One area that shows great potential is in medicine with the development of new nanopharmaceuticals. According to a report published by BCC Research, the market value of the worldwide nanomedicine industry was $72.8 billion in 2011. The market is estimated to grow at a CAGR of 12.5% to reach $130.9 billion by the fiscal year 2016. The market for anti-cancer products was valued at $28 billion in the fiscal year 2011 and is anticipated to reach $46.7 billion by the fiscal year 2016.
The pharmaceutical industry is undergoing a revolution and it is clear that many in business and science are predicting that nanopharmceuticals will play a major role in the future of medicine. The driving force for this revolution is the need to develop new drugs to meet market demand. However, it is becoming extremely difficult to develop new drugs the traditional way and an alternative R&D approach has to be found. Nanopharmaceuticals may be the answer. To understand why, we must first examine the current state of the pharmaceutical industry and how it will respond to the socio-economic changes that are occurring in the world.
Taxol Is an Example to Follow
Pharmaceuticals can be broadly classified into two categories: patent-protected high-priced branded drugs and low-cost generic drugs. However, the pipeline for developing new drugs is rapidly declining because of the extremely high costs of research and development. It can cost up to $1 billion and take 10 years to develop a new drug, and companies are reluctant to make this investment because there is uncertainty as to whether they can recoup their investment and make a profit in today’s business climate of reducing healthcare expenses.
So if it’s too expensive to make a new drug what can a company do to survive? One way is to simply engage in price-cutting and make up in volume what was lost in pricing. This is the approach taken by most generic manufacturers. The consequences of this approach will be the survival of the fittest, and fewer manufacturers of generic drugs in the future.
Another way is to take an existing drug and to make it better in some way (e.g. safer or more effective so that it is not subject to price competition from generics). So how do you make an existing drug better? You can’t easily change the chemistry of the drug itself, that’s more-or-less fixed. You can, however, change the way the drug is delivered and utilized in the body. And this is where nanopharmaceuticals will play a major role in the future.
Consider the case of Abraxane®, which was the first novel drug nanoparticle formulation to be successfully commercialized. The way this drug was developed, registered with FDA, and marketed is a case study in how all future nanopharmaceuticals will be developed.
Taxol® (paclitaxel) is a drug used to treat breast cancer. The drug is insoluble and has to be dissolved in castor oil before it is infused intravenously into the patient. When the patent for Taxol expired, it became open to generic competition. One manufacturer of generic paclitaxel developed a novel method of drug delivery using nanosized particles of paclitaxel coated with human albumin called Abraxane®. Patients tolerated the albumin-paclitaxel nanoparticles better than paclitaxel in castor oil and the time for drug infusion was shortened significantly. So the general conclusion was that this could be the best generic version of paclitaxel available. But here is where it gets really interesting. Abraxis petitioned the FDA to consider the Abraxane as a reformulated Taxol, not generic Taxol, under the 505(b)(2) regulation, to obtain marketing approval without all the requirements of a full-fledged NDA and yet have limited market exclusivity of a new drug. Abraxane’s clinical trial showed that it has a different Safety and Efficacy profile compared to Taxol, so it’s a de facto “new drug” for marketing purposes.
This special 505(b)(2) regulatory approval route by the FDA is extremely important because it opened up a new approach for developing new drugs at a fraction of the cost of more traditional development. Now it is possible to take any generic drug and change the delivery system to create a new drug with all the advantages that this brings. It also means that small companies can compete on more equal footing with large pharmaceutical companies because R&D costs can be much less of a barrier to innovation. Innovator companies developing novel nanopharmaceuticals will become prime targets for acquisition or partnerships with large, established companies.
Nanosized Drug Delivery Systems
The term “nanopharmaceuticals” covers a diverse collection of different nanosized drug delivery systems that can be used to create a new combination drug. These include nanoparticles, nanoemulsions, liposomes, dendrimers, nanocapsules, and lipid nanospheres to name a few. This article will focus on nanoparticles and liposomes to illustrate the significant advantages that these new combination drugs have over current drugs.
If you take an insoluble drug such as paclitaxel and make it into nanosized particles, then the particles behave just as though they were in solution. They flow freely inside the blood vessels and do not clog up the circulation. And, because they are nanosized, the surface area of each particle is very large compared to the volume and therefore the drug can dissolve more readily and become bioavailable. This could prove significant in the area of cancer drugs where 40% of all cancer drugs are insoluble. Nanosizing them would make them more “soluble” and therefore more bioavailable in the body.
Another way to treat insoluble drugs is to dissolve them in a lipid solution (e.g. oil) and then emulsify the drug-in-oil solution to prepare a nanoemulsion composed of nanosized droplets of oil containing the drug. Depending on the phase temperature of the oil, it will either remain as an oil above this temperature or it will harden to form solid lipid nanospheres below this temperature. As discussed earlier for nanoparticles, many insoluble drugs can also be treated as nanoemulsions or lipid nanospheres to make them better.
Soluble cancer drugs present a different kind of problem. When a soluble cancer drug is injected into the patient, it quickly distributes into all the body tissues so that only a small fraction of the drug actually reaches the tumor. Most of the drug enters normal tissues where it kills normal dividing cells, causing the serious side-effects associated with chemotherapy. Another disadvantage to soluble drugs is their rapid elimination from the body through the kidneys. Here again, nanopharmaceuticals comes to the rescue. Soluble drugs can be encapsulated within nanosized lipid vesicles called “liposomes” that will change their behavior for the better within the body.
Liposomal drugs provide a good example of the many advantages that nanopharmaceuticals have. For example, although liposomes are so small that they can circulate freely within the blood system they are too large to pass out through the endothelial pores of normal blood capillaries and penetrate into normal tissues and cause harm. Second, when a drug is enclosed within a liposome it is protected from being detoxified by the liver so that more drug is bioavailable to act upon the tumor. Third, because the drug is released gradually over time as the liposomes begin to leak, there is less risk of an acute systemic toxic reaction. Finally, there is more drug bioavailable for a longer period of time to act upon the tumor and inhibit its growth.
Liposomes are composed of a lipid membrane made up of phospholipids (e.g. egg lecithin) surrounding an aqueous interior. The simplest way of encapsulating a soluble drug is to hydrate the dried phospholipids with a drug solution whereupon a portion of the drug solution becomes entrapped within the interior of the liposome when it forms. Liposomes can also be used to carry insoluble drugs inside the lipid membrane layer by dissolving the drug in the lipid, drying the lipids and then hydrating the dried lipids with an aqueous solution.
One important feature of liposomes is that they can be made to be a certain size (e.g. 100 nm) so that they are small enough to pass through the enlarged endothelial pores of “leaky” blood vessels supplying the tumor and penetrate into the tumor tissue where the drug is released for maximum effect. This can result in ten times the amount of the cancer drug reaching the tumor as compared to the free drug.
Finally, there is ongoing research into developing specialized liposomal drugs that can target the tumor by attaching a tumor targeting antibody to the surface of the liposomes. These are called immunoliposomes. There are a number of anti-tumor antibodies developed that can target specific growth factor receptors on the cancer cell. For example, there is an antibody called Herceptin® that targets Human Epidermal Receptor -2 (HER-2) that is over-expressed in certain breast cancers; and another antibody called ErbituxR that targets Epidermal Growth Factor Receptor (EGFR) present in certain cancers of the head and neck. Animal studies showed that when the HER-2 antibody was attached to the surface of liposomes incorporating a cancer drug, the immunoliposomes bound to the breast cancer cells and killed them.
The Next-Generation of Novel Drugs
As pointed out earlier, there is a variety of different nanosized drug delivery systems such as liposomes, micelles, dendrimers, nanocapsules, and nanoparticles under development. Within each delivery system there is also a tremendous amount of variety in the physical and chemical components that can be used to make up each individual combination drug. Each new combination drug will have its own unique safety and efficacy profile. In the final analysis, the success or failure of any new drug will depend on its performance in clinical studies in comparison to other competing pharmaceuticals.
Nanopharmaceuticals represent the newest generation of novel drugs being developed. There are extensive ongoing research studies underway, and substantial investments being made in this area of medicine. It will be interesting to see which particular novel drug/delivery combinations will be the ones to succeed.
REFERENCES:
1. BCC Research Report, http://www.azonano.com/news.aspx?newsID=24136
2. Kahn, Jennifer (2006). "Nanotechnology". National Geographic 2006 (June): 98–119.
3. Cancer Nanotechnology. “Going Small for Big Advances”. U.S. Department of Health and Human Services. National Cancer Institute. January 2004.
4. Torchilin V. P. Targeted Pharmaceutical Nanocarriers for Cancer Therapy and Imaging. AAPS Journal 2007; 9 (2) Article 15.
5. Drummond et al. Optomizing Liposomes for Delivery of Chemotherapeutic Agents to Solid Tumors. Pharmacological Reviews. Vol.51 No 4. pp 691-742, 1999.
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