FORMULATION - Parenteral Advances | Get Local with Targeted Delivery

Maybelle Cowan-Lincoln

A new range of polymer implants and programmable microchips is paving the way to more personalized therapies

There are three major parenteral drug delivery routes: intravenous, intramuscular, and subcutaneous, as well as several more rarely used routes such as intra-arterial.¹ Recently, however, interest has piqued in new parenteral technologies that facilitate targeted local drug delivery.
Parenteral delivery can be the route of choice under several circumstances:

• When the plasma levels of a drug must be carefully controlled;
• When it is necessary to avoid the “first pass” metabolism through the liver or minimize the risk of harmful side effects resulting from systemic delivery;
• When the patient is not conscious or not capable of taking the drug orally; and
• When administering drugs with a short half-life.²

The parenteral route provides the best solution for overcoming the challenges of delivering proteins and peptides. These agents are easily degraded by enzymes found in the gastrointestinal tract, and the large size of the molecules makes transdermal delivery difficult. In addition, proteins and peptides have very short half-lives in vivo, so they must be injected multiple times over the course of a day.
Novel controlled release parenteral technologies can reduce injection frequency and the accompanying pain, thereby potentially improving patient compliance.³ But this solution comes with its own set of problems. In addition to the pain of multiple injections, drugs taken by injection follow the pattern of first-order kinetics—high levels in the blood after administration followed by a sharp fall in concentration. At peak levels, toxicity can be an issue, and efficacy can decrease as levels fall. An ideal implantable system would include an electronic feedback device to control drug release.

Zero-Order Release

Controlled drug release from implantable parenteral devices may also be able to achieve the elusive goal of sustained zero-order release. This means that the rate of drug release remains constant, minimizing the risk of toxicity and the inconvenience of frequent dosing. This is particularly important when the drug concentration must fall into a narrow window between the minimum effective concentration and the maximum safe concentration.⁴
Strategies to come close to zero-order release have included multiple injections and implantable pumps. But these methods fall short of ideal. Frequent injections are inconvenient and painful, and implantable pumps require surgery to implant, refill, or remove. In addition, these pumps can only be used with drugs that are stable at physiological temperature. Research continues to look for a more efficient technology to achieve zero-order release.
continues below...

CASE STUDY: The Electronic Implant Revolution

EMS and NEMS devices are the basis for technologies that will effect a sea change in the treatment of many diseases. Implantable devices complete with micro- or nanochip technology that allows them to respond to physiological changes can virtually automate the management of certain chronic diseases and provide lightning fast interventions for emergency situations. Two systems on the leading edge of this research are the “artificial pancreas” and the “personal paramedic.”¹

www.artificialpancreasproject.com

According to the American Diabetes Association, approximately 25.8 million Americans suffer from diabetes, with 7 million of these undiagnosed. And, each year, 1.9 million new cases are discovered in people aged 20 and older.² The most important thing diabetes patients can do to maintain their health is to strictly control their blood glucose levels. But for a variety of reasons—pain and inconvenience among them—many do not. This often results in debilitating pathologies later in life, including blindness, kidney failure, and amputations.³
To promote better disease management, the Juvenile Diabetes Research Foundation (JDRF) launched the Artificial Pancreas Project six years ago. The JDRF has formed a consortium of government and academic researchers, along with private corporations from the United States and Europe, to work collaboratively toward the development of the first fully functional unit.⁴
The artificial pancreas would be a miniature, closed-loop device composed of a glucose monitor, a miniature pump powered by a MEMS chip to deliver insulin, and a power source. The artificial pancreas would continuously monitor blood sugar levels and automatically release the precise amount of insulin needed, practically automating diabetes management.
Another breakthrough MEMS-powered device is the “personal paramedic” or Implantable Rapid Drug Delivery Device (IRD3). An implantable delivery system designed for ambulatory emergency care, the IRD3 allows for rapid delivery of cardiac resuscitation drugs such as vasopressin.
The IRD3 is made up of three layers: the reservoir where the drug is stored, the membrane that seals the reservoir to prevent the drug from leaking out or foreign substances from penetrating, and the actuation layer. In the actuation layer, micro-resistors heat fluid to form bubbles once certain cardiac symptoms are detected by the MEMS microchip. The increased pressure caused by the bubbles ruptures the membrane, allowing the medicine to be released from the reservoir at a rate of approximately 20 µl in 45 seconds.⁵
The treatment of diabetes and certain types of heart disease can be transformed by these drug delivery systems. Their success can also stimulate a creative and vibrant commercial environment, fueling the discovery of more ways MEMS devices can improve the management of many conditions.

References

1. Staples M. Microchips and controlled-release drug reservoirs. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2010;2(4):400–417.
2. American Diabetes Association. Diabetes statistics. Available at: www.diabetes.org/diabetes-basics/diabetes-statistics. Accessed Oct. 3, 2011.
3. Schetky LM, Jardine P, Moussy F. A closed-loop implantable artificial pancreas using thin film nitinol MEMS pumps. Paper presented at: International Conference on Shape Memory and Superelastic Technologies; 2003; Pacific Grove, Calif.
4. MacRae M. The artificial pancreas project. American Society of Mechanical Engineers. August 2011. Available at: www.asme.org/kb/ news—articles/articles/bioengineering/the-artificial-pancreas-project. Accessed Oct. 3, 2011.
5. Elman NM, Ho Duc HL, Cima MJ. An implantable MEMS drug delivery device for rapid delivery in ambulatory emergency care. Biomed Microdevices. 2009;11(3):625-631.

Polymer Implants

click for larger view

Polymer scaffolds made from chitosan can serve as temporary biodegradable drug depots

A popular controlled delivery device is the polymeric implant. These systems fall into one of two categories: nondegradable and biodegradable. An example of the former technology is the Norplant five-year contraceptive device. Hollow polymer tubes are filled with a drug suspension that dissolves into the polymer, then diffuses through the tubing walls.
Biodegradable polymer implants are usually made of microspheres containing a drug. Once injected, the polymer dissolves, releasing the drug into the system. A new technology under development uses biodegradable polymer rods implanted in the marrow of infected bones to deliver fluconazole to treat fungal osteomyelitis.⁵
Some exciting developments are being pursued in creating polymer scaffolds to serve as temporary biodegradable drug depots. These structures can be made from natural polymers such as collagen or chitosan, or from synthetic polymers that do not promote inflammation and are bio-degradable, biocompatible, and nontoxic.⁶
One of the most successful drug scaffold models is the injectable polymer depot. A liquid liposomal solution or suspension is injected subcutaneously or intratumorally, where it forms a semi-solid scaffold that releases the drug right at the target site. This method offers several benefits, including local drug retention and sustained release.

In addition to delivering pharmaceuticals, polymeric scaffolds have been designed to continously release growth factor cells to promote tissue regeneration.

Prefabricated polymeric scaffolds have also gained attention as delivery systems for small-molecule drugs and various bioactive molecules. These systems are manufactured outside the body and must be implanted surgically. Biodegradable and nondegradable materials are being tested as possible scaffold materials; the drawback of nondegradable materials is, of course, the necessity of surgical removal at the end of therapy.
In addition to delivering pharmaceuticals, polymeric scaffolds have been designed to continuously release growth factor cells to promote tissue regeneration. For example, vascular endothelial growth factor—a signal protein manufactured in cells that promotes the growth of new blood cells, a process known as angiogenesis—has been incorporated into a scaffold. In a recent study, increased blood vessel density was noted at the implant site. These results demonstrate an increase in angiogenic potential. Tissue regeneration typically uses prefabricated scaffolds requiring surgical implantation and removal, but research on injectible hydrogel scaffolds is ongoing.⁷

Getting a Charge

Exciting advances are being made in the development of implantable drug delivery devices using micro- and nanoelectromechanical systems. Called MEMS and NEMS, respectively, this technology employs microchips that contain micro- and nano-scale programmable electronic circuits.⁸
MEMS and NEMS devices offer complex functionalities that could potentially overcome many of the shortcomings and inconveniences of conventional drug therapy, including complicated dosing regimens and fragile or easily degradable active ingredients. Drugs can be released from a reservoir by electrical signals programmed into the micro- or nanochip. With MEMS technology, timing and dose amount can be precisely controlled, and drugs can be delivered to precise locations. Myriad dosing options can then be available, including delivery on demand, programmable dosing cycles, and automated dosing of multiple drugs.
Another delivery system that utilizes MEMS chips is the micropump. Unlike mechanical micropumps, actuated by one of various mechanisms, including electrostatic, electromagnetic, and piezoelectric energy (utilizing the electric charge that naturally collects in crystals, bone tissue, DNA, and other material in response to mechanical stress), some micropumps utilize MEMS microchips. These pumps must minimize chip and device size and must be made of biocompatible materials. They must be able to operate for weeks to years without presenting much risk to patients, must deliver a relatively steady flow rate, and must either use minimal power or be remotely rechargeable.

Medtronic’s ACT Insulin pump.

In even more exciting research, MEMS and NEMS technology is contributing to the emergence of personalized medicine, the science of optimizing treatment based on individual genetics and physiology. Delivery devices containing standard drugs could include micro- or nanochips and possibly a biosensor to provide physiological feedback. This complex device could maximize therapeutic flexibility and efficiency by tailoring drug delivery to the patient’s needs as revealed by the biosensor.
This type of system could be used to create an “artificial pancreas” for diabetes patients. It would comprise an insulin reservoir and a biosensor to monitor blood glucose levels. The sensor would communicate with a MEMS/NEMS-based drug delivery device to regulate insulin release and also transmit data to an external device for use by the patient or physician. Data for dosing flexibility and control could also potentially be received by the device. This technology has not yet been perfected, but once successfully implemented, it could revolutionize the treatment of a large patient population.
In addition to the benefits for long-term drugs, MEMS- and NEMS-based systems can also provide emergency care. Currently, a “personal paramedic” is being developed to work in tandem with current cardiac devices such as a pacemaker. This device, called the IRD3 (Implantable Rapid Drug Delivery Device), could release drugs used in cardiac resuscitation, such as vasopressin, when needed. The IRD3 could also be used to treat angina patients by releasing vasodilators on demand.
Microreservoirs that employ MEMS devices are a combination of drug reservoir systems and polymer matrices. Microreservoirs are implanted drug delivery systems used for proteins, hormones, pain medications, and other drugs. Each tiny reservoir, covered with a gold membrane, contains a single dose. The dose is released when one microreservoir is exposed to anodic voltage from the MEMS chip, causing the membrane to rupture.

Smooth as Silk

An artificial pancreas would be a miniature, closed-loop device composed of a glucose monitor and a miniature pump to deliver insulin powered by a MEMS chip.

Silk fibroin is another material being studied as a polymer vehicle for sustained local drug delivery. A recent study conducted at Tufts University evaluated the efficacy of silk fibroin to encapsulate the anticonvulsant adenosine in a biocompatible and biodegradable drug reservoir.
Adenosine is a promising treatment for drug-resistant epilepsy. When given systemically, however, it causes severe side effects, including suppressed cardiac function. Local delivery using a reservoir placed in the brain may provide the answer. However, polymers commonly used to coat reservoir devices have significant drawbacks. Some are nondegrading or require organic solvents that can damage encapsulated drugs. Others release drugs too quickly.
Silk-based implantable systems, on the other hand, offer numerous advantages. Silk fibroin is biodegradable, biocompatible, and strong; it is used as suture material for the brain and nervous tissue. But the study demonstrated that silk fibroin can successfully achieve the parenteral drug superobjective. Adenosine reservoirs coated with eight layers of 8% silk fibroin material exhibited zero-order release. Reservoirs with four layers of 8% silk fibroin exhibited near zero-order release.

References

1. Gad SC, Cavagnaro JA, Nassar AF, et al. Formulations, routes, and dosage design. In: Gad SC, ed. Pharmaceutical Sciences Encyclopedia: Drug Discovery, Development, and Manufacturing. New York: John Wiley and Sons; 2010:10-15.
2. Paolino D, Sinha P, Fresta M, Ferrari M. Drug delivery systems. In: Webster JG, ed. Encyclopedia of Medical Devices and Instrumentation. 2nd Ed. New York: John Wiley and Sons; 2006:437-486.
3. Gad SC, Tamilvanan S. Progress in the design of biodegradable polymer-based microspheres for parenteral controlled delivery of therapeutic peptide/protein. In: Gad SC, ed. Pharmaceutical Manufacturing Handbook: Production and Processes. New York: John Wiley and Sons; 2008:393-427.
4. Pritchard EM, Szybala C, Boison D, Kaplan DL. Silk fibroin encapsulated powder reservoirs for sustained release of adenosine. J Control Release. 2010;144(2):159-167.
5. Soriano I, Martín AY, Évora C, Sánchez E. Biodegradable implantable fluconazole delivery rods designed for the treatment of fungal osteomyelitis: Influence of gamma sterilization. J Biomed Mater Res A. 2006;77(3):632–638.
6. Mufamadi MS, Pillay V, Choonara YE, et al. A review on composite liposomal technologies for specialized drug delivery. J Drug Deliv. 2011;2011:1-19.
7. Chung HJ, Park TG. Surface engineered and drug releasing pre-fabricated scaffolds for tissue engineering. Adv Drug Deliv Rev. 2007;59(4-5):249-262.
8. Staples M. Microchips and controlled-release drug reservoirs. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2010;2(4):400–417.