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Genetic Engineering News Drug Delivery Systems Click here to go directly to the portion of the article which references PPTI. Innovations in drug delivery systems have been driven by medical, technological and economic factors. A benefit of non-invasive drug delivery is improved quality of life for patients. Drug delivery systems can provide improved bioavailability and higher therapeutic index, resulting in increased efficacy, decreased side effects and reduction in dose requirements. Longer half-lives of labile biological therapeutics, controlled release of drugs and continuous maintenance of acceptable concentrations of drugs can be attained by drug delivery systems. According to Robert Langer, Ph.D., professor of chemical and biomedical engineering at MIT (Cambridge, MA), Procardia XL (Pfizer, New York, NY), the extended release formulation of nifedipine, "is an example of a real success in dramatically improved therapeutic and side effect profiles, just through innovative delivery." Furthermore, drug delivery systems can target therapeutics to specific tissues and sites of disease. Dr. Langer speculates that local and targeted delivery will become a major focus of development, especially "delivery to sites that are not easily accessible, such as the sinuses, nerves and the brain." In his recent review article in Nature [1998; 392 (Suppl.): 5-10], Dr. Langer estimates that sales of advanced drug delivery systems in the U.S. in 1997 were nearly $14 billion. The economic impetus for pharmaceutical companies to improve the safety and efficacy of existing drugs is comprised of several factors, according to Dr. Langer. He adds, "Extension of patent protection is a consideration, but the driving force is for extending the useful [market] life of a medication, versus the enormous cost of developing a new one. Social and economic requirements to lower the total cost of disease treatment foster a rich environment for invention and application of delivery techniques." Examples of innovative drug delivery technologies, including implantable devices and pulmonary, transdermal and ophthalmic delivery systems, are listed in Table 1, as well as new polymer and hydrogel vehicles under development.
As vehicles for drug delivery, biodegradable polymers displaying predominantly surface erosion characteristics are preferred for their simplification of sustained release rates of drug and their avoidance of dose dumping upon final hydrolysis of polymer. Guilford Pharmaceuticals (Baltimore, MD) and Protein Polymer Technologies (PPTI; San Diego) are developing these types of polymers. Atrix Laboratories (Fort Collins, CO) is developing a thermosensitive, biodegradable hydrogel vehicle that is injected as a liquid and rapidly gels in the body. Implantable Delivery Systems Implantable delivery systems may provide extended release of therapeutics, reduction in clinical interventions, patient freedom from multiple injections and improved patient compliance. Alza Corp. (Palo Alto, CA) and its related company Crescendo Pharmaceutical Corp. (Palo Alto, CA) are sponsoring Phase III clinical trials of the Duros Leuprolide device for palliative treatment of advanced prostate cancer. The device, which is inserted through an incision, is designed to deliver leuprolide (an LHRH agonist) continuously for up to 12 months. The matchstick-sized device encloses a semipermeable membrane and an osmotically driven piston that releases leuprolide through an orifice at one end of the device. Pulmonary Delivery Systems Advantages of pulmonary delivery of therapeutics include lowered invasiveness compared to that of injection, high absorption of undegraded biotherapeutics and the ability to target drugs to sites of respiratory disease. Efficient delivery of therapeutics to the expansive alveolar surface of the deep lung, however, is challenging. Andaris, Ltd. (Nottingham, U.K.), Inhale Therapeutics Systems (San Carlos, CA), Aradigm (Hayward, CA), and 3M Pharmaceuticals (St. Paul, MN) are pursuing pulmonary delivery of proteins, peptides and hormones. Andaris is focused on inhaled and intravenous delivery of biopharmaceuticals and small-molecule drugs. Terence Chadwick, M.D., director of R&D and chief medical officer, explains that "Andaris has developed a proprietary microcapsule technology that has wide application" for drug delivery. During a spray drying process, microcapsular size "can be tightly controlled, which enables us to design delivery vehicles for targeting different parts of the body." A change in the charge of the microcapsule can direct medication to or away from the reticuloendothelial system. Microcapsules at least 15µm in size can be used for regional or depot delivery. In contrast, microcapsules less that 5µm have the proper aerodynamics, when used with a dry powder inhaler device, to penetrate deep into the lung. "Insulin is our lead molecule in this area," reports Dr. Chadwick. Inhale Therapeutics is developing dry powder aerosol delivery of insulin and other macromolecules. In their process, a critical amount of water is removed from a protein, the protein strands immobilize one another, and a state of highly enhanced chemical stability of protein results. Inhale reports it has produced 1µm to 5µm particles without significant degradation of protein therapeutic, developed proprietary methods to fill non-flowing powders into unit dose blister packs and designed an efficient, mechanical inhaler device. When the handle on the dry powder inhaler is lifted and squeezed, compressed air is stored. Depression of a button on the device releases a stationary cloud of fine powdered therapeutic into the inhalation chamber. "The delivery efficiency is three to six times greater than that achieved with other approved devices," according to John Patton, Ph.D., co-founder and VP of research. With the Inhale device, the reproducibility of drug delivery to the bloodstream is equivalent that of subcutaneous injection. Phase IIb clinical trials of Inhale's device for pulmonary delivery of insulin in diabetics are sponsored by their collaborator, Pfizer. Dr. Patton notes that, if future trial "results are successful, this will be the first time that a non-invasive method of administering insulin has been found -- a Holy Grail in medicine since insulin's discovery in the 1920s. The human aversion to being stuck with a needle goes much deeper than can be explained by the transient pain involved. This aversion must have a deeper sociobiological explanation, probably rooted in the evolutionary advantage conferred by an aversion to having skin penetrated by foreign objects." Transdermal Delivery Alza, an established leader in transdermal delivery of therapeutics, and Crescendo have a programmed, low-voltage, transdermal patch for delivery of insulin in preclinical development. The product combines electrotransport technology (E-TRANS) and a novel skin interface technology for delivery of large molecules (Macroflux). Moreover, Alza is collaborating with Janssen Pharmaceutica (Titusvill, NJ and Beerse, Belgium) in the development of E-TRANS fentayl, a programmed, low-voltage transdermal patch for opioid control of acute pain. E-TRANS fentanyl is in Phase III clinicals. The theoretical advantages of the device include its non-invasive nature; its pulsatile delivery of drug; its portability; its ability to provide rapid relief from pain; the ability of the patient to control, within prescribed parameters, their analgesia; and the ability of the physician to see how many doses have been delivered. Ron Haak, Ph.D., [VP] of technical development at Alza, elaborates on the benefits of patient-controlled analgesia system and potential benefits of E-TRANS fentanyl. "Contrary to popular opinion, patients use less pain medication when they self administer." Another advantage of the device is that it frees "patients from the I.V. pole." Dr. Haak believes that the E-TRANS technology offers the ability to deliver medication in time-dependent patterns or by feedback. However, he notes that "this technology is reserved, at the moment, for compounds that are skin-friendly, have dosing rates below 10mg per day;" and have size, charge, and solubility properties necessary for efficient transport. Ophthalmic Delivery Typical pharmaceuticals marketed for ophthalmic diseases are eye drops and systemic drugs. Disadvantages of eye drops include the requirement for repeated administration, delivery of insufficient or fluctuating doses of drug to the eye and lack of penetration of the medication into the posterior chamber of the eye. A limitation to use of systemic medications for ophthalmic disease is the possibility of toxicity caused by high concentrations required for therapeutic efficacy. Oculex Pharmaceuticals (Sunnyvale, CA) is developing drug delivery vehicles to overcome some of these challenges. Jerry Gin, Ph.D., founder, president, and CEO, believes that his company's products "will revolutionize the ophthalmics pharmaceutical industry by formulating approved drugs with biodegradable, controlled-release polymers." Their lead product, Surodex (a novel formulation of dexamethasone), has had successful clinical trial results overseas and is in Phase III trials for use following cataract surgery in the U.S. According to Dr. Gin, "patients receiving Surodex showed reduction in intraocular inflammation after cataract surgery within days, rather than after a month or more for patients receiving the drug by eye drops. This technology also reduces the complications seen due to fluctuating levels of medication and patient non-compliance." Also in Oculex development pipeline are controlled-release antibiotics for post-surgical use and treatments for chronic inflammation of the eye, age-related macular degeneration, diabetic retinopathy and CMV retinitis. According to Dr. Langer, "technical breakthroughs in materials, improvements in stabilization of drug molecules and advances in transport of complex biomolecules will create avenues for drug delivery that were previously thought impossible. Some inventions in microelectronics and nanotechnology may allow completely new types of therapeutics, such as miniature repair or delivery robots." Linda Brewer-Condon, Ph.D., is a senior consultant and Holly Abrams, Ph.D., is a director of biopharmaceutical consulting at Technology Forecasters, Inc. (TFI; Alameda, CA; (510) 747-1900; www.techforecasters.com/biotech.html). TFI is a market research and consulting firm for the biotechnology and high technology industries.
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