(R)evolutionary parenterals — new opportunities for drug delivery

Evonik outlines new opportunities for drug delivery via advanced parenteral formulations, the positives and the pitfalls.

The parenteral drug delivery landscape is undergoing a revolution, due to a combination of new drug findings and transforming formulation technologies. Not surprisingly, each of these topics has an influence upon the other.

The interest in the development of drugs such as peptides, for example, has spurred the search for novel formulations. Peptides, as is the case with many potent new drugs, cannot be administered orally because of poor absorption and stability. Yet daily injections are tedious to perform and thus result in low patient compliance.

That drawback has led to increasing exploration into more complex parenteral formulations that take advantage of extended-release capabilities. These offer prolonged efficacy of one week to several months after a single injection and include bioabsorbable delivery forms such as injectable microparticles and implants. Products based on biotechnology, however, require great diligence during formulation to retain stability and circumvent biological barriers that would prevent the dosage form from reaching the intended site.

Modern parenteral drug delivery systems — new therapeutic options

With today’s drug delivery technologies, it is no longer the molecular structure of the drug alone that determines where it is released in the body, but also the properties of the carrier. Additionally, these properties can be tailored to specific requirements of the treatment goal. That means the carrier can deliver more of the drug to a pre-determined site, shield it from premature degradation, or isolate delicate organs from the drug and thus diminish toxicity.

A good example of the beneficial effect of parenteral drug delivery can be seen with the commercial drug product Doxil, which was one of the first nano drugs to be approved by the FDA. Doxil was created by assimilating the anti-cancer agent doxorubicin, which can have substantial cardio toxicity, into a liposome drug delivery system that sidesteps the heart. Thus, it is an illustration of drug delivery technology used to improve existing drugs.

These new methods of delivery also offer potential for designing drugs specifically for use with particular delivery systems, while, as noted earlier, the reverse is also true.

Drug delivery technologies make it possible to develop new types of therapeutics. A case in point is messenger RNA (mRNA), which promises exciting advances in new treatments. As mRNA degrades in vivo and is unable to penetrate cells on its own, it can only function through the use of a suitable drug delivery system.

Delivering mRNA using lipid nanoparticle technology has enormous potential because the expression of almost any protein can be induced. This enables its use in treating genetic diseases such as cystic fibrosis where key proteins need replacement due to deficiency or damage.

The mRNA delivery technology could also be applied for the creation of vaccines with antigens capable of direct expression by the body (in situ synthesis). The result would be an improved immune response, as it would appear to the body to be a common viral infection.

Innovative approaches to nanoparticle production have been facilitated by liposomal drug delivery. Today it is possible to deliver substantial quantities of a drug while at the same time augmenting bioavailablity. Solid lipid nanoparticles, for example, have made pulmonary delivery of large amounts of drug possible — with minimal amounts of excipient delivered to exact targets within the lungs.

Potential and benefits of targeted drug delivery

There is enthusiasm about the potential to target drugs, which includes putting a drug where you need it and delivering it, in place, over a long time-period. For example, work is being done to develop formulations to reduce inflammation within the knee. This would prevent the drug from circulating within the body and causing unnecessary side effects, while allowing efficacious levels of the drug to be contained within the knee area.

At the same time, many new products have been recently launched, including those for treatments in the sinus, eye and periodontal regions. What the future holds cannot be accurately predicted, but it is not impossible to imagine local delivery to the spine, bones, within the brain or even as a factor associated with tissue regeneration and stem cells — or to rebuild knee cartilage.

Challenges of complex parenteral formulations

There are many challenges to developing complex parenteral formulations, which makes it more time-consuming and involved in comparison to conventional formulations. With injectable microparticles, the manufacturing process must be robust and tightly controlled. This is because, together with the drug, a particular polymer morphology will be created within the particles that will be susceptible to the slightest instability. In addition, as more and more highly potent APIs are developed, GMP requirements as well as worker safety become crucial issues that demand increased attention.

In addition, there is no direct cause-and-effect between plasma concentration and drug activity with injectable nanoparticle formulations. The drug within the delivery system only becomes active after it has been released. So, during development, outcome predictions can only be based on screening models and not on plasma drug levels as with conventional drugs. Also, with these complex formulations, excipients deliver important functionalities that need to be precisely controlled to achieve consistent therapeutic results.

With sophisticated formulations, it is necessary to consider the entire end-to-end development and manufacturing process, especially in terms of scalability. This means that from the beginning, thought must be given to issues such as material needs for a Phase I study and how those needs might change during clinical testing and commercialization. Characterization of the formulation is crucial to avoid a complete process re-design at a later date.

Complex parenteral formulations have and will continue to improve patient outcomes, but their development calls for expertise and dedicated experience. Evonik Health Care offers a range of services including consulting, formulation development and commercial manufacturing of complex parenteral formulations. Through innovation, building infrastructure, developing new process technologies — such as FormEZE microencapsulation — and creating intellectual property, Evonik continues to contribute to the commercialisation of these formulations and thus to improved therapies.