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Genetic Engineering News Researchers Advancing Biopolymer Systems as Vehicles for Delivering Drugs Click here to go directly to the portion of the article which references PPTI. Technological innovation is driving rapid growth in the research and production of biopolymers. These versatile materials have applications in all sectors of the economy including use as adhesives, lubricants, soil conditioners, absorbents and high-strength structural materials. However, biopolymers are ideal for drug delivery systems and related technology. Researchers at Atrix Laboratories (Fort Collins, CO), for example, have developed Atrigel®, a drug delivery and biomaterial system composed of biodegradable polymers. The system is compatible with a broad range of compounds that includes traditional, small organic molecules, like antibiotics and drugs for high blood pressure, as well as the newest protein and peptide biotech products. The company has demonstrated the systemic delivery of peptide hormones, such as luteinizing hormone releasing hormone (LHRH) used in treatment of prostate cancer. Atrix can tailor release rates from Atrigel either to the specific drug (releasing it through degradation of the polymer and diffusion of the drug out of the polymer) or to the condition to be treated. Atrix scientists have produced a dental product called the Atrisorb® Barrier for Guided Tissue Regeneration (GTR). Using Atrigel technology, the product was cleared for sale in the U.S. in 1996, and is currently being sold in 12 international markets to treat periodontal disease, which affects more than 45 million people in the U.S. alone. Liquid Polymer System Atrisorb uses a liquid polymer system to form a semi-solid film that can be implanted to transform in situ to a rigid barrier that enhances the healing responses in gum surgery. The Atrisol aerosol system forms a thin polymeric barrier over surgical sites to prevent fibrous adhesions. Atrix recently announced successful results of Phase III clinical studies with a product called Atridox™, which serves as a non-invasive treatment for periodontal disease. The company submitted the studies in a New Drug Application (NDA) to the FDA in March. Atridox combines the Atrigel biodegradable polymer system with doxycycline, an antibiotic that has proven effective against the bacteria associated with periodontal disease. The produce is applied to the infected periodontal pocket as a fluid, where it molds to the shape of the problem area and quickly solidifies, releasing doxycycline for a period of seven days, as it is bioabsorbed. The Atridox therapy is intended to be repeated at appropriate intervals as part of a regular periodontal maintenance program. Last December, Atrix established a corporate alliance with Block Drug Corp. (Jersey City, NJ), a dental products company, by licensing the North American and European marketing rights to its dental products. Atrix also has a marking alliance with Heska Corp. (Fort Collins, CO) to sell a periodontal therapy for companion animals. With respect to the future research efforts, Lee Southard, Ph.D., president and chief scientific officer of Atrix, says, "Throughout 1997 we will be focusing on the development of our Atrigel technology for non-periodontal drug delivery and biomaterial applications." "Using genetic engineering and biological production methods, we have developed the means to produce virtually any protein composition consisting of repeating blocks of defined amino-acid sequence," claimed Joseph Cappello, Ph.D., earlier this year at the "Recent Advances in Drug Delivery Systems" symposium in Salt Lake City. Dr. Cappello is a scientist at Protein Polymer Technologies, Inc. (PPTI: San Diego, CA), a development-stage biomaterials company working in the areas of surgical repair and drug delivery. In 1991, PPTI introduced ProNectin® F, a compound that formulates into a thin, transparent coating, or membrane on which cells can grow. In 1994, the company commercialized SmartPlastic® Cultureware, in which ProNectin F is presented in ready-to-use form on the surfaces of disposable labware for culturing human and animal cells. PPTI is developing a new generation of biomaterials, called ProLastin polymers, that are recognized and accepted by human cells for directing their growth and the regeneration of tissues. This family of water-soluble protein polymers undergoes an irreversible solution-to-gel transition under physiologic conditions. ProLastin consists of combinations of silk-like and elastic blocks in various lengths. Even at high concentrations, these solutions are fluid and, thus, can be injected through fine-gauge hypodermic needles. Existing ProLastins may serve to adequately release compounds under controlled conditions. Company researchers foresee the prospect of using ProLastin as a framework on which to design and build better-suited, functional protein biomaterials specifically for drug delivery. PPTI is collaborating with Ethicon, Inc. (Somerville, NJ), a subsidiary of Johnson and Johnson, to develop commercial surgical tissue adhesives and sealants for wound closure. Skin Delivery Solutions Scientists at Advanced Polymer Systems (APS; Redwood City, CA) have developed a device, called Microsponge® Systems, to enhance topical pharmaceuticals and personal-care products applied to the skin. These cross-linked polymers form microscopic, sponge-like spheres that serve as reservoirs to dispense active substances over extended periods of time. The spheres also act as containers to protect certain substances from absorption by the body and as absorbent receptacles to collect undesirable substances, like facial oils. APS also acquired full right to DOW Corning's (Midland, MI) Polytrap technology and the responsibility for the continuing commercialization of Polymeric Transport Systems, which are integral to a wide range of cosmetics, toiletries and other personal care products. Polytrap is a highly cross-linked polymethacrylate co-polymer that is an ultralight, free-flowing, white amorphous powder. The compound is capable of absorbing excess surface skin oil up to four times its own weight without overdrying the skin. In February, the FDA approved Retin-A Micro (tretinoin gel) for the treatment of acne. The topical medication is the first ethical pharmaceutical containing Microsponge delivery systems. One problem with Retin-A, which has been marketed by Ortho Pharmaceuticals (Raritan, NJ), a division of Johnson and Johnson, since 1971, is that the highly effective medication irritated the skin of some individuals. "FDA marketing clearance of Retin-A Micro is a significant milestone for ethical pharmaceutical application of our delivery systems technology," says John J. Meakem, Jr., chair and CEO of APS. In March, the company announced the signing of a definitive license and supply agreement with [Sothys USA], Inc. (Miami, FL) to market Microsponge-based retinol to beauty salons and spas for use in improving the appearance of aging skin. Retinol, a pure form of vitamin A, has remarkable capacity for maintaining the skin's youthful appearance. Microsponge systems enable the product to stabilize retinol into a form that has low potential for irritation. Previously, APS signed retinol agreements with Avon Products (New York City) for marketing to consumers and with Medicis Pharmaceutical Corp. (Phoenix, AZ) for dermatologists. Scientists at APS have developed a new formulation of 5-fluorouracil (5-FU), a drug for treatment of actinic keratosis, pre-cancerous skin lesions. This product has completed Phase II clinical trials, financed by partner Dermik Laboratories (Collegeville, PA). APS has a second NDA for marketing Melanin-Microsponge sun protection cream, which uses melanin to provide broad-spectrum sun protection. New products under development include microsponge systems to deliver active ingredients to lower gastrointestinal tract, and bio-erodible microspheres for oral and implantable drug delivery. Renal and GI Medications GelTex (Waltham, MA) is developing non-absorbed, polymer-based pharmaceuticals that selectively bind and eliminate target substances from the intestinal tract. Researchers at GelTex announced positive results from a second Phase III trial of RenaGel phosphate binder for the control of elevated serum phosphorous levels in chronic kidney failure patients. The study demonstrated RenaGel's advantage in decreasing serum phosphorus levels, compared to the current phosphate binder standard, calcium acetate, according to company officials. The clinical trial also confirmed RenaGel's ability to control blood levels of parathyroid hormone, a key contributor to renal bone disease. "We are now focusing our efforts on compiling our data to support an NDA for RenaGel, which we expect to file in the fourth quarter of 1997," says Mark Skaletsky, Ph.D., president and CEO of GelTex. GelTex also has received a patent covering CholestaGel, an oral polymer-based, non-absorbed pharmaceutical for the treatment of elevated cholesterol levels. CholestaGel acts to decrease blood cholesterol levels by selectively binding to bile acids in their stomach, preventing their reabsorption and resulting in their elimination through the digestive tract. CholestaGel is currently in Phase II clinical trials. Arthritis Biomatrix (Ridgefield NJ), which develops viscoelastic biomedical products, has signed a multi-million dollar marketing and distribution agreement with Wyeth-Ayerst (Philadelphia) to market Synvisc, which is a viscosupplementation product for the treatment of osteoarthritis of the knee. It is one of a series of medical products based on Biomatrix proprietary hylan technology. Hylans also are used in therapeutic medical applications and skin care products. Last November, an FDA panel recommended that Synvisc be approved for marketing in the U.S. Synvisc has received the CE mark for marketing in the European Economic Area. Polyphosphoesters Guilford Pharmaceuticals (Baltimore, MD) has acquired exclusive rights to a new patented drug delivery technology from Johns Hopkins University. The novel class of biodegradable, implantable polymers, known as polyphosphoesters and used for targeted drug delivery, were discovered by Kam Leong, Ph.D., of the biomedical engineering and materials science department. These biodegradable polymers have distinct characteristics that make them potentially useful for a variety of sustained-released drug delivery human therapeutic applications. Guilford has rights to an array of biopolymers, each with unique characteristics that may be useful for a variety of applications. "We also now have the ability to develop a wide range of proprietary implantable products containing taxoids, topoisomerase inhibitors and other chemotherapeutics for the targeted and controlled treatment of [solid] tumors," says Craig R. Smith, M.D., Guilford's president and CEO. "Taxoids are emerging as some of the most important new drugs for cancer. However, these compounds can also have significant adverse side effects." Fifty years ago, a researcher in Sweden found an impurity in sugar beet juice produced by the microorganism Leuconostoc mesenteroides. The discovery led to the patenting of hydrolyzed dextrans, primarily as plasma volume expanders. Early studies on the cross-linking of dextran led to the founding of a new company, Pharmacia Fine Chemicals, which later became Pharmacia Biotech (Uppsala, Sweden; Piscataway, NJ). The cross-linked dextrans were given the [appellation] Sephadex (SEparation PHArmacia DEXtran). Using Sephadex technology, they initially developed separation products for gel filtration, ion exchange and affinity chromatography. Dextrans feature a number of attractive product characterististics -- hydrophilicity, stability, purity and the capability of forming clear and stable solutions. Also, dextrans, which are derived from renewable resources, are degraded by ecological systems. Current dextran applications include photographic and photocopying processes, formulations for skin and eye care products, and in vivo diagnostics, i.e., iron-dextran complexes for improving the differentiation of biological images in magnetic resonance imaging. Pharmacia Biotech is looking to expand the use of dextrans in the stabilization of vaccines and diagnostics, areas where they are already employed. Dextrans and their derivatives are finding an increasing number of applications in diagnostic, consumer and industrial processes. Pharmacia Biotech is working with U.K.-based Leeds University to develop dextran derivatives for stabilizing proteins and other biomolecules. In addition, the firm recently discovered that dextrans offer considerable advantages for the flocculation of cells from cell cultures in industrial bioprocessing.
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