GSAS Harvard Biotechnology Club

With the expansion of pharmaceuticals into the areas of peptide, protein, and DNA therapeutics the standard mechanisms of drug delivery are no longer sufficient. These molecules are far less robust than small molecule drugs when given orally in pill form. Peptides and proteins are quickly digested in the stomach and most never reaches the blood stream. The same is true for DNA therapies.

The field of drug delivery, driven by this need, has made key advances in increasing the stability of protein and peptide therapies using polymer technology. But polymers have made a larger impact in the area of long-term drug delivery. Another area that has seen a lot of attention is specific targeting of drugs to the disease area. Enhancing the uptake of large molecules has also been an increased focus in the field, with new portals of delivery being defined. Outside of the biochemical realm, many companies have also worked on making drugs easier to take and use.

A major problem with standard drug dosing is that 2-3 time a day delivery of drugs results in a quick burst of medication at the time of dosing, followed by a rapid loss of the drug from the body. Most of the side effects of a drug occur during the burst phase of its release into the bloodstream. Secondly, the time the drug is in the bloodstream at therapeutic levels is very short, most is used and cleared during the short burst.

Polymer technology has given some solutions to these problems. Drugs embedded in polymer beads or in polymer wafers have several advantages. First, most systems allow slow release of the drug, thus creating a continuous dosing of the body with small levels of drug. This should prevent any side effects associated with high burst levels of normal injected or pill based drugs. Secondly, since these polymers can be made to release over hours to months, the therapeutic span of the drug is markedly increased. Often, by mixing different ratios of the same polymer components, polymers of different degradation rates can be made, allowing remarkable flexibility depending on the medication being used. A long rate of drug release is beneficial for people who might have trouble staying on regular dosage, such as the elderly, but is also an ease of use improvement that everyone can appreciate. Most polymers are made to degrade and be cleared by the body over time, so they will not remain in the body after the therapeutic time.

A second major advantage of polymer based drug delivery is that the polymers often can stabilize or solubilize proteins, peptides, and other large molecules that would otherwise be unusable as medications. Finally, many drug/polymer mixes can be placed directly in the disease area, allowing specific targeting of the medication where it is needed without losing drug to the "first pass" effect. This is certainly effective for treating the brain, which is often deprived of medicines that can’t penetrate the blood/brain barrier.

Alkermes has two polymer microsphere products constructed of PLG. PLG is a polymer of lactide/glycolide, the ratio of which can be varied from 0:100 to 100:0. Additionally, any lactide isomer can be used. This allows for large flexibility in polymer properties, resulting in products that can be resorbed in as little as a week and as long as one year.

InSite Vision, Inc. treats ocular disease using polymer based aqueous mixes of drugs (DuraSite). The use of polymers extends the residence time of drugs on the eye and allows delivery of previously unstable molecules.

DepoMed Inc. uses polymers to reduce the clearance time of drugs taken orally. Their Gastric Retention (GR) System is a polymer-based pill that expands in the stomach after being swallowed. Its increased physical size blocks its clearance through the GI tract. It is eaten away over several hours and passes after useful life.

One problem with polymer microspheres is that they tend to settle rapidly when in saline. This causes poor distribution when they are injected into the bloodstream, as most deposit at the injection site. Secondly, the microspheres can clog the needle opening, blocking injection. Current methods to circumvent this problem involve various viscous mediums to suspend the microspheres for injection.

BioGel Technologies has developed techniques to alter the outside of microparticles that allows them to remain suspended in saline for long periods of time.

Not all sustained release techniques use polymers, other materials are also possible, but they do not dissolve.

Alza Corp. has a sustained release product used to treat advanced prostate cancer.

Obviously the more localized a drug can be delivered, the lower the overall dose needs to be to maintain a therapeutic concentration. This makes medication more effective with lower side effects. It has already been described above how certain polymer products can achieve localized delivery. In addition there are many products on the market in the form of transdermal patches and gels that also enhance local delivery as well as ease of use. However, these types of technologies are impractical for many internal disease areas that can only be accessed by the bloodstream.

Point BioMedical - Manufactures acoustic biSpheres, which are small microparticles with an inner and outer wall. "The inner wall provides physical structure and acoustical control while the outer wall provides the biological interface." These spheres can be filled with medication and injected into the blood stream. When the biSpheres pass through an ultrasound beam, they break open and release their drug payload. This allows physicians to focus the ultrasound beam on the disease area and ensure localized release of medication only in that area.

Scintipharma, Inc. – Has developed the Intelisite capsule. This capsule is the size of a large pill and contains medication sealed inside. The capsule is radio-labeled so that it can be tracked as passes through the GI tract using gamma scintograpy. When the capsule reaches the desired area a radio signal is used to activate the capsule, opening tiny gates in the surface and releasing the drug.

Polymer technology is just one method of increasing the pharmacokinetics of large molecule drugs. Another method of bypassing the detrimental effects of the stomach on large molecules is to find other areas of the body that can allow access of drugs to the bloodstream. Oral delivery is limited for large molecules because they are digested in the stomach. Nasal and transdermal deliveries are inefficient because large molecules cannot cross the membrane into the bloodstream.

Generex Biotechnology has created a lipid based oral mist that allows absorption of drugs across the oral mucosa, thus avoiding the "first pass effect", avoiding GI degradation of the molecules, and increasing solubility of the drug.

Anesta Corp. has developed a similar absorption technology termed the oral transmucosal system (OTS™). This is a drug matrix that is used on the oral mucosa to enhance absorption of the drugs into the bloodstream.

Several companies are working on iontophoresis, a process that uses electic currents to move molecules across the skin. These companies include Hisamitu Pharma and Iomed Clinical Systems.

Several companies are working on using the lungs as a new area for large molecule delivery. The lung’s alveoli represent a huge surface area separated from blood vessels by a very thin membrane.

Inhale Therapeutic Systems – Has developed a dry powder technology for peptide and proteins. An advantage of this system is that peptides and proteins are often more stable in dry form. Secondly, the powdered drugs can be delivered in aerosol form as particles up to 95% drug, whereas aqueous aerosols can contain 1-2% drug. This technology is combined with the PulmoSpheres technology, which allows these powders to be aersolized in a more efficient and reproducible manner.

Aradigm is pursuing a liquid aerosol technology named the AERx^® Pulmonary Drug Delivery System.

One limitation of the lungs for using aerosol particles is that they are often cleared by lung before they have a chance to be absorbed into the blood.

Alkermes has created a mechanism (AIR)for making aqueous drug mixes aerosolize in a much larger form, such that the physical size (5-30 mm) of the particle prohibits its clearance by the immune system. Additionally, because the new structure is a large and open, no additional drug is used to increase the size.

Improvement in the delivery of drugs to the brain, which is normally off limits because of the blood/brain barrier, has also been made.

Three companies have made significant strides in one large area of improved drug delivery from the aspect of ease of use. Their contribution has been in needle-free delivery systems. This technology has been around for several decades, but only recently has it been refined to work as a portable and disposable system. Needle-free systems avoid needle phobia, and are far less prone to contamination danger normally associated with needle-sticks.

Bioject uses CO2 to power injection of medication through the skin. This type of delivery is claimed to be better than needle injection because the blast creates a very large tissue disruption and wide areas of drug delivery. Needle injections leave a large bolus of injected material , much of which is not in contact with the tissue surrounding it.

PowderJect has a needle free system that blasts in powder forms of drugs using helium gas. The drug mass used in this system is much smaller than in liquid systems, and deposits over 2 cm². The smaller claimed amount of tissue distension should trigger fewer pain receptors.

Ease of use improvements are often directed at those people who cannot readily swallow standard pills. This is one area in which sustained release systems are advantageous. The patient doesn’t have to ever take medication, they just need to go to the doctor to get another dose every few months. This is especially important for the elderly, who may require many medications and often have trouble keeping track of when to take each. However, there are other ways to deliver drugs orally than in pill form.

Alkermes has a system that it targets for elderly and pediatric use, two populations for which taking pills is often difficult.

Blood/brain barrier - The blood-brain barrier is a structure of microvessels that limits diffusion of substances between cells. The endothelial cells of the brain's capillaries form tight junctions that limits permeation into the brain.