OsoBio featured in Contract Pharma article: “Advances in Drug Delivery” Contract Pharma June 2011
Jun 6, 2011 – Improved methods for the development, manufacture, and administration of drugs, particularly increasingly complex biologics such as protein and peptide therapeutics, are more in demand than ever and are being met with advanced drug delivery options. Expansion of biologics in the marketplace has fostered the exploration of drug delivery methods such as prodrug delivery, and technologies such as Hot-Melt Extrusion. Product life cycle management is also driving drug delivery technologies. With fewer new drugs coming to market, pharmaceutical companies increasingly look to hold onto product revenues of existing drugs through new drug delivery options, reformulations and product line extensions (PLE), aimed at improving either safety, efficacy, patient compliance and ease of use (or all of the above)!
The latest drug delivery trends arise from the impact of current pharma and biopharma R&D. “The drug delivery market is forecasted to grow annually by about 10% until 2013,” said Sheila Dell, Ph.D., vice president of Product Innovation at Catalent Pharma Solutions. “Oral types will remain the largest drug delivery category while parenteral, inhalation and implantable systems will grow the fastest. And eventually, parenteral formulations will surpass oral dosages due to changes in the market trends in the type of molecules that are being discovered and commercialized.” Additionally, self-administered injectable devices are gaining in popularity amidst chronic diseases and the changing healthcare environment. Inhaled drug delivery formats are expanding to accommodate everything from pain medications to autoimmune disease targets and vaccines, and drug formulation strategies are taking on the challenges that lurk between API and administration.
R&D’s Impact on Drug Delivery
With the increasing complexity of drug candidates in development and shifts in drug research strategies and methodologies, how are drug delivery technologies being impacted by current pharma/biopharma R&D? According to Mike Marek, technical project manager at OSO BioPharmaceuticals Manufacturing, LLC, “It is through increased efficacy, reduced side effects, continuous dosing (sustained release) and increased compliance, among other attributes, that drug delivery technologies are impacted by current pharma/biopharma R&D. Drug companies — from start-ups to biotech to big pharma — are involved in developing novel drug delivery systems resulting in a number of approvals.” He noted that approved dosage forms range from Vivitrol (sustained release naltrexone) indicated for opioid addiction, a microsphere dosage form, to Sylatron (peginterferon-2b) and Cimzia (certolizumab pegol), both pegylated proteins providing longer plasma half life with fewer side effects.
In addition to drug delivery advances that have resulted in improved safety, efficacy, and compliance, challenges have necessitated enhanced collaboration among R&D and drug delivery from formulation to packaging. There are significant formulation challenges with how newly developed APIs are used. According to Jamie Beggs, market development manager at Celanese EVA Performance Polymers, “Limited bioavailability has plagued some of these new APIs, which are inherently less soluble in typical excipients, or there is the challenge of larger, more complicated molecules with biologics. More demand is placed on the formulation strategy, delivery systems, and ultimately, the excipients. Alternative excipients, which can be used in conjunction with novel pharmaceutical combination devices or via different routes of administration, are one way to help researchers avoid discarding promising compounds because they can’t find a way to deliver them effectively. Examples of formulation techniques helping scientists tackle the problem of poor solubility are amorphous solid solutions and dispersions. Hot-melt extrusion, one way to create a solid dispersion, is a processing method that is gaining popularity and acceptance, and it is also a technique that is highly suited for thermoplastic polymer excipients like ethylene vinyl acetate (EVA).”
The development of complex compounds affects all aspects of drug delivery and the roles of formulation and device require an increasingly collaborative effort among drug development and delivery strategies. According to Graham Reynolds, vice president of marketing and innovation at West Pharmaceutical Services, Inc., “New, sensitive biologic products are forcing the industry to deal with packaging and delivery systems much earlier in the process. The traditional container, which has historically been made of glass, has the potential to interact in a negative fashion with these products. For instance, in a vial format, glass delamination is a potential issue. In staked-needle syringe systems, there are considerations such as adhesives, tungsten and silicone oil that can cause interactions.”
The industry is seeking alternative materials in order to get around the issues associated with glass and sensitive biologics. “New materials, including break-resistant cyclic olefin polymers, such as Daikyo Crystal Zenith and unique designs, allow for easier and safer administration,” said Mr. Reynolds. “These systems are not only manufactured from a novel plastic material that reduces the risks of breakage, but the dimensional tolerances, quality standards, and freedom from materials such as silicone oil, tungsten or adhesives, help the systems provide the combined benefits of a plastic with the features necessary to contain a sensitive biopharmaceutical. This also provides significant flexibility in delivery system design, whereby device development is not constrained by the shape and dimensional variability of existing glass containers.”
Trends & Challenges
Drug delivery is playing an increasingly significant role in the quest for new product opportunities as the pharmaceutical industry faces patent and pipeline challenges. Also, growing healthcare costs are shifting in-patient treatments to the home setting. As a result, injection delivery methods are on the rise, particularly for the treatment of chronic conditions. “While oral drug delivery is still the most active in terms of deals being signed, the market has evolved over the past few years with a variety of goals now being sought beyond the more traditional oral extended/controlled release options,” noted Fidelma Callanan, senior director, marketing and communications at Elan Drug Technologies, which was recently acquired by Alkermes. These include targeted site delivery, pulsatile release (intended to deliver a burst of drug at predetermined intervals), and bioavailability enhancement strategies. Beyond oral delivery, one of the most active areas is that of depot injectable delivery. Recent notable approvals include the anti-psychotic Invega Sustenna product, which provides for once-monthly treatment option for patients.
The most effective delivery of biologics to date remains the injection route. “Because biologics are often large molecule products that do not transport well through non-injectable delivery methods, delivery devices such as auto-injectors are often the best choice for administration,” said Mr. Reynolds of West. In the injectable device realm, prefillable syringes, pen injectors, electronic patch injectors and depot injectable delivery methods are all making significant headway in the growing area of home delivery or self-administration. The growth in these home delivery systems can, in part, be attributed to increasingly prevalent illnesses like diabetes and autoimmune diseases that require self-administration of medications. While these delivery methods represent breakthroughs, they are subject to limitations. Factors such as drug volume, dosing schedules, and the symptoms the drug is treating, all come into play with each method.
Prefilled syringes (PFS) highlight the benefits and limitations of various injectable technologies, as pointed out by Mr. Reynolds of West: “Prefillable syringes can aid in patient compliance, but most are still based around conventional glass syringes. Also, newer drugs, including those with high viscosity or that need to be administered in high volume, can present administration challenges. Pen injectors and multidose cartridges, which can be used for those who have frequent needs, are limited to specific therapies such as diabetes and growth hormones. Additionally, easy-to-use auto-injector systems, which are based on prefillable syringes, provide a more convenient method for delivering drug products, especially for patients who may have dexterity or needle phobia issues. There is a growing trend in the industry toward the use of these systems.”
There is another alternative injectable method that mitigates some of the administration roadblocks encountered with the PFS and pen injector. “The electronic patch injector system, which can deliver a large dose over an extended period of time, simplifies administration by automating processes and equipment, and can move drug infusion therapies from hospital-based to home-based settings. Newer systems, such as West’s electronic patch injector, also offer significant benefits through the inclusion of electronic systems to control dose rate, volume and also provide feedback to help compliance,” said Mr. Reynolds. As devices become more and more complex, the concept of downloading information from the drug device is another growing trend. The goal is to not only improve patient compliance, but also to provide precise information about the frequency and the amount of drug delivered.
These injectable devices not only result in ease-of-use for the patient or administrator, but also potentially help manufacturers conserve costly drug product. “Biologics can be very costly and manufacturers are increasingly seeking new ways to minimize waste. PFS, with their premeasured dosage, have the potential to reduce dosing errors and increase patient compliance while potentially saving manufacturers money. Unlike single- or multi-dose vials that may require drug product overfill by as much as 30% to ensure adequate withdrawal, a PFS can virtually eliminate the need for excess overfill. An increase in PFS and delivery systems, as well as auto-injectors, is likely. Additionally, patch-injector systems, which can provide larger doses or multiple doses over a period of time, likely will experience growth, particularly in the oncology area, where lengthy administrations may move from the hospital setting to the clinical or home setting,” added Mr. Reynolds.
In the area of respiratory drug delivery, there have been notable advances to mechanisms such as dry power inhalation (DPI), and pressurized metered dose inhalation (pMDI) systems that have piqued interest in this delivery method and expanded the playing field to include medications that treat a greater variety of illnesses. “Inhaled drug delivery is becoming quite popular as a drug delivery method today. In addition to treating simple ailments such as nasal congestion, the treatment and management of flu, pain, migraine, etc., is seeing increased acceptance with this delivery format. Also, the use of intranasal drug delivery for prophylactic vaccines is projected to grow significantly,” said Dr. Dell at Catalent Pharma Solutions.
“There is considerable interest in delivery systems that administer drugs directly into lungs. Systems such as DPI are gaining momentum. For pMDI systems, new propellants that have minimum adverse impact on environment are also increasingly being considered. Nasal sprays have been shown to be very effective for the delivery of small molecules,” said Vitthal Kulkarni, Ph.D., scientific advisor, Research & Development, DPT Laboratories. Although inhalation devices, such as pMDI and DPI delivery systems, have been associated with complex regulatory compliance and dosing issues, more advanced delivery systems are taking dose content and uniformity out of the hands of the patient.
“For inhalation, we see a continued pressure to reduce dosing variability and increase efficiency,” said Anne Roush, business development manager at 3M Drug Delivery Systems. “Our DPIs are quite efficient at deagglomerating the powder (separating the individual particles from each other) so the drug can reach the intended region of the lung for the maximum therapeutic benefit. Improvements in delivery technologies that aid patient compliance continue to be important. New inhalers now have features such as dose counters and dosing feedback mechanisms that help assure the patient that they’ve received their medication.”
Additionally, advances in inhalable drug delivery devices have impacted formulations in that these systems can expand the range of molecules that can be delivered or enable the device to be more efficient and dose sparing. “One of 3M’s DPIs, for example, doesn’t require a formulation aid such as lactose, thereby potentially eliminating a substantial amount of formulation development work and allowing more drug candidates can be considered for inhalation delivery,” noted Ms. Roush.
Before these increasingly complex drugs reach their destination device, there exists the elaborate matter of formulation. New manufacturing technologies are emerging to resolve some of the common barriers to successful drug delivery. These drug delivery technology trends, according to Mr. Marek of OSO Bio, include prodrugs (activated in vivo, resulting in less toxicity) heat-activated liposomes for targeted drug delivery, nanoparticles, and monoclonal antibodies conjugated to toxins, immune modulators or pegylated.
Poorly soluble compounds and protein and peptide therapeutics present some of the greatest drug delivery challenges. In an effort to get drugs to reach their disease target, a variety of methods are being employed. Also, technologies such as
hot-melt extrusion and pegylation are improving outcomes. Prodrug design, aimed at optimizing drug delivery to minimize undesirable drug properties while retaining the desirable therapeutic activity, has proven an important means of improving drug efficacy. PEGylation, a process by which polyethylene glycol chains are attached to protein and peptide drugs, has helped to resolve degradation issues and improve pharmacokinetics. Also, Hot-Melt Extrusion (HME), the process of pumping materials through a die under elevated temperature into a new uniform product, represents an efficient manufacturing process and also has the potential to improve product quality and efficacy.
“Different strategies can be applied to poorly soluble drug compounds. The use of proper surfactants, combinations of surfactants, use of co-solvents, or lipids will typically improve solubility. There are also newly developed ‘solubility improving’ excipients that may help improve solubility of drug substance in the aqueous phase. Using micronized API in combination with solubilizing agents is also used to improve solubility. Other techniques to improve solubility that are useful for certain drugs include hot-melt extrusion or forming ‘eutectic mixtures’ of API with suitable excipients,” said Dr. Kulkarni of DPT.
According to Mr. Marek, “Peptides and proteins can be pegylated to provide ‘stealth’ properties in order to increase serum half life. Proteins and peptides can also be conjugated to monoclonal antibodies for targeted drug delivery. Additionally, ‘nanotechnology’ — incorporating drugs, proteins and peptides into nanospheres — will likely have an increasing role in drug delivery.”
Ms. Callanan of Elan Drug Technologies noted, “As a consequence of the clear trends emerging from the drug discovery process, it is expected that solubility-limited oral absorption will continue to pose a significant challenge in small-molecule drug development. Several relevant technology approaches, each capable of enhancing drug solubility, are available. They include solid amorphous dispersions, pharmaceutical co-crystals, self-emulsifying and self-microemulsifying drug delivery systems, and from Elan Drug Technologies, the NanoCrystal technology.” This technology boasts five licensed products on the market and more than $2 billion in annual in-market sales, ranking it among the successful technologies available for poorly soluble compounds.
Building on the NanoCrystal technology, EDT is now advancing a new, hybrid particle-engineering approach, called NanOsmotic technology. “The attractiveness of NanOsmotic technology,” according to Ms. Callanan, “arises from its ability to maintain a drug in its original crystalline form until biologically activated.” Following activation, a thermodynamically enhanced form of the drug is delivered and maintained for a period of time sufficient to achieve absorption. Accordingly, NanOsmotic technology offers a number of potential performance advantages over alternative technologies in the poorly water-soluble drug delivery space, noted Ms. Callanan, including enhanced bioavailability, improved chemical and physical stability, higher drug loading and the ability to achieve programmable release of drug for extended periods of time.
The increased focus to create more palatable delivery methods for patients has resulted in more convenient transdermal routes and nasal delivery. However, oral delivery continues to defy research efforts. “While delivery of proteins and peptides orally would seem like an obvious field of study for drug delivery companies, success to date has been very limited. The search for formulation approaches that are stable, bioavailable, and can be readily manufactured and acceptable to the patient, has led to major advances in development of nasal and controlled release technology. And while strides are being made in fundamental research in areas including oral delivery, transdermal delivery, pulsatile and ‘on demand’ delivery of peptides and proteins, it still remains the elusive holy grail of drug delivery,” said Ms. Callanan of EDT.
“3M’s microneedle technology is very conducive to delivery of macromolecules like proteins and peptides, achieving a similar pharmacokinetic profile to IV administration,” said Ms. Roush at 3M. “For certain drugs that require rapid onset of action, the pulsatile profile of MTS might be more effective than subcutaneous or intramuscular injection. For delivery of protein and peptide vaccines, the intradermal route has advantages because the drug is presented to the area with a rich source of immune cells. Additionally, if lung delivery is desired, DPIs may be a viable method for delivery of proteins and peptides.”
Ms. Roush also described how 3M’s MTS technology impacts formulation: “Using 3M’s MTS technology, the barrier of the stratum corneum is eliminated to enable delivery of a wider variety of molecules transdermally (eg, large molecules such as monoclonal antibodies). With solid MTS (sMTS), API is coated and dried on the microneedle, allowing one to deliver solid API through the skin. This feature of sMTS may also eliminate cold chain storage for some drugs and vaccines.”
While major advances have been made to improve drug delivery options for protein and peptide therapeutics, delivering them more and more effectively and with greater ease to patients, remains highly sought after.
The pharmaceutical industry continues to take advantage of drug delivery technologies in its efforts to add years to product revenue streams. Although more traditional approaches are often used in order to improve the likelihood of approval, emerging drug delivery technologies are peeking the interest of drug developers. “While many approaches exist to ‘lifecycle manage’ a product, those pursued using drug delivery approaches have proven more effective than most, particularly where patient/clinical benefits are apparent. New formulation strategies have been shown to deliver the best returns on investment, proving significantly more effective than an OTC/branded generic route, repositioning, or a new indication. A Merrill Lynch industry report found that 87% of ‘switch and grow’ strategies not only sustained the value of the original franchise, but increased its sales following the switch to the improved product. A good example is Ritalin LA, developed by Elan, which grew Novartis’ methylphenidate franchise by 62% in its first year following launch,” said Ms. Callanan.
Improving safety and efficacy tops the list for companies seeking enhanced drug delivery methods for existing products. Also, more efficient drug delivery can lead to cost savings when dealing with expensive API. “One area where we are receiving strong interest from our customers is sustained or controlled release formulations,” commented Ms. Beggs of Celanese. “More specifically, our customers are
looking to create formulations that are delivered over an extended period of time via a mucosal or subcutaneous route. In some cases, they are also seeking to deliver the APIs locally at the specific site of indication versus dosing systemically. Formulators can use these techniques to create products that have improved safety and efficacy profiles through lower dosing with less variation in blood plasma API concentration.
When working with these advanced delivery methods, an emphasis must be placed on designing a formulation that adequately tailors the release profile of the API. This necessitates a strong, open relationship between excipient providers and drug/device formulators.”
“The intradermal delivery area is emerging as a potential way to obtain a desired pharmacokinetic profile with a faster onset or targeting drugs to the lymphatic system,” noted Ms. Roush of 3M. “These PK profiles are difficult to match via other routes of administration. MTS offers the potential for a faster onset of action and a reduction of injection site reactions. Intradermal delivery via MTS has shown improved bioavailability when compared to subcutaneous or intramuscular injection, which may translate to similar efficacy at a reduced dose.” If the API is expensive, comparable efficacy at a reduced dose can have real benefit to both pharmaceutical companies and patients.
Self-administration of injectable medications is a fast growing trend that will likely pick up speed as drugs advance through the pipeline, and to offset healthcare costs associated bringing treatment options for chronic illnesses from the hospital to home setting. Also, the once-insurmountable challenges around poorly soluble compounds are being met with incremental success. While protein and peptide therapeutics hold great potential in the treatment of serious diseases, improved drug delivery methods remain sought after due to their fragile nature, large size, and instability. Establishing advanced drug delivery mechanisms in this area is imperative for the future success of modern medicines.