Overview of drug delivery

Effective chemotherapy with paclitaxel is relying on the development of new delivery systems that can provide localized sustained release and reduced toxicity at the same time. One approach to drug localization and controlled pharmacokinetics is direct injection of drug-loaded-microspheres into tumor tissue. Unfortunately, the current methods of obtaining biodegradable polymer microsphere are complicated, with poor or no control over the microsphere size. Moreover, they generate microspheres of wide size distributions, which, in turn, leads to little control over release rates.

Solid microspheres

Control of microsphere size and size distribution are the ultimate goals of drug delivery, since a particular release rate and a desired route of administration require a particular sphere size. Using ink-jet technology and single emulsion-solvent evaporation techniques, MicroFab has obtained paclitaxel-loaded PLGA microspheres of narrow size distribution and controlled diameter (figure below).

PLGA microspheres, 50um in diameter, produced using ink-jet technology and loaded with Paclitaxel.

The manufacturing procedure did not affect the pharmacological efficacy of the encapsulated drug, as indicated by HPLC chromatograms and confirmed by tissue culture assay (figure below).

Comparisons of standard Paclitaxel and Paclitaxel extracted from the fabricated microspheres. Top: HPLC comparison. Bottom: Tissue culture comparison.

Jetted microspheres displayed a sustained release for at least 50 days. The in vitro released amounts were in a range proven to be adequate for inhibition and reversal of tumor growth.

Release kinetics results.

The advantages of jetted microspheres include:

• Highly uniform size
• Controllable size
• Control over release rates
• Controllable and recipe-flexible manufacturing protocol
• Easy to scale-up manufacturing (by using array printheads or multiple printheads)
• Aseptical and easy to automate fabrication
• Less toxicity:
  • jetted microspheres can be used as injectable drug delivery systems to deliver antineoplastic drugs directly at the tumor site, avoiding in this way the side effects associated with systemic administration.
  • local formulation is free of toxic adjuvants which are normally used in systemic therapy as solubility enhancers.
• Biodegradable, thus no need for surgery to remove them.

Multilayer microspheres

Many types of cancers do not respond to just one drug, but to a combination of at least two cytotoxics or two anticancer drugs. Moreover, combined therapy may reduce the risk of recurrent cancer. However, problems exist as the two drugs have different dosage requirements when administered subsequently. As opposed to microspheres consisting of a solid polymer microsphere, double-layer microspheres consisting of a core of one polymer surrounded by a coating of a second polymer could be an important step toward solving these problems. The two loaded drugs can attack two different cancer cell types. Therefore, the microspheres will have impact on a broader range of cancer types. The two polymers can be chosen so that their release rates are different, and the amount of drugs released per day will be different.

Sequence of events in the generation of the hollow spheres. The jet of two concentric fluids breaks down into spheres under an external perturbation produced by a piezoelectric element.

At MicroFab we have built a system that was used to produce hollow microspheres. The system consists of two concetric tubes. The outer tube is used to inject the liquid that forms the outer shell while air is injected in the inner tube. Air can be replaced with a second fluid thus generating the multilayer spheres.

Transdermal Delivery

MicroFabs JetLab® II Platform can be used to dispense and print drugs, polymers and adhesives for transdermal delivery applications. Applications include microneedle coating/filling; precision drug dispensing onto flexible films, including multi-layer or multi-drug; and precise printing of drug/polymer combinations.

Nasal & Inhaler Delivery

Ink-jet technology can be used to manufacture solid powders for pulmonary drug delivery, create vapors for pulmonary delivery, and generate liquid droplets for nasal delivery. Vapor delivery is based on MicroFab's AromaJet® Technology, which can project aromas for marketing and simulation applications, and create personalized fine fragrances. AromaJet® Technology's digital control has been used in medical diagnostics applications and explosives vapor detector calibration.

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