Delivering Therapeutic Proteins - Drugs, Devices and Delivering Strategies

The complex structure of these therapeutic substances require special formulation and delivery strategies, creating special challenges for drug developers, their formulation technology , delivery device partners. The stakes are high. The current list of approved therapeutic proteins will grow at an exponential rate as the convergence of automated drug discovery and biotechnology production methods create new biological drugs for an expanding number of previously intractable ailments. Currently, more than two-thirds of all therapeutic proteins for chronic diseases are sold as combination pen or auto-injector products. We expect the impressive success of combination drug-device products to continue their dominance on a total market value basis. And while injection will remain the dominant route of administration for protein drugs for the rest of the decade, the recent clinical success of several inhaled protein products will result in escalating interest in inhalation as a protein drug delivery method. Work on stabilized oral formulations is also making progress. In the near term, the cost per dose of recombinant proteins will continue to provide device technologists with enough running room to continue developing rather elegant protein-device combination products.

In recent years, the number of protein-based pharmaceuticals reaching the marketplace has increased exponentially. The clinical application of these drugs is limited by a lack of desirable attributes for adequate absorption or distribution. It therefore becomes critical to formulate these drugs into safe, stable and efficacious delivery systems. Because these drugs face formidable enzymatic and penetration barriers when administered orally, peptide and protein drugs have until recently been marketed almost exclusively for parenteral administration.

A limitation of the parenteral route for delivery of peptides and proteins is the extremely short half-lives of these drugs – in the order of a few minutes. This demands repeated administration, which is inconvenient to the patient. For this reason, non-parenteral routes of administration are being pursued. Another approach is to incorporate controlled release parenteral formulations, where a single injection may release the drug over several weeks or longer.

These combination products, where the drug and device are clinically tested and approved as a single product entity, are becoming one of the fastest new drug categories. Combination drug delivery products are growing at an annual rate of fourteen percent across all technology segments, and will total $38 Billion in 2008. The growth of combination products is having a significant effect on the way drugs and devices are developed. Cooperation between device designers and drug developers is occurring much earlier in the drug development cycle, allowing device designs in many cases to be tailored to the bioavailability targets and pharmacokinetic profiles of specific drug therapies. In the near term, the cost per dose of recombinant proteins will continue to provide device technologists with enough running room to continue developing elegant protein-device combination products.

Methodology:

Research methodology is based on primary research in the form of in-depth interviews with key market participants, technology developers, distributors, industry experts, and market influencers, a list that includes regulatory officials, industry trade groups, and materials standards organizations.

Primary data is evaluated and normalized against secondary sources including trade journal articles, technical literature, industry publications, company data sheets and published information, and statistical data from government agencies and trade associations.

Forecasts and projections of market demand and future market activity are derived using standard modeling and statistical techniques.


The oral delivery of therapeutic proteins

Therapeutic proteins represent currently a significant part of the new pharmaceuticals coming on the market every year. The progresses in biotechnology have accelerated the economical, large-scale production of therapeutically active peptides and proteins, monoclonal antibodies, hormones and vaccines, making them readily on hand for therapeutic applications. At the present, they show a strong position in the novel area of nanomedicine, using nanotechnology for medical applications for both institutional and industrial fields. Most of these proteins are used for life-threatening and seriously debilitating diseases such as diabetes, cancer, rheumatoid arthritis or hepatitis. The high activity and specificity of proteins compared to the more conventional, low molecular weight drugs often allows for a better treatment of these diseases. However, the production and the delivery of these proteins occur under unfavorable stress conditions.

Advances on an effective oral delivery system for proteins require a comprehensive perception of their physicochemical properties, such as molecular weight, hydrophobicity, ionization coefficient and pH stability, as well as of the biological barriers that limit protein absorption through the gastrointestinal tract. The important therapeutic proteins and peptides being explored for oral delivery include insulin, calcitonin, interferons, human growth hormone, glucagons, gonadotropin-releasing hormones, encephalin, vaccines, enzymes, hormone analogs, and enzyme inhibitors. These are outstanding model proteins used in the pharmaceutical development, mostly due to its well-established physical-chemical properties and social impact of their therapeutical applications.

Strategies to improve the oral bioavailability of proteins have ranged from changing their physicochemical properties by modification of their lipophilicity and enzyme susceptibility, to adding novel functionality using transport-carrier molecules that are recognized by endogenous transport-carrier systems in the gastrointestinal tract and/or to their inclusion in specially adapted drug carrier systems. Marketed polymeric-based systems have attracted considerable attention in the controlled release in targeting particular organs/tissues, as carriers of DNA in gene therapy and in their ability to deliver proteins, peptides, hormones, antibodies and genes. They can effectively deliver the proteins to a target site and thus increase the therapeutic benefit, while minimizing side effects. Protein association with polymer-based carriers, such as polymeric microparticles, nanoparticles, hydrogels or patches is one of most promising approaches proposed to improve oral protein bioavailability. Polymer-based carriers can protect proteins from the gastrointestinal environment and allow the modulation of physicochemical and protein release properties and consequently the biological behavior. Also, from the perspective of improving oral absorption, the major effect of carriers is to increase epithelial membrane permeability, thereby leading to higher bioavailability.

The problems facing oral delivery of peptides and proteins have traditionally been approached from many different angles, namely formulation, encapsulation, macromolecular conjugation and chemical modification, but there are many other criteria that must be satisfied to bring an oral protein formulation to the market. For example, the low bioavailability implies a large variation in absorption and a high manufacturing cost, which is unacceptable for the development of most peptide and protein drugs. For proteins like insulin that has a relatively narrow therapeutic window, the effects on intestinal absorption of age, genomic factors, physiological conditions and other individual variations must be carefully investigated. Finally, most peptide and protein drugs require chronic administration and hence the effects of long-term oral administration of absorption carriers on both the intestinal and systemic physiology must also be carefully evaluated..

Delivery of therapeutic proteins to the mucosa using genetically modified microflora
Drug delivery through mucosal surfaces offers a panorama of opportunities. The advantages are clear and include safety, ease of administration and higher social acceptance, although the major disadvantages are drug availability and appropriate drug targeting. Most mucosa are well equipped to manage the presence of bacteria and many are actually permanently colonised with a specific microflora. Such microbiota may become attractive tools for the delivery of a specific niche of protein therapeutics. These proteins can be produced from genetically modified microbes that are common to the mucosa, and their delivery to the host tissues has been demonstrated. This concept is being developed for the delivery of proteins to the intestine, but has also been applied in delivery to the vagina, nose and mouth.