Issue: November / December 2012, Posted Date: 12/3/2012

Recent Advancements in Drug Delivery: Novel Formulations & Technologies Offer Improved Treatment Options



Debbie Toscano is a Senior Industry Analyst with the Frost & Sullivan North American Healthcare practice. Utilizing more than 20 years of life sciences industry experience, she maintains particular expertise in analysis and interpretation of scientific data as well as preparation of deliverables with attention to technical detail. Mrs. Toscano has an experience base covering a broad range of sectors, including focus on diabetes and metabolic diseases, cardiovascular diseases, and preclinical animal modeling and pharmacology. Prior to joining Frost & Sullivan, she conducted preclinical research with Novartis Pharmaceuticals. Mrs. Toscano earned her BS from Delaware Valley College in Biology and her Master's Certificate from Thomas Edison State College in Clinical Trials Management. 

By: Debbie Toscano, Senior Industry Analyst, Frost & Sullivan


The pharmaceutical and biotechnology industries have come a long way when it comes to advancements in drug discovery. New "druggable" targets and mechanistic approaches to treating even complex diseases are constantly discovered and optimized, generating a rich pipeline and continuous supply of fresh therapeutics for difficult diseases, such as autoimmune inflammatory disorders (for example, rheumatoid arthritis, inflammatory bowel disease), cancer, hepatitis C, and other infectious diseases, as well as neurological conditions, such as multiple sclerosis, to name a few.

However, developing a safe and effective drug is only part of the picture - perfecting the delivery of that drug into the patient is also a significant aspect of the total pharmacotherapeutic regimen. It is generally accepted by the pharmaceutical industry that the oral route of delivery is most preferred by the patient. However, this is not always possible or optimal due to formulation challenges or specifics of the particular indication being treated. For example, biologicals, such as vaccines or therapeutic antibodies, typically must be injected directly into the bloodstream because oral ingestion would result in the destruction of the fragile protein composition. Also, orally administered drugs tend to be distributed systemically, whereas the diseased portion of the body may be localized to a single organ or tissue. Thus, oral administration and systemic distribution may result in unnecessary exposure to the drug and unwanted side effects that could potentially be avoided with targeted drug delivery and isolation at the source of disease. Therefore, pharmaceutical and drug delivery companies are thinking outside of the box to address the issues associated with sub-optimal drug delivery.

This market brief will discuss a few recent innovative approaches to drug delivery with a focus on some of the therapeutic areas most relevant to the current pharmaceuticals market.


As seen in Figure 1, oral administration tops the list of approved pharmaceuticals, with approximately 7,468 total products on the market or approved for marketing. However, when looking at the development pipeline, injectable agents outnumber oral agents, with approximately 3,327 injectable agents in development versus 2,686 oral agents (Figure 2), as a result of the booming biotech industry. Medical advances, such as in biologicals, have revolutionized pharmacotherapy for complex diseases, such as rheumatoid arthritis, Crohn's disease, diabetes, and multiple sclerosis. Products like tumor necrosis factor (TNF) inhibitors for rheumatoid arthritis or glucagon-like peptide-1 (GLP-1) analogues for diabetes offer patients true disease-modifying benefits as opposed to simply treating the symptoms, and these benefits generally outweigh the discomfort associated with injection. All other things being equal, subcutaneous is generally the preferred injectable route as it can be easily performed by the patient at home using delivery devices, such as autoinjectors or pen injectors. However, even with the most sophisticated pen injectors, it still may be considered an unpleasant experience by many patients.

Tailoring the delivery of injectable drugs is mainly dependant on the specifics of two parameters: formulation and device. When injection is a necessity, new delivery technologies can improve the experience in several ways. For example, formulation enhancements can reduce the frequency of administration, reduce the volume needed for each injection, or reduce side effects associated with the formulation, such as immunogenicity. Delivery device improvements, such as a smaller needle or autoinjectors that improve ease of self-injection, can significantly improve the patient experience. Although the pharmaceutical industry makes many attempts to move away from injectable administration, injectable drugs continue to fill the development pipeline as demonstrated in Figures 2 and 3.

Several companies are making great strides in improving the patient experience of self-injection. For example, Ratio, Inc. has thought outside the box in developing their novel self-injection device, which resembles an adhesive patch rather than a typical pen injector. This clever device, dubbed the NuPrivo SC, is a disposable pump that slowly delivers a subcutaneous dose of medication over a period ranging from 5 seconds to 24 hours and can deliver volumes up to 5 milliliters. Rather than having to perform selfinjection by pinching the skin and holding a pen injector in place, the patient simply adheres this pump-patch to a suitable location, such as the abdomen, and, with the press of a button, the device slowly injects the medication. In addition to improving ease of use, the slow delivery also reduces trauma and discomfort associated with the injection of larger volumes because the drug is allowed to slowly disperse rather than forming a pocket beneath the skin. Because the device uses hydraulic power of an expandable gel to drive the injection, the shelflife and utility is greatly enhanced compared to a device that relies on battery power. This device could be used with any drug with no need to reformulate, and even high-viscosity formulations can be successfully delivered. The NuPrivo is slated to begin clinical trials in 2013.

Formulation improvements that extend the half-lives of drugs in the body, thus reducing the frequency of administration, are always welcomed by patients wishing to inject less often as well as physicians looking to improve their patients' compliance with their medication. There are several methods used to accomplish this, but one of the more popular is PEGylation, which involves attaching polyethylene glycol (PEG) to the drug. PEGylation is quite effective in extending the half-lives of drugs, such as peptides and antibodies, allowing for frequency of administration to be reduced from daily to weekly, or even to monthly in some cases. However, long-term exposure to PEG can result in immunogenicity reactions. In response to this issue, Caisson Biotech is capitalizing on a serendipitous discovery and is developing a non-PEG polymer based on the body's own natural, unmodified, part of the heparin sulfate molecule, heparosan. Heparosan polysaccharide sequences make up about 30% of the body's heparin sulfate (found in most cells/tissues) and heparin, but heparosan is distinctly different heparin/heparin sulfate, in that it has no heparin sulfate or heparin-like biological activity. Some pathogenic bacteria are able to synthesize heparosan and they use this to coat themselves to hide from the immune system. Because heparosan is normally present in the body, the immune system does not recognize the "heparosancoated" bacteria as foreign. Upon discovery of the capability to synthesize this polymer at the bench, scientists at Caisson Biotech decided to put it to use to extend the half-lives of biologicals and other drugs. By attaching synthetic heparosan to a drug molecule, an extended-release formulation similar to PEGylation can be created but with much less risk of an immunogenic reaction. Additionally, the half-life of a drug-heparosan conjugate can be easily customized by simply altering the defined size of the polymer.


Vaccine development is one example of a highly active pharmaceuticals market segment. Vaccines have been in use since the 18th century when the vaccine for smallpox was discovered. Since then, there have been extensive improvements in the efficacy and safety of vaccines as well as the breadth of infectious diseases we can be protected against. However, vaccines are still not 100% foolproof, and there is still much room for improvement, including administration. Generally speaking, vaccines are administered via injection into the muscle, regardless of the specific pathogen being immunized against. This manner of administration typically evokes the best immune response in the patient. However, a clinical-stage Dutch biotechnology company called Mucosis is challenging this theory with its line of vaccines being developed for transmucosal administration via the nose or mouth, a method that not only is more patient friendly but has been shown to be superior in eliciting an immune response to infections such as influenza. The theory behind this novel approach is that many infectious agents, such as influenza, enter the body via the mucosal surfaces of the respiratory system, which has its own immunological defense mechanisms designed to block or inactivate pathogens. Therefore, if a vaccine is administered via the same route that the pathogen uses to invade the body, the immune response to the vaccine more closely resembles the natural immune response. Mucosis has shown that its mucosally administered vaccines can elicit both a systemic and local immune response to vaccination, which should translate into improved protection. Mucosis' lead program is SynGEM®, a mucosally administered vaccine to prevent infection by respiratory syncytial virus (RSV), a virus that commonly infects young children and the elderly for which there is currently no vaccine. SynGEM is currently in the preclinical stage of testing. Mucosis has recently announced positive results from a Phase I clinical study of FluGEM®, successfully demonstrating proof-of-concept of its vaccine technology platform dubbed Mimopath®.


Treatment of gastrointestinal disorders, such as inflammatory bowel disease, is one example of a therapeutic area buzzing with drug development activity due to the significant unmet need that still exists. Treatment of severe cases of inflammatory bowel disease (Crohn's disease and ulcerative colitis) has seen significant improvement with the approval of biologics, such as Remicade (infliximab, Johnson & Johnson), Humira (adalimumab, Abbott), Cimzia (certolizumab pegol, UCB), and Tysabri (natalizumab, Biogen Idec/Elan). However, systemic exposure to these and other treatments can be associated with adverse effects. Thus, pharmacotherapy of gastrointestinal disorders, such as inflammatory bowel disease, can be challenging due to the need to medicate only the bowel while avoiding unnecessary systemic exposure to the drug. If the disease is confined to the lower end of the bowel, such as in distal ulcerative colitis, localized medication can be administered via suppository, enema, or foam. However, this route of administration may not be the most preferred by the patient. Advancements in oral formulation technologies are addressing this issue by enabling the oral delivery of medications that are only released in the intestine with little to no systemic absorption, with the result of effective therapeutic treatment of the bowel and reduced side effects.

Cosmo Pharmaceuticals, based in Italy, is developing a line of products using their Multi Matrix MMX® technology that enables the controlled release of the drug in the lumen of the colon. The technology works by using a pH-resistant coating that delays the release of the drug until it reaches the lower digestive tract, where it is slowly released, providing topical treatment at the site of inflammation, where it is needed with reduced systemic absorption. Cosmo's lead product, Lialda®, has been available in the US since 2007, where it is marketed by Shire. Lialda is a once-daily oral form of mesalamine, a drug commonly prescribed for the treatment of ulcerative colitis. A similar product with budesonide as the active ingredient is awaiting approval by the US FDA and will have the trade name of Uceris if approved. Uceris will be indicated for the treatment of ulcerative colitis as well.

Sigmoid Pharmaceuticals, located in Ireland, is developing a similar medication. Its lead product candidate for ulcerative colitis, CyColTM, has just successfully completed a Phase II clinical study. CyCol is a controlledrelease formulation of cyclosporine, a powerful immunosuppressive drug. Using its proprietary drug delivery technology platform SmPillTM, CyCol delivers cyclosporine directly to the colon with minimal systemic absorption, resulting in greatly improved tolerance.

Avaxia has a different approach to gastrointestinal-targeted therapy. This innovative biotech located in Massachusetts is developing oral antibodies created by collecting antibodies from the milk of immunized cows. Because antibodies secreted in the colostrum (first milk) of cows and other mammals are naturally designed to withstand degradation in the digestive tract, orally administered therapeutic antibodies can theoretically be created by immunizing cows against the desired antigen. In the case of treating inflammatory bowel disease, anti-TNF therapy is a well-established treatment for this and other autoimmune inflammatory conditions, such as rheumatoid arthritis. However, systemic administration of this drug via injection can result in unwanted side effects. By delivering anti-TNF antibodies directly to the site of inflammation in the gastrointestinal tract, Avaxia hopes to provide effective localized immunosuppressive therapy with greatly reduced side effects normally seen with the systemic delivery of TNF inhibitors, such as infections resulting from generalized immunosuppression.


A safe, effective, economical, and patientfriendly drug delivery method is a key factor for the success of a pharmaceutical product. Medicinal chemists and biologists have the critical task of discovering and developing new and innovative mechanisms that can address unmet medical needs by treating diseases more effectively and with greater safety and tolerability. Capitalizing on optimized drug delivery technologies that are designed to address both effective administration and patient acceptance can be a critical element of the final product that can take it to the next level and potentially transform a novel yet ordinary product into a potential blockbuster.

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