COVER STORY
STAR BURST Photomicrograph of crystals of celecoxib sodium ("dots") converting to needlelike crystals of celecoxib ("star") during exposure to an aqueous solution. Careful formulation strategies can avoid such problems and improve the bioavailability of the drug.
NEW WRINKLES IN DRUG DELIVERY Technology platforms by themselves are no longer enough—now companies need products to generate value CELIA M. HENRY, C&EN WASHINGTON
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delivery field has focused on creating new forms of established drugs. Drug delivery has been seen as a method of "life-cycle management" to extend product franchises by offering improved versions of drugs as patents are getting ready to expire. In other cases, drug delivHTTP://WWW.CEN-ONLINE.ORG
ery companies have created their own versions of drugs that are off patent. Now drug delivery companies are starting to position their technologies earlier in the drug development timeline. Alza Corp.'s efforts are a prime example. Speaking last December in Hawaii at the U.S.Japan Symposium on Drug Delivery Systems, Alza President Howard B. Rosen described how his company, located in Mountain View, Calif, is becoming involved C & E N / MARCH 1 , 2004
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COVER STORY with the pharmaceutical development process as early as the discovery phase. "We now have access to new molecular entities to which we can apply novel drug delivery technologies," Rosen said. "This is a relatively new area of focus for us and the industry as a whole, as most drug delivery products that have been brought to market have been based on off-patent compounds or life-cycle management concepts." Alza, part ofJohnson & Johnson since 2001, now plays a role in various stages of the drug life cycle, Rosen said. Although still involved in life-cycle management, it is now also involved with developing methods to deliver new chemical entities and biopharmaceutical products. Alza scientists are working with discovery chemists to do what Rosen called "enabling activities." For example, they might take a compound that has a short half-life in the body and manipulate the pharmacokinetic profile using drug delivery Such drug delivery activities can help drugs that are notoriously difficult to deliver, such as poorly water-soluble compounds, stay in the pipeline. "By applying drug delivery earlier in the development process, there is a potential to improve productivity as well as product outcomes and create truly best-in-class products," Rosen said. "Working back to Phase I to III clinical trials, drug delivery is looked at to fill the space between early and late clinical development." One consequence ofbeing involved earlier in the process is that smaller quantities of the drug substance are available. When drug delivery scientists work with marketed products to devise new delivery methods, they have the luxury of working with kilogram quantities. At the early discovery stage, they often have access to only milligrams. Therefore, they must come up with new methods of testing delivery options. IN THE PAST, drug delivery companies have positioned themselves as technology companies, but now it's no longer enough for drug delivery companies to rely solely on their technology platforms. They need tangible products. At the Drug Delivery Partnerships meeting, held in Los Angeles in late January, "products" and "value" were major themes. "It's all about products," said financial analyst David M. Steinberg, managing director ofequity research for specialty pharmaceuticals and drug delivery at Deutsche
Bank Securities in San Francisco. "That's where the value comes in." Because products are so important in imparting value to the industry and investors, Steinberg suggested that the "right" business model for drug delivery companies includes having multiple technology platforms and multiple product opportunities, representing "more shots on goal." With only one technology, a company's prospects are limited without a blockbuster drug, Steinberg said. He pointed out that as the health care system tries to contain costs, "me too" products will "fall by the wayside" and "differentiated, high-value drug delivery products will win."
their "inability to see around corners." He cited the example of the Eli Lilly/Icos product Cialis, one of the most recent entries in the erectile dysfunction market. The compound started out as a project between Glaxo and Icos. However, because the inhibitors had no clear value in cardiovascular disease or inflammation, which was what Glaxo was interested in, Glaxo gave the product to Icos, who then teamed up with Lilly The growth in drug delivery deals needs to be seen in the context of jump-starting discovery Longman said. The big drug delivery deals are still small compared to deals with bio tech companies. That's because
BREATHE DEEP Nektar Therapeutics is developing pulmonary delivery strategies for a number of drugs, including insulin. The micrograph shows insulin particles that are used in the device. Roger Longman, managing partner at Windhover Information in Norwalk, Conn, spoke in Los Angeles about deal making in the drug delivery industry He said that big pharma is increasingly interested in shortcuts or "jump-starts" to discovery When a pharmaceutical company enters a deal with a drug delivery or specialty pharmaceutical company it is usually paying for the recognition of established value rather than the discovery of a new compound. Longman said the average up-front value of deals has increased dramatically because this recognition ofvalue is increasing. Nevertheless, Longman said that pharmaceutical companies still often fail to see the value ofproducts, which he ascribed to
the drug delivery deals are seen as bringing lower value to the company he noted. One of the problems has been the "genericization" of drug delivery Longman said, citing controlled release and patch technologies as examples. "Without a significantly novel system, it's difficult to do more than a modest up-front deal," he said. Drug delivery companies are being pushed to create products, Longman observed, because their partners are looking for proof that a technology will pan out. "The feasibility period doesn't end until the drug delivery partner can demonstrate the finished product," he said. The opportunities for small drug delivery companies will increase as the large
"If the value is not clear, the price will always be too high. If the value is clear, the price won't really matter." 38
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pharmaceutical companies continue to consolidate, Steinberg said. He pointed out that in mature industries such as the petroleum and automotive industries, the top 10 companies account for 80 to 95% of the industry's total sales. In the pharmaceutical industry, the top companies account for only 57%, leaving a significant portion of the pie for companies not in that upper tier. IT'S IMPORTANT TO determine the value of a product before committing resources to its development, Eugene M. (Mick) Kolassa told the audience in California. The perspective of the different parties involved plays a large role in determining that value. Kolassa, managing partner at Medical Marketing Economics and adjunct professor at the University of Mississippi, Oxford, pointed out that manufacturers, physicians, patients, and insurers all view value differently For manufacturers, value is found in a number of areas. Technology can provide a barrier to other companies and thus help a company stake out an exclusive area or extend the life of a patent. Another source of value is in new disease indications. New technology can open up additional pricing options and expand a product line. Finally value can come from improved patient compliance. Patients and physicians both find value in reduced side effects and simplified dosing, which improve the quality of life and ease of use. Payers are concerned with improved compliance and decreased health care costs. A number of key questions help determine value, Kolassa said. What does the disorder cost society? What is the potential to reduce costs? What information will be required to demonstrate savings? What potential is there to increase costs but improve patient outcomes? The answers to these questions can establish whether a product is worth developing. Kolassa offered a simple rule of pricing and value: "If the value is not clear, the price will always be too high," he said. Likewise, "if the value is clear, the price won't really matter." He pointed out that "a delivery system is only as good as the value it brings to the market in the minds of the customers." The incremental value of a new product is determined by the unmet needs and the urgency of the condition it treats. For example, a new medication to treat ear infection would be much less valuable than one to treat stroke, which is a critical condition with few medication options. Steinberg believes there are a number HTTP://WWW.CEN-0NLINE.ORG
of important technologies for the future of drug delivery. He said that oral controlled release has been a "big winner" for the drug delivery industry Steinberg disagrees with the widely held notion that oral delivery has completely become a commodity item. Pulmonary delivery is an area that is generating broad interest and has the potential to provide successful products. One product that Steinberg believes has the potential to generate more than $ 1 billion annually is Exubera, an inhaled insulin being developed as a collaboration between Nektar Therapeutics (formerly Inhale Therapeutic Systems) and Pfizer. John S. Patton, founder and chief scientific officer of Nektar, believes that inhaled insulin will be a "breakthrough product." Patton told the audience at the Hawaii meeting that the main problem with Exubera thus far has been fear. A few cases of pulmonary fibrosis, a disease characterized by scar tissue in the lungs, have been observed, but they appear to be caused by preexisting conditions rather than the pulmonary delivery He said that 50 patients have already been taking Exu-
bera for more than six years, and their blood glucose levels are as well controlled as by injection. In fact, he told C&EN, the precision of dosing is better with the inhaled insulin than with injection. The Phase III study for Exubera has been completed. However, it has not yet been determined when the New Drug Application will be filed with the U.S. Food & Drug Administration. Several other companies are also working on inhaled insulin, but Patton thinks that Nektar has a significant head start. INSULIN is just the "tip of the iceberg" for delivering drugs through the lung, according to Patton. Most people think of pulmonary delivery as a topical method for respiratory illnesses such as asthma, but all asthma drugs are absorbed systemically, he said. Similarly, other drugs could be delivered through the lung, which offers rapid onset of the medication and avoids first-pass metabolism in the liver. Patton believes that pulmonary delivery is an excellent option for vaccines, especially against pathogens that are introduced through the lungs.
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COVER STORY Nektar is working on other applications of pulmonary delivery as well. The company is collaborating with Chiron to develop inhalation antibiotics for treating pulmonary diseases. Speaking at the California meeting, Peter Challoner, head of inhaled drug delivery at Chiron, said that delivering antibiotics by inhalation would minimize systemic exposure to the drug and immediately achieve a high drug concentration at the infection site. Other companies are also working on methods for pulmonary delivery At the California meeting, Alan J. Bitonti, vice president for research at Syntonix Pharmaceuticals in Waltham, Mass., described his company's Transceptor technology, which delivers drugs using an antibody receptor that is usually responsible for transporting immimoglobulins across epithelial cells. The drugs—including proteins, peptides, small molecules, and antisense oligonucleotides—are linked to a fragment
of an immunoglobulin G, creating a fusion molecule. Because the specific receptor, known as FcRn, is primarily expressed in the upper respiratory tract, patients can inhale drugs by breathing normally Most pulmonary delivery approaches require the drug to reach the deep lung and thus compel patients to alter their normal breathing patterns. The fusion molecule crosses the cell membrane through a process called pinocytosis, in which cells take up fluids in tiny vesicles . Through the process of endothelial recycling, the plasma membrane captures the drug by forming a vesicle around it and then releasing the drug back into circulation, which increases the time the drug circulates in the body Syntonix is initially focusing on improv-
"It's almost like a Trojan horse. Once you're in, it doesn't matter how you got in."
HIJACKER Transceptor technology for delivering drugs, from Syntonix Pharmaceuticals, takes advantage of the FcRn receptor, which is responsible for the transport of immunoglobulins across epithelial cells. A fusion molecule consisting of a drug and part of an immunoglobulin enters the cell via pinocytosis (shown bottom left). It moves across the cell and enters the bloodstream. The drug is absorbed by endothelial cells lining the blood vessels and recycled back into the bloodstream, extending the circulating lifetime of the drug (bottom right).
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ing already successful protein drugs. The firm's lead drug candidate is an erythropoietin fusion molecule. Compared with the Amgen product Epogen, the erythropoietin fusion molecule is longer lasting, and pulmonary administration is competitive with subcutaneous injection, Bitonti said. Brooks Adams, director of business development at Chrysalis Technologies in Richmond, Va., described his company's Aria pulmonary delivery technology, which is based on a soft: mist aerosol. The aerosol is generated by a thermomechanical process in a heated stainless steel capillary without using propellants. The drug remains in the capillary for only a short time, minimizing the opportunity for it to be thermally degraded. The excipient system is vaporized and then cools, forming a low-velocity aerosol stream. The system can be configured to create a variety of particle sizes, from 1 to 5 |xm and even nanoparticles smaller than 100 nm, making the system appropriate for both local and systemic applications.
FINDING WAYS to expand the applicability oftransdermal drug deliverywas another common topic at the recent meetings. In the most familiar transdermal technologies, such as nicotine patches, drugs passively diffuse through the skin. Companies are now working on ways to actively drive drugs through the skin. Rosen described a product for acute pain management that incorporates Alza's E-Trans technology to deliver the medication fentanyl through the skin using low-level electrical current. Patients control when they receive the drug, but they can't receive a dose more frequently than once every 10 minutes. The device is preprogrammed to administer up to six doses an hour and 80 doses per day Each system is designed to become inoperative after 80 doses or 24 hours after the first dose has been administered, whichever comes first. Judith Kornfield, vice president ofbusiness development at TransPharma Medical in Lod, Israel, described her company's technology for crossing the barrier presented by the stratum corneum, the outermost layer of skin. An array of microelectrodes is placed on the skin, and a radio-frequency current is passed through the electrodes. The process creates pores deep enough to cross the stratum corneum but not to reach nerves or bloodvessels. A HTTP://WWW.CEN-ONLINE.ORG
patch containing the drug of interest is then placed over the area of skin, and the drug enters the body via passive diffusion. The technology can be used with a broad range of molecules, from hydrophilic or hydrophobic small molecules to proteins. Another transdermal technology was described by James Garrison, vice presi dent for business development at Vyteris, located in Fair Lawn, N J. Founded in 2000, Vyteris is a drug delivery company based on technology that was acquired from Becton Dickinson. Vyteris' technology is based on ion tophoresis, in which an electric current is used to actively drive the drug through the skin. By adjusting the amount of current passed through the device, one can pre cisely control the rate and amount of drug that is administered, Garrison said. By sep arating the patch and the controller, the company hopes to lower the cost and ease the regulatory process, he said. Vyteris attempts to identify established drugs that can be developed to Phase III clinical trials with little risk. The compa ny's lead product is a transdermal lidocaine. Vyteris believes that the product has the potential to be a $400 million seller, Gar rison said, and it hopes to get the product on the market this year. Other near-term candidates at Vyteris are drugs for deepvein thrombosis and migraine. Steve Wick, a senior technical manager in the 3M Drug Delivery Systems division, described his company's transdermal tech nology To disrupt the barrier properties of the stratum corneum, 3M uses arrays of plastic microneedles. The needles are 40 fxm across at the base and 100 to 400 |xm long. When the array is used as a pretreatment method, the needles are applied and then removed. Then a patch is applied to the treated area. When hollow micronee dles are used, the needles are left in place and the channels that they create remain open. Hollow needles can be used to deliver liquids. 3M is investigating the microneedles as a delivery method for vaccines. The nee dles can be coated with a protein or vaccine adjuvant, left on the skin for about an hour, and then removed. The vaccine is then de posited on the skin. Company researchers have done in vivo tests in animals of the immunization efficiency and rabbit stud ies show minimal skin irritation. In initial human tests, people perceive little pain with the microneedles. The company ex pects to move into clinical trials later this year, Wick said. Although drug delivery technology is often identified with devicelike applicaHTTP://WWW.CEN-ONLINE.ORG
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G E T T I N G M I S T Y A soft mist aerosol is generated thermomechanically in the functioning prototype of the Aria pulmonary delivery system (shown) by Chrysalis Technologies.
tions, the drug molecule itself can be part of both the drug delivery problem and so lution. For example, many drug com pounds can crystallize in a variety of forms known as polymorphs. The wrong poly morph can be at best ineffective and at worst dangerous. TransForm Pharmaceuticals, located in Lexington, Mass., focuses on using highthroughput methods to find the optimal physical form of a drug to be used. "Form needs to be coupled with formulation," Colin R. Gardner, chief scientific officer at TransForm, said at the Hawaii meeting. "Developability is the key factor in find ing a new drug. Potency is easy to come by The physical properties are critical." Gardner pointed out that once a drug is in the body, the body doesn't know or care how it got there. "It gets in the blood stream, and it's going to be in the form that's in equilibrium with blood," he told C&EN. But getting the drug into the body in the first place depends on the physical form of the drug. One form may work best for getting the drug through the gastroin testinal tract, for example, and another form may be better for cutaneous admin-
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istration. Regardless of how the drug gets into the plasma or the circulation, it ends up in the same form. "It's almost like aTrojan horse," G a r d n e r remarked. " O n c e you're in, it doesn't matter howyou got in." TransForm's core solid-state technolo gy is known as CrystalMax. It is used to perform high-throughput crystallization experiments using combinatorial mixtures of solvents and additives to find alterna tive solid forms of drugs, such as poly morphs, salts, hydrates, and cocrystals. The solids are analyzed using R a m a n spec troscopy and X-ray diffraction, and they are grouped according to sirnilarities in the patterns. Despite TransForm's reliance on high-throughput methods, Gardner em phasized that high-throughput technolo gies are most successful when coupled with good science and scientific intuition.
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GARDNER PRESENTED celecoxib (the cyclooxygenase-2 inhibitor found in Cele brex) as a case study of how the right form of the drug can improve the performance. Although celecoxib has the most sales of the COX-2 inhibitors, it's poorly water sol uble and has some performance issues. It's only moderately bioavailable, has slow on set, and has a nonlinear pharmacokinetic profile, due largely to poor aqueous solu bility Using a novel form of celecoxib in a customized formulation, TransForm was able to increase the bioavailability of the drug from 4 0 % to 95%, with a faster onset, and to achieve a linear p h a r macokinetic profile in a dog model. TransForm has used its technology to identify the various forms of sertraline, the active ingredient in the antidepressant Zoloft, which is already known to be highly polymorphic with 18 known solid forms. In more than 6,200 ex periments, TransForm sci entists identified 36 forms of sertraline. TThey were al so able to identify a variety of acceptable counterions. They found 18 crystalline salt forms, including seven that were previously unknown. Three of the salt forms were sig nificantly less polymorphic than the HC1 salt in the marketed product. Gardner also described TransForm's work in high-throughput formulation dis covery In one set of experiments, an ac tive ingredient that Gardner did not iden tify was tested with 18 different excipients to find which combination gave the best
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THROUGH S K I N A product using Alza's Ε-Trans transdermal delivery system to deliver the pain medication fentanyl awaits FDA approval. performance in terms of optimizing mul tiple parameters of a formulation. T h e excipients were tested individually and two or three at a time in a total of more than 4 , 0 0 0 experiments. T h e researchers found that ternary excipient combina tions gave t h e best results. T h e y also found that the rank of individual excipi ents did not accurately predict their per formance in mixtures. A collaboration with Alzais one of TransForm's "spectacular successes," G a r d n e r told C & E N . "They've changed t h e whole way transdermal delivery is done at an ear ly stage," he said. Rosen described the collaboration as the de velopment of a screening platform to find optimal formulations for trans dermal drug delivery. "Through the twofold in novation—platform and formulations—we can capture the maximum value from our drug portfolios," Rosen said. Capturing that value is what drug de livery companies need to do. Moving for ward, the challenge for drug delivery com panies is to b e c o m e more t h a n just platform companies. T h e s e companies need to turn their attention to developing actual products that can bring value to themselves and society Companies are ris ing to the challenge, and the transforma tion has already started. •
'Through the twofold innovation— platform and formulations— we can capture the maximum value from our drug portfolios."
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