Gel Implants: Novel Delivery for Hydrophobic Drugs
The collaboration between MacroMed, Inc. (Salt Lake City, Utah) and Samyang Genex (Seoul, Korea), announced on Feb. 23, brings together two companies with exciting manufacturing technologies. Samyang Genex has a proprietary plant cell culture technique for producing Genexol, its brand of the anticancer drug Paclitaxel; MacroMed has developed ReGel, patented drug delivery systems based on injectable polymer gels that make it easier to administer water-insoluble drugs intravenously.
Derived from the Pacific yew tree, Paclitaxel (also known as Taxol [Bristol-Myers-Squibb]), prevents cell replication by inhibiting the cell's ability to enter a critical stage of mitosis (cell division). Paclitaxel has been approved for treatment of breast and ovarian cancers, and is also used to treat a number of other malignancies, including bladder, lung, gastrointestinal and head and neck cancers. Sales of Paclitaxel approached $1 billion in 1997.
For several years the Pacific yew was the only source of Paclitaxel and related drugs, known as taxanes. Production involved an inefficient, costly extraction process from yew tree bark. Samyang Genex was the first company to successfully develop a practical cell culture technique that spared the rare yew tree while providing a steady, reliable supply of the drug. Samyang Genex expects full production of Genexol in second quarter 1998.
Cell culture solves one problem with Paclitaxel, namely how to get a lot of the drug relatively inexpensively. It does not address two interrelated dosage-related problems, however: toxicity and hydrophobicity.
Taxanes are extremely toxic materials, causing severe hypersensitivity reactions and damage to blood cells and the nervous system. In addition, Paclitaxel is difficult to produce in a formulation suitable for intravenous use. The drug's hydrophobicity requires it be formulated as an emulsion of castor oil and water. The emulsion itself causes an immune response similar to an allergic reaction, which exacerbates the drug's tonicity. Injectable gel formulations reduce toxicity by eliminating the irritating oily component of the emulsion dosage form.
MacroMed's ReGel undergoes unusual phase change behavior: At just below room temperature the material is liquid and may be injected; at body temperature the material forms a solid gel. ReGel formulations injected intramuscularly or subcutaneously from solid, well-defined drug depots which are slowly degraded by and absorbed into the body, releasing the gel's drug cargo over weeks or months.
MacroMed's pharmaceutical partners provide the company with active, and ReGel/drug combinations are processed as sterile liquid solutions at MacroMed. "Poorly soluble drugs are much better candidates for ReGel formulation than soluble drugs," says MacroMed Corporate Development Director Jim Herrin. "Water-soluble drugs tend to leak out of the matrix, whereas lipophilic drugs cling to it until the body degrades the polymer."Good drug candidates for ReGel formulation include steroids, lipophilic hormones, and any lipophilic drug whose efficacy requires sustained release or constant infusion.
MacroMed has several other related drug delivery systems in various stages of commercialization:
- Hygel, whose phase behavior is opposite to that of ReGel's, was described in the journal Nature last year
Oligospheres, an aqueous-based delivery system for short- to intermediate-term sustained delivery without an initial "burst" of drug
Thermospheres, a particle-based version of ReGel
SqueezGel, aqueous materials for oral delivery within coated tablets
Beta-Cell Targeting, an artificial pancreas
By Angelo DePalma
MacroMed expects to enter a clinical trial with a ReGel/Genexol formulation in early 1999.