April 15, 2007 (Vol. 27, No. 8)

Painlessly Increasing the Efficacy of Drugs While Simultaneously Reducing Toxicity

A new delivery system for vaccines using biodegradable polymer microspheres may reduce the need for booster shots, as well as stimulate cellular-mediated immunity—an immune response not activated in traditional vaccines. Iowa State University researchers reported these findings at the recent “American Society for Microbiology Biodefense and Emerging Disease Research” meeting in Washington, D.C. The technology enables the slow release of antigens, which could mean that vaccines given in a series could, in the future, be administered as a single dose. Provoking a cellular-mediated immune response could also enable vaccines to be developed for the first time for intracellular diseases, like tuberculosis, malaria, and HIV/AIDS.

This research is but one example of work being done that is improving how antigens, macromolecules (i.e., proteins and carbohydrates), water-soluble molecules, genes, and nucleic acids are delivered. More efficient and painless delivery of drugs is replacing injections and intravenous infusions for many patients.

Polymer-based Delivery

Much of the new technology is based on advances in polymer science and the ability to produce much smaller particles than ever before. Brookwood Pharmaceuticals(www.brookwoodpharma.com) has 30 years of experience with biocompatible, biodegradable polymers and 25 products on the market. A spinoff of Birmingham’s Southern Research Institute, Brookwood has developed technology consisting of scaffolding of peptide or other biological macromolecules. Its scaffolds may be formed into rods, fibers, microparticles, meshes, and other 3-D shapes, depending on desired use, for sustained drug release up to 12 months, says executive vp and CSO Tom Tice, Ph.D. The lactide/glycolide polymer Brookwood uses resorbs at predetermined times, leaving only the biological structure induced by the scaffold behind.

The company has 14 products in its pipeline, which include an orthopedic microparticle; an infectious disease vaccine; a CNS implant; an anticancer drug; an anticancer liposome; and a drug-eluting, non-vascular stent. Recently it also acquired Alkermes’ (www.alkermes.com) Medisorb external (extended release) polymer business.

“We are seeing a big need for new delivery vehicles for parenteral drugs, in particular; new chemical entities; and existing drugs,” says Dr. Tice. The company’s VaxCap vaccine delivery is microparticle-based, which by targeting the skin’s dendritic cells, can produce mucosal and systemic responses, as well as antibody and cell-mediated responses. The vaccine produces injectable, hydrophobic drug particles and injectable solid implants for systemic or local delivery—parenteral, oral, intranasal, intradermal, or other routes. Brookwood also does GMP manufacturing of clinical and commercial quantities.

Tyrosine-derived Polyarylates

TyRx (www.tyrxpharma.com) is developing drug-covered devices based on tyrosine-derived polyarylates, says CEO William Edelman. It has three products: PIVIT CRM, a mesh pouch designed to protect patients implanted with either pacemakers or defibrillators from infection; a surgical mesh reinforcement for hernia operations that elutes anesthesia; and a dissolving coating designed for cosmetic surgery implants to prevent scarring. In all cases, the coating breaks down into tyrosine, an amino acid, while releasing various drugs.

TyRx’ products are not considered drugs by the FDA, and because there are similar devices already on the market, the FDA does not require clinical trials for these products. TyRx must, instead, prove that its products are equivalent to those already approved and can perform the claimed functions. In October 2006, TyRx submitted a premarket application for PIVIT CRM, which is coated with the antibiotics rifampin and minocycline. In January, the company entered into an alliance with C.R. Bard for the device.

In the future, TyRx plans to produce devices with combined functions (i.e., anti-infective and antiscarring, or antiscarring and analgesic) and other products that will complement its existing portfolio, such as resorbable anti-infective coatings for additional cardiovascular and cosmetic implants, Edelman says.


Aphios (www.aphios.com) is developing a series of biodegradable polymer microspheres (nanospheres) that encapsulate a range of drugs. It has developed a scalable, single process to produce biodegradable polymer nanospheres using fluids without organic solvents—its SuperFluids technology—to encapsulate proteins, says CEO Trevor Castor, Ph.D. Many other types of microspheres are produced in a five-step, costly process using organic solvents that denature proteins. Aphios are monodisperse polymers, and as such, can be used for the controlled release of viral vaccine antigens because they improve the stability of antigens in the body for long periods of time.

Aphios’ portfolio also includes phospholipid nanosomes for increased efficacious delivery and reduction of toxicity of hydrophobic drugs such as camptothecin (Camposomes), paclitaxel (Taxosomes), and bryostatin (Bryosomes).

Hydrophilic compounds, such as recombinant proteins, are encapsulated in the aqueous core, whereas hydrophobic compounds, such as anticancer drugs and water-insoluble drugs, are trapped within lipid bilayers.

Encapsulation masks the water-insoluble nature of drugs. The company’s protein nanoparticles can deliver insulin, proteins, nucleic acids, and a range of enzymes. Its carriers are being used for CNS, oncology, infectious diseases, and nutraceuticals.

Flamel Technologies (www.flamel.com) has two drug-delivery platforms for delivering new and extant drugs: the Medusa and Micropump® technologies. Medusa is a self-assembled poly-amino acid nanoparticle injectable system, which is geared to deliver first- and second-generation long-acting protein drugs. It uses naturally occurring hydrophilic and hydrophobic amino acids to form a stable polymer that forms stable nanoparticles spontaneously in water, not solvent. The amphiphilic character of the polymers drives the self-assembling of the nanoparticles in water.

These nonimmunogenic nanoparticles, which are 20–50 nanometers in diameter, are composed of 95% water and 5% polyamino acid polymer. They are robust over a wide range of pH values and can be stored as stable liquid or stable dry forms. The company says this formulation reduces the intensity of the peak administration, which is the cause of many side effects, and maintains the concentration of protein drugs for at least two weeks or more in dog models, offering a long duration of action with improved efficacy, as well as improving the solubility-viscosity of insoluble protein drugs such as IL-2. They are also inexpensive to produce.

Two second-generation products, Basulin (insulin) and IFN alpha-2b XL, are the most advanced (Phase II and Phase I, respectively), followed by IL-2XL (Phase I). Human growth hormone and IFN beta XL are in animal studies.

Flamel’s Micropump is designed for oral, controlled-release delivery of small molecule drugs, with special utility for pediatric and geriatric patients. Micropump I enables extended-release, and Micropump II enables delayed and extended-release (up to 24 hours) by enabling drugs to remain longer in the small intestine. This multiple-dose system contains 5,000 to 10,000 microparticles per capsule or tablet, which releases 200-500 micron-sized microparticles in the stomach and small intestine, where each microparticle releases the drug by osmotic pressure at an adjustable rate (controlled for Micropump I or delayed for Micropump II) and over an extended period of time.

Flamel has deals for its Micropump technology with GlaxoSmithKline(www.gsk.com) for Coreg-CR, a beta-blocker in Phase IV registration; with Servier(www.servier.com) for an ACE-inhibitor; and with Merck(www.merck.com) for an undisclosed drug. It is also developing Genvir (acyclovir), Metformin XL, and Augmentin SR.

Patch Drug Delivery

Altea Therapeutics (www.alteatherapeutics.com) is developing a needleless PassPort patch System to deliver large molecules, including hormones and analgesics, using a unique method of skin microporation. Its patch is attached to a metallic filament array, which, when activated, produces tiny aqueous channels in the outer layer of the skin. The patch is then aligned over the newly formed aqueous pores into which it releases its contents, which travel to the bloodstream.

“Our PassPort technology creates focused bursts of thermal energy to ablate skin, creating microchannels in the skin’s stratum corneum, which fill with interstitial fluid,” says CEO Eric Tomlinson, Ph.D. The fluid produces a hydrophilic environment, modifying the naturally hydrophobic nature of skin, which normally blocks the uptake of many drugs. The device is painless, producing only a light touch sensation for two milliseconds, and incorporates a smart technology that provides correct dosing control.

“Patients like the idea of a patch; the problem is that patches did not work for numerous water-soluble drugs or for which delivery through the skin was inefficient,” says Dr. Tomlinson.

Altea is targeting major medical markets with four molecules— night-time and daily basal insulin, apomorphine for Parkinson’s disease, and fentanyl for pain control, all in Phase I and poised to begin Phase II later this year. In February, Altea agreed with Teikoku Seiyaku to use the PassPort system for Parkinson’s disease.

In January 2007 Altea announced positive clinical results from a Phase I trial with the basal insulin patch showing efficient, sustained, and constant delivery of insulin at therapeutic levels over a 12-hour period, compared to subcutaneous injection of a long-acting insulin analog. It is also developing a 24-hour patch; both will be used by patients with Type 2 diabetes.

Dendrimers as Drug Carriers

Avidimer Therapeutics (www.avidimer.com) is producing nanosized polymer dendrimers, or “avidimers,” that act as inert scaffolding for imaging and/or therapeutic agents, which are attached via chemical linkers. The avidimer complex also includes multiple targeting vectors, which increase drug payload, tightly attached to the dendrimers to guide the desired molecules to target tissue. The vectors employ cell surface markers expressed on diseased cells to guide the avidimers to diseased, not healthy cells.

A dendrimer is generally about 5 nm in diameter, which is about the same size and shape as a molecule of hemoglobin. A fully loaded avidimer is smaller than 15 nm in diameter and flexible, enabling it to move without recognition throughout the body, according to the company. Avidimers are delivered via injection and are excreted within 72 hours via the urinary tract.

Avidimer is focusing on cancer. Its lead candidate, ATI-001, is formed by the covalent attachment of 4–5 folic acid molecules and 5–6 methotrexate molecules to a dendrimer backbone.

The linker mechanism employed to attach drugs to avidimers are chosen either to retain the drug on the dendrimer throughout its lifetime or allow the drug to disassociate (i.e., cleave) after delivery to its target. Maintaining the drug attached to the dendrimer in transit to the disease target is important in sparing healthy tissue, i.e., minimizing toxicity, but in some cases, the drug must be released from the dendrimer at its intended destination to express biological activity, while in other cases, the drug retains its activity when attached to the dendrimer, the company reports.

ATI-001 targets cancers that overexpress the high affinity folate receptor on ovarian, breast, lung, and colon cancer, among others. A study published in 2005 demonstrated that this drug was significantly more efficacious in vitro and in vivo with much less toxicity compared to free methotrexate administered at comparable doses.

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