What are the current critical industry issues that have made drug delivery such a hot topic?
Shaukat Ali, Technical Service Manager, BASF: Drug delivery has been a hot topic for many years and continues to face many challenges. These challenges have become more pronounced because of the increased number of poorly soluble new chemical entities (NCEs), and the industry’s ability to develop appropriate technologies to enhance their bioavailability. The impact of this bioavailability challenge has been the launch of fewer marketed drugs. The other challenges stem from effective “controlled” delivery of highly soluble drugs over an extended period of time to avoid dose dumping and/or any side effects. Moving forward, addressing the issues related to effective delivery of poorly soluble drugs and highly soluble drugs will continue to be a focus in the industry.
Nila Das, PhD, Senior Research Investigator, Bristol-Myers Squibb: Trends towards insoluble drugs having issues of low or inconsistent bioavailability is an area that will continue to make drug delivery a hot topic in the coming years. The need to develop biologic drug products and the related issues such as instability of proteins, consideration of alternative routes of administration, or development of new modalities such as antibody-drug conjugates will stimulate the growth of drug delivery technology in the coming years. Conjugation of highly hydrophobic chemotherapeutic drugs may increase the unfolding and aggregation behavior of the native antibodies. Consequently, it becomes very critical to control the quality of the ADC drug products through the judicious choice of excipients in the formulations.
Kevin O’Donnell, Associate Research Scientist, Dow Pharma & Food Solutions and William Porter, Associate Research Scientist, Dow Pharma & Food Solutions: One of the most critical industry issues today is that of poor drug solubility which has arisen largely due to high throughput research and combinatorial chemistry. Without adequate solubility, the likelihood of commercial success of these molecules is drastically reduced resulting in this being a very active area of research. Special patient populations, such as pediatrics, can further complicate this issue.
Jasmine Musakhanian, Scientific & Marketing Director, Pharma-ceutical Division, Gattefossé USA: Developing new and effective medicines necessitates the discovery of drug entities with higher specificities for the disease targets, ideally with none or minimal side effects. That is of course only half the battle. Delivery by the dosage form, the route of administration, the rate, and the extent of the drug entity being delivered to the disease site can only be made possible by formulation or the drug delivery system.
In effect, there is no shortage of drug molecules for development. Emerging from highthroughput screening and computational models based on cell biology, are libraries of contemporary drugs, laden with significant issues: burgeoning molecular sizes, structural complexities, and very poor solubility characteristics. Meanwhile, over 40% of currently marketed drugs could benefit from improved solubilization, modified rate of absorption, and or better patient compliance.
With such a rich pool of drug candidates, pharmaceutical sciences have in recent decades turned focus to alternative drug delivery systems as a means to improving drug pipelines.
Can you tell us about some new drug delivery technologies and/or processes that are helping pharmaceutical companies bring new products to market or are reviving older products?
Ali: Conventional formulation technologies have limited scope in development of drug products. As the number of difficultto-develop compounds continue to rise, the industry is taking much bolder steps in evaluating the non-conventional technologies for effective delivery to mitigate risks while enhancing the efficacy of drugs. Formulation technologies involving the physical or morphological modification process such as micronization, and the chemical modification process such as salt formation with inorganic and organic acids, and creating prodrugs with water soluble entities are a few examples of classical approaches, especially for low dose drugs requiring enhanced bioavailability. With the continued interest in polymer based solid dispersion technologies including spray drying, hot melt extrusion, Kinetisol and electrospraying/electrospinning, and the lipid/surfactant based liquid dispersion technologies such as self emulsifying/microemulsifying delivery systems (SEDDS/SMEDDS), the industry is taking more innovative approaches, especially for medium and high dose drugs by embracing such technologies to bring them to market much faster. The availability of new and novel excipients also plays an important role in innovating delivery technologies for newer molecules and also helping to revive the marketed drugs for making better and smarter pills.
Das: Protein delivery systems will continue to revolutionize the pharmaceutical industry. Although such drug delivery systems can be based on the conventional parenteral route of administration, they are often challenged by poor patients’ compliance. However, owing to inherent susceptibility of proteins to degradation in the acidic environment of the stomach as well as to gastrointestinal enzymatic degradation, most of the commercially available biologic drug products are administered via the parenteral route. As a result, research will continue to focus on alternative routes of administration such as topical, buccal, sublingual or nasal to circumvent these associated problems. Various dosage forms such as transdermal patches, buccal bilayered films or mucoadhesive gels may be administered by these non-invasive routes of routes of administration.
In addition, novel drug targeting technologies such as antibody-drug conjugates will continue to make progress by delivering highly potent chemotherapeutic agents to specific tumor cells, thereby protecting the patient from the harmful side effects of such agents. Gene therapy can also be a promising technique for the treatment of cancer and other genetic diseases by employing mostly viral vectors to deliver the DNA into the nucleus of the cell without any potential degradation.
O’Donnell & Porter: Technologies capable of generating amorphous solid dispersions are significantly improving the success of challenging molecules. These include hot melt extrusion, spray drying, KinetiSol dispersing, and precipitation techniques. Using an enabling technology such as those mentioned here can increase the performance of a drug without adequate bioavailability to the point of market entry.
Musakhanian: Over the past decades, the drug development tool kit had to expand in order to meet the growing complexity and specificity of new drug candidates. Size reduction and nanonization, salt formation, inclusion into cyclodextrins, co-crystals, amorphous solid dispersions; and lipid-based drug delivery systems are strategies that come to mind.
Among the various technologies that could potentially breathe life into poorly soluble drugs, lipid formulation technologies represent the highest success rate, accounting for over half of the new drug approvals involving solubilization. A second and rapidly growing approach is that of polymer-based solid dispersions.
A widely used and successful lipid approach is that of self-emulsifying drug delivery systems which can be customized to the properties of the drug at hand, to improve solubility, dissolution, supersaturation and route of absorption all at once. Solid lipid nanoparticles are another area of particular interest because they can be engineered to protect the drug against enzymatic degradation, improve its solubility, and its delivery to biological membranes or tumor tissue.
Whereas each drug delivery option may address a different set of formulation challenges, an agnostic approach to drug development technologies can widen the prospects for innovative combination approaches. As an example, lipid systems may be incorporated into polymeric solid dispersions where a micronized drug system is embedded.
How have advanced excipient technologies helped with drug delivery? Are these excipients more important as solubility concerns arise?
Ali: Excipients play an important role in the innovation of drug delivery technologies. Formulation technologies and excipients have a symbiotic relationship, meaning the existence of one is dependent on the suitability of the other. Thus, the synergies of the two in drug development significantly contribute to stability and efficacy of a particular dosage. With the continued increase in poorly soluble molecules in recent years (>80%), the compatibility of excipients contributing to development of delivery technologies, and their functions in supporting the stability of dosages, has sparked a much greater opportunity for both the excipients manufacturers and users to design innovative polymers or solubilizers to tackle these challenges. BASF, with their expertise in polymer chemistry, has demonstrated this time and again by bringing innovative polymers to market including Soluplus®, Kollicoat®, Smartseal® 30 D, and pomymethacrylic acid copolymers amongst others.
O’Donnell & Porter: While it is a long and challenging process to bring a new excipient to market and no excipient specific regulatory approval path currently exists, the need for new, functional excipients has greatly increased due to the pressing issue of poor drug solubility. Nevertheless, as drug molecules have become more demanding, new excipients are being launched that allow or improve use in functional technologies, stabilize drugs in a metastable state, increase formulation shelf life, modify drug release, and improve process efficiencies. These excipients are critical to the success of many challenging to formulate compounds, especially those with poor solubility.
Musakhanian: Many of the lipid excipients currently used in drug delivery for solubilization and bioavailability enhancement were considered to be novel in the 1990’s. Over time, significant amount of animal and clinical data have been amassed to justify safe levels of use for each excipient category. These include glyceryl and polyglyceryl esters of fatty acids; polyoxylglycerides or fatty acid esters of different PEG’s; propylene glycol esters of laurate or caprylate; and sorbitan esters. Additionally, creation of the USP/NF and EP monographs has helped define the standards of identity and quality, much needed for their qualifications as pharmaceutically acceptable excipients. Gattefossé alone is responsible for over 25 new lipid excipient monographs.
If a company is having drug delivery/solubility problems with a product in development is there a “checklist” of items/steps, based on the latest technologies that they need to review before shelving a product?
Ali: All the decisions rest on the industry. The obvious challenges are the availability and supply of new chemical entities. Requiring the challenges associated with poor solubility and multistep synthesis of NCEs, the industry is taking aims at using the spray drying dispersion technology wherein the smaller amounts of NCEs are screened rapidly against a range of polymers and solubilizers, thus saving time and cost. As a result, if not restricted by use of organic solvents, a lead formulation is quickly identified with only a smaller amount of active. This is essential to identify other formulation technologies such hot melt extrusion, a solvent free with continuous advantages of downstream process capabilities yielding the desired dosages. In instances where the development of solid oral tablets is restricted by the stability and desired bioavailability due to either high melting points and/ or partitioning coefficients ( log P), alternatively, the liquid dispersion technology is typically the choice of poorly soluble NCEs. With the advent of new and existing excipients, especially, those lipid based solubilizers and surfactants and also the availability of a range of pharmaceutically suited solvents and co-solvents, the SEDDS/SMEDDS are highly considered as a choice for liquid dispersion in soft gel capsules. Furthermore, with the advent of solid matrices such as silica, microcrystalline cellulose among others for development of supersaturated emulsifying systems (s-SEDDS/SMEDDS) in pellets and tablets with attainable compressibility and increased shelf life, the industry is also considering an alternative viable option for such dosages.
O’Donnell & Porter: When formulating a molecule that has delivery or solubility problems it is crucial to understand all relevant properties of the drug such that the most appropriate enabling technology can be selected. This includes proper thermal characterization when considering processes such as hot melt extrusion, solubility in organic solvents when considering spray drying, and correctly matching the drug to the excipient(s) capable of providing the needed functionality.
Musakhanian: The more is known about the attributes of the drug entity, the easier it is to pinpoint the technology or formulation approach appropriate for its delivery. So the drug entity and its challenges to bioavailability are on the top of the formulator list.
The other important item on the checklist is a good understanding of the options available. Many service providers offer graphic and or tabulated guides for choosing possible avenues for new drug development.
Gattefossé for example offers detailed formulation guidelines for pre-formulation and also for late stage development. These guidelines describe the rationale and the analytical methods for screening, evaluating, and selecting the best possible formulation for the drug at hand. Included in these guidelines are in-vitro analytical approaches to screening of lead formulations for preclinical/clinical studies which stand to save both time and cost in the drug development process.
What do you see as the major industry critical issues over the next five years in regards to drug delivery?
Ali: The number of poorly soluble molecules will continue to rise over the next 5 years and beyond. As the number continues to rise, the understanding and collaboration between excipient users and manufactures will increase to address these issues. If this approach is not taken we can anticipate the launch of fewer molecules every year. With the continued demands in parenterals and biologics and to a lesser extent, the unavailability of excipients, the industry is poised to embrace new and novel excipients/solubilizers to help expedite drug development.
Das: The major critical issues that we can expect to see in the next 5 years in regards to drug delivery are the challenges involved in the delivery of poorly soluble drugs and overcoming the low bioavailability issues on administration of such drugs. Some of the common approaches employed to overcome such low or irreproducible bioavailability issues are particle size reduction or formulation of lipid systems. However, while designing lipid based delivery systems, the safety of the lipid excipients, amounts of surfactants employed in the formulations, the ability of such systems to undergo self-emulsification in the GIT, and the particle size of the resulting dispersions are some of the critical factors in the successful formulation of a lipid based delivery system.
The other major critical issue that we will continue to witness over the next five years in regards to drug delivery are the unique challenges associated with protein delivery systems such as the stability issues of proteins, the poor absorption of proteins via the oral route, irreproducible absorption and often poor bioavailability when administered via the mucosal routes such as buccal, nasal amongst others.
O’Donnell & Porter: Considering molecules entering development today are 5-10 years away from commercialization, the issue of poor solubility will remain prevalent for the foreseeable future. In addition to this, the delivery of biologics and biosimilars will become a major topic as they progress in development and gain additional regulatory approvals. The need for novel devices to deliver these types of molecules is likely to grow as well.
Musakhanian: A significant issue that will continue to elude drug discovery sciences is striking the right balance between the drug molecule properties that are responsible for therapeutic activity on one hand and the chemical attributes that raise druggability concerns like poor solubility, higher metabolism, and increased toxicity, on the other.
Drug lipophilicity for example is a necessary prerequisite to drug activity and emerges at increased frequency. In spite of the strong association between lipophilicity and pharmacological activity, to evade solubility and dissolution challenges in later development stages, many potentially good drug candidates may have been excluded from drug delivery pipelines. By tapping into the large body of scientific evidence and exploiting the elucidated mechanisms and pathways for absorption of lipophilic molecules, it is likely to see genesis of shelved or previously dismissed molecules.
Arching knowledge and expertise between the upstream drug discovery and the downstream formulation possibilities is another critical challenge for the pharmaceutical industry.
By careful examination of each formulation approach, understanding the challenges it can address alone or in combination with other technologies, it is possible to carve a path with newer therapies, at a faster and more efficient manner.