$26 a common delivery need (such as modified- delivery, within the reach of biologics companies billion sales in 2004 and would experience 16% release or orally disintegrating tablets) and others for whom oral delivery has growth up to 2008. He added that orally traditionally been viewed as out of the question. delivered products accounted for 84% of the sales 2. highly specialised technologies meeting a With a remarkable claim such as this, the of the top 50 selling drugs worldwide. niche demand or a need with a high company has met with scepticism and even technological barrier to entry (for example, oral derision over the years. Having made significant Oral products go from strength to strength, delivery of fragile macromolecules, or precision progress and generated robust data despite its but the oral drug delivery sector is by no means release at specific locations within the GI tract) critics, here it presents encouraging evidence that an easy one to succeed in. In fact it has to some eligen does indeed fulfil its promise. extent become a victim of this popular delivery In this issue we are delighted to present route’s success. Firstly, drug discovery efforts articles from six of the leading names in oral drug The primary purpose of this publication is to are directed at generating compounds that are delivery. It is of course up to the reader to decide provide a platform from which companies can readily orally deliverable and have the right into which, if either, of the two categories above describe their oral drug delivery systems and pharmacokinetic/pharmacodynamic profile the technologies described might fall. outline their merits using scientific data and study without the need for any specialised delivery results. However, during the process of choosing a technology. Secondly, when an oral drug Various aspects of oral drug delivery are drug delivery partner it is important not to delivery technology is needed, it is common for covered including: oral controlled-release; orally underestimate the significance of “soft factors” – pharma companies to develop them in-house. disintegrating tablets (ODTs); fixed-dose essentially the factors such as company culture, It’s worth the effort because the technology is combination capsules; oral macromolecular business practices and individual employees’ likely to be useful to them in the future since the delivery; and the move to a specialty pharma personalities, which decide whether a good day-to- majority of products in the pipeline are business model. day working relationship between two administered orally. Thirdly, the potentially organisations will be possible. This is especially large rewards of developing a successful oral Three of the articles in this issue are contributed important when considering a shortlist of similar delivery system have meant that the market is by companies discussing their ODT systems. Side technologies fulfilling similar functions. now awash with hundreds, if not thousands, of by side, these provide an insightful comparison of undifferentiated oral drug delivery companies competing technologies, and taken together the In addition to enabling those readers seeking with equally undifferentiated technologies. papers provide a detailed overview of the latest partnerships for oral drug delivery systems to developments, current issues and trends within this learn about the technologies described in terms For pharma companies requiring a third rapidly growing sub-sector of oral drug delivery. of science, specifications and compatibility with party technology to deliver their compounds, it their own needs, it is my intention that this is difficult to find the right partner. For the The contribution from Penwest publication should also allow the reader, through delivery companies hoping to enter, although Pharmaceuticals discusses the recent approval and the written word of the authors, to get to know the sheer size of the oral delivery technology launch of Opana ER and the first definitive step in the companies themselves a little in terms of market could to some extent improve the its strategy to leverage its oral drug delivery their business strategy, manner and style. chances and potential degree of success, things expertise in the transformation from a technology are significantly more difficult than they might provider to a specialty pharmaceutical company Guy Furness initially seem. focused on neurology. Publisher
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GROWING SALES AND NEW OPPORTUNITIES FOR ORAL FAST DISSOLVE
ORAL FAST DISSOLVE TECHNOLOGY IS OFTEN EMPLOYED WITH SUCCESS AS PART OF PRODUCT LIFECYCLE MANAGEMENT STRATEGIES, AND IS POPULAR IN THE OTC AND PRESCRIPTION ONLY MARKETS. HERE, DR IAN MUIR, VICE-PRESIDENT OF OPERATIONS AT CARDINAL HEALTH, EUROPE, GIVES AN OVERVIEW OF THE CURRENT TECHNOLOGY LANDSCAPE, DISCUSSES STRENGTHS AND LIMITATIONS, AND LOOKS AT HOW THE MARKET WILL DEVELOP IN THE FUTURE.
The drug delivery sector of fast dissolve products The lyophilised systems have been by far the has grown rapidly from sales in 2002 of about $850 most successful among them in terms of sales million to 2005 were estimated sales were around value, sales volume and number of worldwide $1.4 billion (IMS Data). Despite this success there product approvals. The technology around these is no agreed regulatory definition of what consti- systems involves taking a suspension or solu- tutes a true fast dissolve product. It is generally tion of drug with other structural excipients and, accepted that products fall into this field if they dis- through the use of a mould or blister pack, form- solve in the mouth in less than 30 seconds, which ing tablet-shaped units. The units or tablets are is what distinguishes them from traditional effer- then frozen and lyophilised in the pack or vescent, chewable or immediate release tablets. mould. The resulting units have a very high There are some class characteristics, which all porosity (see figure 1), which allows rapid water fast dissolve products have in common (see table or saliva penetration and very rapid disintegra- Dr Ian Muir 1). In fact the market has really been defined by tion. Figure 2 shows an orodispersible tablet Vice-President of Operations at Cardinal Health, Europe the success of the various proprietary fast dissolve (ODT) produced using Cardinal Health’s Zydis delivery systems and their ability to meet the needs technology, disintegrating over three seconds. North American Contact: of the patient, formulators and marketing groups. Dose-handling capability for these systems Stacey R. Vaughan The use of drug delivery technology in the differs depending on whether the active ingredi- Cardinal Health product management lifecycle is well known to all ents are soluble or insoluble drugs, with the Director Business Development Zydis North America in the pharmaceutical sector. Key to the success of dose capability being slightly lower for the for- 14 Schoolhouse Rd. a drug delivery-based application is that there is a mer than for some tablet based systems. The Somerset, NJ 08873 clear unmet need or benefit to the use of the chosen units are capable of incorporating a range of T: 610-667-2511 F: 610-667-2950 system. A technology selection process is most suc- taste-masked materials and have more rapid dis- Mobile: 610-716-6611 cessful when considering the market, patient and integration than tablet-based systems (table 3). E: [email protected] clinical requirements and increasingly the reim- Compressed tablet-based systems are produced bursement environment for the product. Bringing using standard tablet technology by direct com- Rest of World Contact: Michele Stokes these four factors together significantly enhances pression of excipients. Depending on the method Regional Account Manager the chances of market acceptance. Some examples of manufacture, the tablet technologies have dif- Cardinal Health, International of considerations in each area are listed in table 2. ferent levels of hardness and friability. This results Sedge Close Headway, Great Oakley in varying disintegration performance (see table 3) Corby FAST DISSOLVE TECHNOLOGIES and packaging needs, which can range from stan- Northamptonshire NN18 8HS dard HDPE bottles or blisters through to more spe- For ease of description, fast-dissolve tech- cialist pack designs for product protection – CIMA Mobile: 07919 044666 nologies can be divided into three broad groups: Labs’, PackSolv, for example. E: [email protected] lyophilised systems, compressed tablet-based The speed of disintegration for fast-dissolve http://www.cardinal.com/pts/ systems, and thin film strips. tablets compared with a standard tablet is
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achieved by formulating using water soluble Product Characteristics excipients, or super-disintegrant or effervescent Rapid and complete disintegration in less than 30 seconds components, to allow rapid penetration of water into the core of the tablet. The one exception to Dispersion of the dosage form in the mouth without water this approach for tablets is Biovail’s Fuisz tech- Oral solid delivery system nology. It uses the proprietary Shearform system to produce a drug-loaded candy floss, which is Packaging which provides a safe and stable marketed product then used for tableting with other excipients. Table 1: Key characteristics of orally disintergrating systems These systems can theoretically accommodate relatively high doses of drug material, including Market Patient Clinical Payer taste-masked coated particles. The potential dis- Patent protection Ease of use Alternative route of Cost effectiveness advantage is that they take longer to disintegrate administration than the thin-film or lyophilised dosage forms. Market exclusivity Possibility of greater Reduced side effects Application in clinical compliance subset with unmet The loose compression tablet approach has need increasingly been used by some technology hous- Stable manufacturing platform Application in clinical Reduced dose Compliance linked to es, branded companies and generic pharmaceuti- subset with unmet need clinical outcome. cal companies, for in-house development of line Cost-effective manufacture Palatable product Bioequivalence Price versus convenience for OTC extension and generic fast-dissolve dosage forms Stable device or packaging Cost effectiveness - - ORAL FILMS Proven regulatory & market - track record. - - Although oral film systems, the third class, Table 2: Key considerations in technology platform evaluation have been in existence for a number of years, they have recently become the new area of inter- entered the ethical prescription market. est in fast-dissolve pharmaceutical drug delivery. In contrast the market for thin film strips is This is largely as a result of the success of the mainly in the consumer vitamins, minerals and consumer breath freshener products such as supplements (VMS) and OTC areas. Active Listerine PocketPaks in the US consumer market. ingredients which appear to be suitable are vita- Such systems use a variety of hydrophilic mins, supplements such as melatonin and polymers to produce a 50-200 mm film of mate- CoQ10, and some OTC ingredients. An example rial. This film can reportedly incorporate soluble, of the type of developments in this area are the Figure 1: Magnified cross section of a insoluble or taste-masked drug substances. The deals between Bioenvelop and NutriCorp, who lyophilised ODT, showing the highly film is manufactured as a large sheet and then cut have approval for a range of products in Canada porous structure into individual dosage units for packaging in a including benzocaine, caffeine and menthol. To with novelty and ease of use. On a clinical level range of pharmaceutically acceptable formats. give another example, Leiner Health Products this can translate into better compliance. There remain a number of technical limita- have an exclusive deal to sell MonoSol film strips For some drugs capable of being absorbed via tions with the use of film strips. The volume of for OTC products, the first of which is reported as the pre-gastric route, the use of a fast-dissolve sys- the dosage unit is clearly proportional to the size a melatonin supplement. tem can result in the drug being absorbed more of the dose, which means these extremely thin quickly and more reproducibly, compared with a dosage forms are best suited to lower-dose prod- RATE OF DISINTEGRATION standard tablet. In these specific cases the speed of ucts. As an example of this, Labtec claim that the dispersion, and therefore the relative amounts of RapidFilm technology can accommodate doses One question, often asked, is whether the rel- drug retained in the mouth or the proportion of the of up to 30 mg. This clearly limits the range of ative speed of disintegration is important in the dosage form swallowed before dispersing, could compatible drug products. The other technical selection between fast-dissolve products. At a make a difference to the pharmacokinetic profile. challenge with these dosage forms is achieving general level there are various reports in the sci- Drug molecules which are likely to be suit- dose uniformity and unit dose packaging, which entific literature and from consumer preference able for delivery via this pre-gastric route are is an area for differentiation in the technology studies, which show patient preference for fast generally soluble in saliva and have a high parti- providers such as LTS and Cardinal’s DelStrip. dissolve over a standard tablet if they are given tion coefficient (log P>1) – characteristics often The much-heralded advent of major branded the choice. This preference is usually linked associated with CNS active compounds. A good products in this area still seems some way off. This may be partly due to the technical difficul- ties of taste masking and dose loading, but also the fact that there appears to be fewer commer- cial barriers to entry into this field. In 2001 and 2002 it was reported that many significant therapeutic products would launch using this technology over the next two or three years. Whilst there has been a five-fold increase 1 seconds 2 seconds 3 seconds worldwide in the number of thin film strips since 2002, very few if any such products have Figure 2: Rapid disintegration of a lyophilised Zydis tablet in minimal volume of water
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Product Technology Diameter Start End example where this route of administration has (mm) (seconds) (seconds) been used to commercial and clinical advantage is the Zydis based selegiline product, Zelepar. Alavert 10mg CIMA 10.0 22.7 32.8 The ODT version provides equivalent therapeutic Benadryl Fast Melt - 11.2 10.9 15.7 plasma levels to the 10 mg standard oral tablet with doses of only 1.25 mg and a resulting reduc- Claritin Reditabs Zydis 11.1 0 3.8 tion in the metabolite associated side effects. Excedrin Quicktabs - 17.5 11.8 25.8 Currently, products developed and manufac- tured using Cardinal Health’s Zydis, CIMA Lab’s Maxalt MLT Zydis 11.0 0 1.8 Orasolve and Janssen’s in-house Quicksolv tech- NuLev CIMA 14.0 7.9 13.9 nologies account for more than 75% of US sales Remeron Soltab Quicksolv 9.7 22.3 56.6 of fast-dissolve products (see table 4).
Xilopar 1.25mg Zydis 11.0 0 2.8 ... TO THE FUTURE Zofran Zydis Zydis 9.0 0 2.2 Not surprisingly, with a large market and sig- Table 3: Disintegration times for marketed fast dissolve products (Source: Bohnacker nificant brands, there have been a number of gener- R et al, Pharm Ind 2005, Vol 67(3), pp 327-335) ic filings in the fast-dissolve area, some of which have entered the market and others are awaiting the Product Technology resolution of patent or regulatory reviews. Table 5 Zyprexa – Eli Lilly Zydis – Cardinal Health shows just some of the reported examples of fast dissolve-based generic applications. Claritin Reditab – Schering Plough Zydis – Cardinal Health Within the patient population, fast-dissolve Zomig ZMT – Astra Zeneca Orasolv – Cima (Cephalon) has applications in some increasingly important Maxalt MLT – Merck Zydis – Cardinal Health demographic groups, such as elderly and junior age groups. Zofran ODT – GSK Zydis – Cardinal Health The switch of products from the prescription- Prevacid Solutab - TAP Unknown only to OTC markets in the US and EU will also Risperdal – Janssen Quicksolv – Janssen drive increasing interest in more consumer-ori- entated and differentiated dosage forms. This is Table 4: Top ODT products ranked by sales where consumer-orientated products may start to have a greater role in the pharmaceutical arena, Product Technology provider and a number of the thin-film technology and other fast-dissolve products could clearly have Mirtazapine Teva applications in the OTC area. Mirtazapine Barr One area that is, as yet, under developed is the Mirtazapine Actavis delivery of biological molecules via the oral route. Many of these molecules are unstable during pro- Mirtazapine Aurobindo cessing and unstable in the acid of the stomach and Clonazepam Kali so parenteral administration is the only option. Tramadol Biovail Some fast-dissolve technologies could be used to produce stable freeze-dried solid tablets Citalopram Biovail and deliver these pre-gastrically in a form that Tramadol Ethypharm allows rapid dissolution in the mouth. The recent European approval of GRAZAX the fast-dis- Table 5: Fast-dissolve generics solve formulation of a purified grass pollen prod- Market Sector Use Of FDDF uct for the treatment of allergic rhinitis shows that delivering a stable form of the protein for local 60% effect can be sufficient to achieve therapeutic out- 50% comes in a more patient orientated dosage form. Figure 3 shows the proportion of approved 40% Japan 30% US fast-dissolve products by therapeutic area and geographic region. CNS applications are clearly 20% EU the most popular in all three regions. The capaci- 10%
% Approved Products ty of fast-dissolve technology to increase compli- 0% ance means that pain management products and
CNS Pain CVS treatments for Parkinson’s disease, depression, Allergy Other schizophrenia, Alzheimer’s disease and other Cough / cold GI Treatment CNS conditions will continue to be strong areas Figure 2: Proportion of fast-disintegrating systems approved, by therepeutic use for development within the fast dissolve field.
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FROM ORAL DRUG DELIVERY TECHNOLOGY TO PROPRIETARY PRODUCT DEVELOPMENT
Penwest Pharmaceuticals is implementing a strategy to make the change from being a drug delivery technology provider to a specialty pharma company. This article outlines how Penwest (Danbury, Connecticut, US) is currently implementing this change. By drawing on its reputation for technical excellence in oral controlled release, and choosing its product development targets intelligently, Penwest is moving forward to attain its goal of becoming a specialty pharma company, marketing its own portfolio of neurology products.
Prepared by ONdrugDelivery on behalf of Penwest Pharmaceuticals
Penwest’s business has been built on developing is indicated for chronic moderate-to-severe pain sophisticated yet simple oral controlled-release in patients requiring continuous, around-the- systems. In the late 1990s, Mylan clock opioid treatment for an extended period of Pharmaceutcial’s Nifedipine XL was the first time. Opana ER is well protected from competi- generic controlled release nifedipine to be tion by several barriers to entry. The FDA has approved, and utilised the proprietary TIMERx® granted three-year exclusivity, and the product technology. The product demonstrated scientific benefits from a strong, multilayered IP estate excellence by meeting the challenge of mimick- strategy. Other barriers to generic entry include: ing the release profile of Alza/Pfizer’s limited availability of the active compound; the Procardia® XL. Its release was followed by sev- substantial technical challenge of avoiding (par- tial or complete) disinte- Dr Anand Baichwal Chief Scientific Officer and Senior PENWEST IS ACTIVELY LOOKING TO gration of the formula- Vice-President of Licensing tion when coming into BROADEN ITS EARLY STAGE DRUG contact with alcohol, something that could DEVELOPMENT PIPELINE BY INVESTIGATING lead to dose dumping IN-LICENSING NCES IN SELECTED AREAS (which TIMERx over- comes but which is an OF NEUROLOGICAL THERAPEUTICS issue with some other technologies); and com- eral other proprietary oral delivery systems – pliance with FDA risk-management strategies. including Geminex® and SyncroDose™ - and a Beyond the US launch, Endo and Penwest are Thomas Sciascia, MD gastro-retentive technology (see figure 1 for also evaluating the international opportunity for Chief Medical Officer more details of these technologies). Opana ER. Opana ER’s forecasted revenue Penwest’s transformation started with the stream is an important component in funding Penwest Pharmaceuticals 2003 sale of its excipients business to the Penwest’s growth over the years ahead. 39 Old Ridgebury Road German firm Josef Rettenmaier Holding GMBH The product is the result of a long-standing Suite #11 and Co. KG, which demonstrated Penwest’s collaboration with Endo Pharmaceuticals, Danbury commitment to pursuing drug development. This which already marketed an i.v. version and was CT 06810 United States was followed by Penwest’s partner Endo looking for an experienced drug delivery com- Pharmaceuticals submitting an NDA to the US pany that could provide a controlled-release FDA for Opana® ER, the oral controlled-release technology for an oral formulation. T: +1 203 796 3700 formulation of the opioid analgesic oxomor- Development costs were shared equally P: +1 203 794 1393 E: [email protected] phone, which utilises the TIMERx technology. (50/50). Endo took responsibility for clinical tri- Opana® ER was approved on June 22, 2006 als and the regulatory process, manufacturing www.penwest.com and is available in 5, 10, 20 and 40 mg tablets. It and marketing. Penwest brought the technology
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Figure 1: Opana® ER. FDA approved June 22 2006, August 14 2006, launched by Endo’s sales force August 14, 2006
(TIMERx), product formulation and IP, and tration. In contrast, Opana ER appears to be a at disorders of the nervous system. Opana ER receives a royalty on profits. true twice-daily formulation. will be a significant asset as Penwest continues Opana ER enters a market for long-acting In a 12-week, randomised, double-blind, to develop its product portfolio. strong opioid analgesics valued at US$3.2 bil- placebo-controlled study, 250 opioid-experienced lion (2005), and the timing of its launch may be patients with chronic low back pain, entered the CNS FOCUSED PORTFOLIO fortuitous for several reasons. First, physician study with a pain score of 70 out of a possible 100, hesitancy over long-acting opioids is waning, indicating moderate to severe pain, despite receiv- Two factors have driven the company’s speciali- and a recent WHO guideline supports the use of ing treatment with another opioid. Patient ratings sation in the therapeutic field of neurology. The round-the-clock analgesia. of Opana ER were more favourable than their rat- first is the excellent fit of neurology with Secondly, the opioid prescriber market is ings of their previous opioid or of a placebo. Penwest’s technologies. Neurological disorders under covered giving Endo the opportunity to Opana ER has also been studied in opioid- usually require chronic/ongoing therapy, Dr achieve good penetration. The company has sig- naïve patients with chronic pain. In first time users, Baichwal, Penwest’s Chief Scientific Officer, nificantly expanded its sales team to support side effects can be unpleasant enough to make the states, often self administered in non-clinical set- Opana ER, adding some 220 new reps to create patient discontinue opiate therapy, and it was tings. This points clearly to the use of long-acting a total sales force of about 600. important to know how this group of patients oral dosage forms. Maintaining constant plasma Among long-acting pure oral opioids, oxy- would tolerate Opana ER. In a multi-center, ran- levels of an active compound while minimising codone (Oxycontin®) is currently the most pre- domized, double-blind, parallel group trial, the dosing frequency is also beneficial in neurology scribed. However, there is clearly room for an safety and efficacy of Opana ER were compared therapies, again pointing to long-acting formula- alternative. Although Opana ER and Oxycontin with a placebo in 205 opioid-naïve patients with tions. “Penwest’s controlled-release technolo- both interact on the µ-opiate receptor, patients moderate-to-severe chronic low back pain. Opana gies can help with compliance and safety by respond differently to different compounds ER demonstrated a statistically significant (p < delivering a steady stream of medicine,” he notes. within this class, meaning that the choice of an 0.0001) difference in pain scores between oxymor- The second addresses product sales and mar- alternative improves treatment options. phone ER and a placebo over a 12-week treatment keting. Prescriptions for neurological products Additionally, in long-term treatment, opiate period, during which the drug was administered are typically written by neurologists – a rela- rotation (switching from one opioid to another twice daily. After titration to an effective and toler- tively small and identifiable group. Penwest has similar product) overcomes the reduced effica- ated dose of Opana ER, adverse events incidence recognised that the type and size of sales force cy that is often seen when one product is used was remarkably low over the 12 week double needed to address this market fits with the spe- over an extended period. blind treatment period, with some of the common cialty pharma model and can be achieved more Of perhaps more interest, is that Opana ER is opioid effects occurring but in a low frequency. quickly than that required to reach, for example, a new, differentiated entrant. Oxycontin may be The FDA’s final approval of Opana ER was the large number of primary care practitioners. an extended-release product, but marketing data a key milestone for Penwest and represented a Dr Baichwal details that the company has indicates that in a substantial number of major step in advancing the company’s strategy adopted a three point strategy. Each aspect of patients, it is being used three times per day of building a specialty pharmaceutical company this strategy is characterised by progressing despite being indicated for twice-daily adminis- with a focus on developing compounds targeted experience and strengths.
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Product Name Indication Development Status 2007 2008 Opana® ER (oxymorphone) Chronic Pain approved and launched - Nalbuphine ER Pain Phase I Phase II Pivotal Trial Torsemide ER Edema/CHF Phase I Multiple Phase II Pivotal Trial PW4110 Epilepsy Formulation Development/POP Pivotal trial - PW4150 Epilepsy Formulation Development POP / Phase I - PW4153 Parkinson's Disease Formulation Development/POP POP / Phase I - PW4158 Parkinson's Disease Formulation Development/POP POP / Phase I -
Figure 2: Product pipeline showing current development status, and expected status for 2007 and 2008
The initial strategy has been to develop developed as a once daily tablet using ple – Torsemide ER offers great development existing compounds that can be improved using Penwest’s Geminex. It provides extended potential. This fits with Penwest’s philosophy of Penwest’s technologies. Penwest currently has release of the drug during the waking hours creating differentiated products. Torsemide ER two named products in its portfolio that demon- when CHF patients need protection from is a clear demonstration of the benefit that its strate this approach: Nalbuphine ER and absorbing dietary salt. technology can bring to an existing compound. Torsemide ER. Chronically treated CHF patients typically In contrast to Nalbuphine ER, which Penwest Nalbuphine ER is a controlled release formu- need to excrete between 150 mEq and 200 mEq plans, if approved, to market itself, Torsemide lation of nalbuphine hydrochloride and incorpo- of sodium per day to prevent water retention ER, if approved, will be marketed by a partner. rates Penwest’s drug delivery technology. weight gain that can lead to cardiac decompen- Clinical indications and development time- Nalbuphine ER is designed to be taken as a sation. The current formulations of loop diuret- lines of these products, together with several other twice-daily tablet. This formulation will have ics have short periods of action during which neurological compounds in Penwest’s pipeline, plasma kinetics derived from both immediate most of the sodium excretion takes place. Short are summarised in figure 2. release and controlled release components. durations can both leave the patient unprotected The second thread of Penwest’s strategy is Nalbuphine hydrochloride is a synthetic opioid for long periods during the day, when sodium the development of external technology-based agonist-antagonist analgesic of the phenanthrene retention is occurring via food, and create the products and the broadening of its technology series and is currently only available as a sterile potential for large urinary volume diuresis after profile. The company is developing products solution suitable for subcutaneous, intramuscu- drug ingestion, resulting in unpleasant side and accessing a portfolio of differentiated tech- lar, or intravenous injection under the brand effects endangering compliance. nologies with specific applications in the neu- name NUBAIN® and as a generic. Annual sales Commenting on clinical trial results released rology field. Importantly, this part of the strate- of this product are approximately US$10 million at the end of 2005, Dr Thomas Sciascia said that gy is not limited to Penwest’s traditional field of - constrained by the currently available formula- the company was “encouraged that the data sup- oral delivery. Feasibility studies are currently tions and indications. If approved, Penwest ports the conclusion that torsemide can be for- underway with several pioneering non-oral expects that oral Nalbuphine ER, which has suc- mulated and administered once daily in a man- delivery systems, the company has revealed. cessfully completed Phase IIa trials, will com- ner that can result in a longer duration of action The final piece of the three-part strategy is pete in the moderate to moderately severe pain than that provided by currently marketed brands the establishment of a proprietary portfolio of market with drugs such as Tramadol®. of the drug. This difference could be significant neurological NCEs. Penwest is actively looking The one non-neurological product in to congestive heart failure patients in a real to broaden its early stage drug development Penwest’s pipeline is Torsemide ER. This is a world situation in which dietary sodium intake pipeline by investigating in-licensing NCEs in controlled-release formulation of the loop- is large and sodium intake occurs throughout the selected areas of neurological therapeutics. diuretic torsemide, and is currently marketed as waking hours.” Areas of interest include niche neurological an immediate release oral formulation branded Retaining Torsemide ER when Penwest has diseases, where small molecule drug develop- Demadex®, for the treatment of congestive decided to concentrate on neurologicals perhaps ment is still needed to treat conditions that are heart failure (CHF). Torsemide ER has been raises some questions, but the rationale is sim- not adequately addressed with available medi-
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cations. Penwest’s goal is to commercialize ensured optimal relations with Wall Street and CONCLUSION these products, if approved, by building a spe- will further support in driving the business. cialty sales force of its own or through out- The scientific team is also stronger. Amy Penwest is not alone in evolving from a technology licensing arrangements. O’Donnel, MD, has been appointed to the new provider to a drug development company, attracted position of Senior Director of Clinical by the growth that can be achieved via the special- BUILDING THE Development joining Chief Medical Officer ty pharma business model. Companies such as MANAGEMENT TEAM Thomas Sciascia, MD, and concentrating the Biovail and Alza have achieved success in trans- company’s focus on therapeutic product forming themselves into high growth, value added The refocused Penwest has built an optimal development. pharmaceutical companies developing important management team, making several key appoint- Penwest has also preserved its drug delivery medicines that have a positive impact on patients. ments to progress the business. Jennifer Good heritage. Dr Anand Baichwal, co-inventor of Penwest plans to capitalise on the opportunities that was appointed to Chief Executive Officer in TIMERx and subsequent oral delivery technolo- lie ahead of them with their experienced manage- June of 2006. With nine years of experience at gies, is the Company’s Chief Scientific Officer ment team, their expertise in drug delivery tech- the company, Jennifer brings the necessary and Senior Vice-President of Licensing. nologies and their knowledge in drug development. expertise, vision and energy to move Penwest Commenting on the company’s positive out- Penwest has built on its past achievements, com- forward in its strategy. The appointment of look he says: “By late 2009, Penwest’s goal is to bining them with its current strength and expertise, Benjamin Palleiko, a former investment banker, be a true development-focused specialty phar- and is poised for a new level of growth through a to Senior Vice President, Corporate maceutical company, selling and marketing its diverse portfolio of drugs primarily targeted at Development and Chief Financial Officer has own portfolio of neurology products.” treating diseases of the nervous system.
PENWEST’S TECHNOLOGY PORTFOLIO
Oral controlled release technology Dual-delivery system which can Releases drug at the desired time based on a natural gum matrix. release drugs or isomers at two and site in the body to coincide different rates. with the body’s circadian rhythm TIMERx achieves a variety of release pattern or to allow drugs to be profiles (First order, Zero order, To achieve the unique release profiles delivered to different sites within Burst CR, etc) for a wide range of different custom granulations are made the GI tract. drugs, accomodating even the most for each drug component. The two difficult actives. drugs are then compressed on a By administering drug at the optimal standard bi-layer press. time after ingestion, SyncroDose can TIMERx can be used in: potentially improve the therapeutic Geminex offers: • Low to high dose drugs benefit of drugs or reduce the dose • Rapid development times which can needed to provide a given therapeutic • Insoluble to highly-soluble drugs result in a speed-to-market advantage. effect. If a reduction in dose occurs, the • Drugs with short half-life and/or side effects of the drug may also be • Custom formulations are made for narrow therapeutic window. reduced or lessened in severity. each drug component to ensure The technology is based on maximum therapeutic benefits. A SyncroDose tablet consists of an acustomised, agglomerated inner core of drug and a surrounding • Special equipment is not required; hydrophilic complex that forms a compression coating containing a standard bi-layer press is all that controlled-releasematrix upon TIMERx® based materials (see below). is required. compression. Lag time is controlled by variations in • Geminex-based products are more the two polysaccharides, xanthan gum The matrix consists of two cost-effective than combination drug and locust bean gum, found in the polysaccharides, xanthan and locust products thatare based on the TIMERx coating. bean gum. Interactions between these application of multiparticulate components in an aqueous technologies. environment form a tight gel with a slowly-eroding core. Geminex can deliver a medication that is therapeutically superior to its individual components.
S chematic of a SyncroDose tablet showing core and coating Schematic of Geminex bilayer tablet
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