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Industry Growth To Continue Through New Technologies
The worldwide drug-delivery arena is growing each year as the increasing aging population is in need of improved methods of administration for products and therapies. Drug-delivery industry growth is being led by the United States as well as emerging markets.
Oral forms remain the preferred method of drug-delivery administration. Gaining in popularity are parenteral, inhalation and implantable systems. Elements impacting the development of drug-delivery systems include reimbursement, environmental factors, and regulatory processes.
Product developers are coming up with better ways to improve therapy performance and safety as patients become more involved in their treatments in an effort to cut down on costs. New electronic technologies for reusable systems and disposable devices are leading to improved sales of auto-injectors. Microneedle technology is on the rise so that medicine can be precisely delivered to areas in need of treatment.
The global drug-delivery market is experiencing annual growth in the mid-to-high single digits. The rising global population and the need for more convenient drug-administration methods have created more opportunities for manufacturers to produce additional drug-delivery systems and therapies.
The U.S. drug-delivery market is anticipated to generate 10 percent yearly growth during 2011 and 2012, according to industry experts.
The worldwide pharma market was projected to grow about 5-7% during 2011 compared to 4-5% growth generated in 2010. U.S. pharma sales were predicted to be up slightly during 2011 compared to 2010.
The industry will continue to grow through more sophisticated drug-delivery systems, says Graham Reynolds, VP of Marketing/Innovation, Pharmaceutical Delivery Systems, West Pharmaceutical Services Inc. “There will be an increase in self-administration of therapies,” he shares. “For novel devices, look for continued trends toward safety and a strong focus on the needs of the patient.”
West Pharmaceutical has developed innovative delivery systems such as the ConfiDose auto-injector system and the SmartDose electronic patch injector. These systems offer a range of options for dose volume, injection time and electronic control/feedback. They are designed to meet the challenges of innovative drug products.
Oral forms are expected to remain the largest drug-delivery category. Parenteral, inhalation and implantable systems are on the quickest growth pace. Industry analysts expect parenteral formulations will eventually surpass oral dosages as the largest segment.
Influencing drug-delivery systems development will be reimbursement, environmental factors and regulatory pathways, Mr. Reynolds says. “In addition, understanding the importance of the drug container as it relates to the integration into the overall drug-delivery system will continue to be a key factor.”
Manufacturers are also accounting for patients’ ability and desire to care for themselves, or have a family member care for them, in the comfort of their own home, Mr. Reynolds notes.
“There can be a cost benefit when transitioning health-care provision from the hospital environment to the home environment or other health-care facilities,” he states. “Effective drug-delivery devices and systems that enable a patient to self-inject can aid this transition. For example, it is now possible to transition from hospital IV to home-administered subcutaneous injection through the use of an electronic patch injector or auto-injector.”
Auto-injectors are becoming more commonly used to deliver medications that treat a variety of therapeutic areas such as rheumatoid arthritis, oncology, diabetes, and multiple sclerosis. As a result, mass production will be required to support the demand for auto-injectors and in turn stimulate various industrial activities to support the manufacturing processes required for development.
Worldwide sales of advanced drug-delivery systems – inhalers, injections and infusion pumps – are projected to grow from a value of $139 billion in 2009 to $197 billion in 2014, according to Cambridge Design Partnership LLP experts. Cambridge Design Partnership is a consulting company that develops drug-delivery devices in the United Kingdom.
Matt Schuman, senior partner at Cambridge Design Partnership, advises manufacturers to learn from other industries that focus on creating differentiation and gaining competitive advantage through innovations in branding, usability and shelf appeal.
“We think, in the future, patients are going to be much more involved in their own treatments to reduce costs and smart drug-delivery technologies are part of what is going to enable this change safely,” says Tom Oakley, Head of Drug Delivery at Cambridge Design Partnership. “As device developers, we are going to have to think of new ways to increase the performance and safety of therapies at lower cost.
“We expect healthcare systems increasingly to make drug choices based on calculations of the total cost of a patient’s disease, and devices that can contribute to reducing overall costs could have significant commercial value. This means looking at system-level solutions integrating drug delivery, diagnostics and health informatics in new patient-centered systems,” he adds.
In the field of auto-injectors, sophisticated use of electronics in reusable systems and disposable devices is causing growth, Mr. Reynolds says.
“There are also trends toward enhanced manual systems, including ergonomic features designed to improve an impaired patient’s ability to deliver a dose from a prefilled syringe,” he states. “There are several well-established companies in this space offering device technologies, and increasing emphasis on new and merging players offering improved patient convenience, and integration between the device and the container.”
In the realm of new technologies, a small band of device-development companies have been attempting to commercialize drug-delivery products based on arrays of microneedles. By establishing channels in the outer most layer of the epidermis, these devices were expected to deliver therapeutic drugs across the skin and into the dermal layers, according to Greystone Research Associates.
Greystone analysts say after years of prototyping unique array designs, a few development programs have migrated toward improving the performance of existing delivery methods. The market availability of microneedle drug-delivery devices such as the Sanofi Pasteur’s Intanza influenza vaccine, which is based on Becton, Dickinson and Co.’s (BD) Soluvia syringe-mounted microneedle array device, is considered a milestone in the transition of microneedle drug delivery from development to market.
Microneedle technology is anticipated to affect healthcare by enabling precise injection of therapeutic agents to prescribed areas below the skin. Microneedle technology is generating commercial viability at a time when drug developers are dealing with new challenges as they assess ways to admi1nister a new class of compounds with important therapeutic potential, according to Greystone.
Radius Health Inc. of Cambridge, Mass., and 3M Drug Delivery Systems of St. Paul, Minn., during 2011 agreed to collaborate together in the microneedle realm to deliver osteoporosis therapy. The BA058 Microneedle Patch will use 3M’s patented Microstructured Transdermal System microneedle technology to administer BA058 through the skin, as an alternative to subcutaneous injection. The patch is expected to combine the ease, convenience, and self-administration attributes of a transdermal patch with the speed and efficiency of a traditional injection. Terms of the agreement were not disclosed.
Radius’ BA058 Microneedle Patch product is undergoing Phase 1 clinical studies. The company’s concluded Phase 2 human testing of an injectable form of BA058 showed that BA058 significantly increased bone mineral density (BMD) after six months of therapy.
Transdermal patches – medicated adhesive pads placed on the skin that release drugs gradually for up to a week – have been available in the United States for more than 20 years.
The first transdermal patch, approved by the U.S. Food and Drug Administration in 1979, delivered scopolamine to treat motion sickness. Since then, more than 35 transdermal patch products have been approved for marketing. Examples include the nicotine patch that helps people quit smoking, the lidocaine patch for relieving pain, and a patch containing hormone derivatives for preventing pregnancy.
LTS Lohmann Therapie-Systeme is one of the world’s leading suppliers of transdermal and oral systems for the international pharmaceutical industry. Using the company’s advanced oral medical wafers, LTS provides flat, film or wafer-like medication for application in the oral cavity. This oral wafer medication systems uses the mouth as a site of both application and drug action.
The Andernach, Germany-based company offers three different oral wafer medication systems to provide the ideal solution for patients’ specific requirements. Depending on the type of oral medical wafer, it is possible to generate different pharmacokinetic profiles, and avoid undesirable side effects in the gastrointestinal tract.
There are three types of LTS oral medical wafers: flash-release wafer; mucoadhesive melt-away wafer; and mucoadhesive sustained-release wafer.
According to LTS, oral medication wafer systems offer many advantages including: therapy restriction of local effects in the oral cavity (for example those indicated by local lesions); effects in the entire oral cavity, such as mouth refreshment or disinfection; swift systemic effects after absorption via the oral mucosae; discreet and easy application (no additional water needed); buccal absorption that bypasses hepatic first path metabolism; and improved bioavailability, enabling lower doses.
3M continues to be a major player in transdermal drug-delivery technology. For decades, the company has pioneered several advancements, including drug-in-adhesive (DIA) technology that has become the industry standard for passive delivery.
The 3M DIA system is a versatile platform that provides compatibility with a wide variety of drugs. This type of patch is less likely to deliver too much medication. Continued advancements allow this system to deliver more than one drug in a single patch, resulting in added patient convenience.
Because the adhesive layer not only serves to adhere the patch layers together and to the skin, but also contains the drug, DIA systems offer advantages in reduced size and thickness as well as improved conformability to the application site. This process helps drive patient preference.
Delivery of drugs through skin has become a popular mechanism for delivering long-term, controlled dosages of various compounds. A drug is mixed with an adhesive and cast into a patch, which is then applied to the skin.
Acrux Ltd. of Melbourne, Australia has developed a revolutionary Metered Dose Transdermal System (MDTS) that enables transdermal delivery of small-molecule drugs without the use of skin patches. The technology is based upon absorption enhancers used for more than 20 years in sunscreens, which the company has applied to treatments that are in clinical testing. These include estrogen, testosterone and a pain-management compound.
Acrux’s business strategy involves taking off-patent or soon to be off-patent drugs and developing them for transdermal delivery. Acrux has entered into collaborations with major pharmaceutical companies such as Pharmacia (now part of Pfizer Inc.). Acrux agreed to partner in March 2002 for the development of transdermal applications for Pharmacia compounds.
One innovative way to deliver drugs transdermally comes from a partnership between the California Institute of Technology (Caltech) of Pasadena, Calif., in partnership with Zcube Srl, a research venture of the Italian pharmaceutical company Zambon. The two entities inked an exclusive research and option agreement to develop and commercialize skin patches that contain embedded carbon nanotubes for delivering drugs. The patches will first be developed to painlessly administer drugs through the skin; other applications are envisioned for future use.
A key aspect of the new skin patches is an innovative technique that partially embeds the nanotubes into the flexible materials in which they are grown. This embedding technique allows one end of each nanotube to be anchored to the patch. The other end protrudes from the patch to deliver drugs to the skin. This technique, which allows for the anchoring and alignment of the nanotubes, neatly overcomes a previous technological shortcoming and will enable new methods of drug delivery. This approach is anticipated to help these therapeutic nanotubes make their way to patient bedsides in a variety of medical applications.
Researchers report an important benefit of the new patches is that they are painless – the nanotubes’ diameter is too small for nerves in the skin to detect. Industry experts believe that drugs can be delivered more effectively via nanotubes than through current microneedle or traditional patch technologies because the sea of nanotubes in the skin patches can be dosed and designed for optimal effectiveness, efficiently delivering drugs across the densest layers of the skin.
There has been a great deal of innovation in terms of drug-container materials used within devices.
“Although glass has been the traditional material of choice for drug containment, it has significant limitations including breakage, glass particulate, visual quality and functional performance,” Mr. Reynolds said. “Many glass systems require siliconization to enable mechanical performance, and this material can interact with drug products.”
FDA is becoming increasingly aware of glass-related quality issues, including breakage, cracks, contamination and particulates (often formed over time due to interaction between the glass and the drug) and there has been a tremendous increase in the number of recalls related to glass issues, Mr. Reynolds reports.
“High-profile recalls have been initiated for drugs that have had issues between the container closure system and the device,” he explains. “For example, if a glass prefilled syringe is used in an auto-injector, there is a possibility of breakage due to the force used to activate the system. It has also been demonstrated that glass syringes within an auto-injector may fracture or break if subjected to a sudden force, and this may not be visually detectable. Other issues, such as uneven siliconization, may result in incomplete injections, and there have been recalls for potential loss of sterility due to cracks in glass syringes.”
Recent developments around the use of polymeric materials for drug containment have allowed delivery-system companies to work closely with drug manufacturers to develop novel systems designed specifically to meet patient needs, Mr. Reynolds says.
“The design and manufacturing flexibility of a polymeric drug container, combined with the ability to create patient-friendly devices designed with human factors engineering, enables the design of more innovative overall delivery systems that may aid in patient compliance through ease of use and enhanced technology,” he explains.
Cyclic olefin polymers such as the Daikyo Crystal Zenith polymer provide a transparent, break-resistant alternative to glass that is also silicone-oil free.
Another trend expanding in the drug-delivery device industry is the increase of combination products, and drug-device combinations in particular.
“Many pharmaceutical companies are gaining interest in drug-delivery device technologies and the accompanying containment materials at a very early stage of drug development,” Mr. Reynolds says. “Companies are finding that incorporating the overall drug-delivery system earlier in their development process enables a potentially faster route through the compliance process and thus to market. This creates increased interest in devices at an early stage.
However, Mr. Reynolds warns, the FDA is placing extra scrutiny on the area of combination products.
“There is uncertainty about how this may impact the drug-development process,” he says. “Clearly, regulatory factors will continue to have a key impact on the future development of delivery systems.”
Any automated process runs the risk that the system does not function effectively, which in this case means the dose cannot be delivered. Risks include failure of the device and failure of the device-container combination.
“In either case, the system would not be able to deliver the drug effectively to the patient,” Mr. Reynolds says. “Understanding how the device and container integrate and interact to ensure effective operation is a critical part of ensuring that the overall drug delivery is effective and safe for the end user.”
3M’s novel dry-powder inhaler technology
3M Drug Delivery Systems provides efficient delivery systems for pharmaceutical companies that develop inhalation therapy. In a clinical study, 3M Drug Delivery Systems found its Conix Dry Powder Inhaler (DPI) achieved bronchodilator efficacy comparable to GlaxoSmithKline Plc.’s blockbuster brand Advair Diskus (fluticasone propionate and salmeterol inhalation powder) while patients with asthma use less drug.
The study compared Conix DPI with Advair Diskus 100/50 in the delivery of a combination therapy (fluticasone propionate and salmeterol xinafoate). Seventeen patients with mild-to-moderate asthma received two treatments separated by 7 to 16 days, according to a randomized, two-period crossover design.
Results of the study showed that Conix DPI achieved a similar improvement in pulmonary function as compared with Advair Diskus. Additionally, the study demonstrated pulmonary delivery of a combination formulation from the Conix DPI device was safe and well tolerated. Patients reported that the Conix DPI device was easy to use.
Conix DPI is designed to deliver a higher respirable (more efficient) dose and a smaller non-respirable (less swallowed) dose to patients. The dry powder inhaler works by using an innovative reverse-flow cyclone technology to deagglomerate and aerosolize drug particles. The inhaler’s design allows formulation flexibility and protection from moisture ingress. The design is engineered to increase the effectiveness of energy transfer from patients’ inspiration to the drug formulation.
Conix DPI is available for use with marketed molecules as well as new chemical entities.
Anatares gains long-term patent protection
Antares Pharma Inc. is a leading U.S. developer of novel and advanced self-injection products, including needle-free injectors and pen devices. The Ewing, N.J.-based company received patent protection in 2011 for one of its devices to deliver treatment for rheumatoid arthritis. The VIBEX platform of needle-assisted jet injection devices was granted patent protection until 2027.
The VIBEX platform is the basis for several products in development by Antares, including VIBEX MTX. This is the first auto-injector in development to potentially enable rheumatoid arthritis patients to comfortably and safely self-inject methotrexate at home.
Antares CEO Paul Wooton, Ph.D., says, “Independent market research commissioned by Antares with 200 rheumatologists has confirmed that physicians, if offered a reliable and patient-friendly method for self-injection, would like to switch many patients to an injectable form of methotrexate, potentially providing reproducible absorption, reduced side effects and a better therapeutic response. Since rheumatoid arthritis patients are often already prescribed methotrexate in combination with injectable biological products, VIBEX MTX may represent a significant revenue opportunity for Antares, potentially as early as in 2013, as we continue to focus on our product based strategy.”
Future growth anticipated for drug-delivery market
The marketplace for drug-delivery systems and their manufacturers is expected to continue growing for many years to come.
“Growth trends in key areas, specifically diabetes, will continue,” Mr. Reynolds says. “Watch for growth in areas such as auto-immune disease as well as sophisticated vaccines. Novel systems to enable the effective treatment of chronic conditions such as high cholesterol and allergies will also grow.
“Pharmaceutical and biotech companies are working closely with drug-delivery device manufacturers at an early stage to ensure that there is efficient development of an overall system to enable cost-effective drug delivery. Cost factors may include the ability to move the product to market as quickly and effectively as possible; reducing in-process rejects due to breakage or lack of function; and the overall cost of quality, which has to be built into a system from the start.”
Diabetes Drug Delivery
Among the various drug-delivery segments that will continue on a growth trajectory for years to come is diabetes.
Since the early 1920s, injectable insulin has saved the lives of millions of people living with diabetes worldwide. With more people being diagnosed with diabetes each year – in 2011, the CDC reported 25.8 million Americans are now living with the disease – the market for insulin is steadily growing.
Worldwide insulin sales have quadrupled in the past decade, exceeding $15 billion. The Danish drug company Novo Nordisk A/S, the world’s largest insulin maker, sold $7.1 billion of insulin in 2010. Those sales could climb by a double-digit percentage annually in 2011 and beyond.
Additionally, spending for therapies to treat diabetes could account for up to 7% of all pharma expenditure in 2015.
A current treatment for diabetic retinopathy is laser therapy, which has side effects such as laser burns and the loss of peripheral or night vision. Anti-cancer drugs may also be used to treat the disease. However, these compounds clear quickly from the bloodstream so high dosages are required, thus exposing other tissues to toxicity.
One novel device in the works is a device that can be implanted behind the eye for controlled and on-demand release of drugs to treat retinal damage caused by diabetes.
Key to the innovation, developed at the University of British Columbia in Canada, is the ability to trigger the drug-delivery system through an external magnetic field. The research team accomplished this by sealing the reservoir of the implantable device – no larger than the head of a pin – with an elastic magnetic polydimethylsiloxane (silicone) membrane. A magnetic field causes the membrane to deform and discharge a specific amount of the drug, similar to squeezing water out of a flexible bottle.
In a series of lab tests, the UBC researchers loaded the implantable device with the drug docetaxel and triggered the drug release at a dosage suitable for treating diabetic retinopathy. The researchers found the implantable device kept its integrity with negligible leakage for 35 days.
Researchers also monitored the drug’s biological effectiveness over a given period, testing it against two types of cultured cancer cells, including those found in the prostate. They found that they were able to achieve reliable release rates.
The device offers improvements upon existing implantable devices for drug delivery, says Mu Chiao, Ph.D. “Technologies available now are either battery operated and are too large for treating the eye, or they rely on diffusion, which means drug release rates cannot be stopped once the device is implanted – a problem when patients’ conditions change.”
The UBC device will not be ready for patient use for several years. Team members are working to pinpoint all the possible medical applications for their device so that they can tailor the mechanical design to particular diseases.
After nearly a decade-long partnership, San Diego-based Amylin Pharmaceuticals Inc. and Eli Lilly and Co. of Indianapolis ended their relationship in 2011 to deliver Byetta to people living with diabetes. Amylin agreed to pay Lilly $250 million to assume responsibility to develop and market the drug to control low blood sugar.
Under the alliance, Byetta (exenatide) was launched in 2005 and has been used by nearly 1.8 million patients worldwide. During October 2011, the U.S. Food and Drug Administration approved Byetta as an add-on therapy to insulin glargine, with or without metformin and/or a thiazolidinedione (TZD), in conjunction with diet and exercise for adults with type 2 diabetes who are not achieving adequate glycemic control on insulin glargine alone.
According to John Buse, M.D., Ph.D., professor of medicine and director of the Diabetes Care Center and chief of the Division of Endocrinology at the University of North Carolina School of Medicine in Chapel Hill, “Byetta is well-suited for use with insulin glargine, offering a simple fixed-dose regimen that can help improve control of blood sugar overall and after meals. In a clinical trial, patients using Byetta with insulin glargine achieved better glycemic control, without weight gain or an increased risk of hypoglycemia, compared to patients using insulin glargine alone.”
Amylin is awaiting word from the FDA on whether the regulatory agency will approve Bydureon (exenatide extended-release for injectable suspension). A regulatory decision is set for early 2012. If approved, the drug will be the first once-weekly treatment for diabetes.
Becton Dickinson, a leading global medical technology company based in Franklin Lakes, N.J., made great strides in 2011 with the development of BD Nano, the world’s smallest pen needle.
“BD is committed to helping improve the injection experience for the millions of people who live with diabetes, as demonstrated by our long history of innovative firsts – the first insulin syringe in 1924, the first 5 mm pen needle in 1999 and the now the world’s first 4 mm pen needle, the BD Nano,” said Linda Tharby, president of BD Medical – Diabetes Care. “We are confident this tiny needle can have a big impact by easing diabetes patients’ transition and ongoing adherence to injectable drug therapy regimens – a key element in helping to reduce the disease’s deadly, debilitating and costly complications.”
Animas Corp. and LifeScan Inc., both of West Chester, Pa., and members of the Johnson & Johnson Family of Diabetes Companies, continues to build upon their existing collaborative efforts to co-develop and market innovative new products and tools for people living with diabetes.
The two companies joined forces to co-develop the OneTouch Ping Glucose Management System. This is the first full-feature insulin pump that wirelessly communicates with a blood glucose meter remote.
Other products include the OneTouch Verio Meter and Test Strip platform, which received FDA clearance, paving the way for a new portfolio of self-monitoring of blood glucose products in the United States.
Continuous glucose monitoring (CGM) is one of the latest advancements in diabetes management, Animas is partnering with DexCom Inc. to develop a continuous glucose monitoring-enabled insulin pump and CGM system. This integrates a DexCom continuous glucose monitoring sensor with an Animas insulin pump. The system has been filed for CE Mark approval in Europe.
Johnson & Johnson expanded its realm of diabetes care by developing the Diabetes Institute. David L. Horwitz, M.D., Ph.D., FACP, chief medical officer of the Johnson & Johnson Diabetes Institute, feels confident that this program can make a positive impact to help improve patient outcomes.
When asked why J&J became involved in diabetes education, Dr. Horwitz responded, “People traditionally didn’t think of J&J as a diabetes company, although we are among the global leaders in our glucose monitoring and pump products. We decided we wanted to make a difference ‘in the trenches,’ using the best practices of adult education to train diabetes educators how to change behaviors and motivate their patients.”
Indianapolis-based Roche Diagnostics U.S., with its business unit Roche Diabetes Care, continues its tradition as a leader in blood glucose monitoring and insulin delivery systems by partnering with DexCom. The two companies signed a research and development agreement in 2011 to integrate DexCom’s next-generation CGM system with the next generation of Accu-Chek insulin delivery systems targeted at the U.S. market.
In the future, users of an Accu-Chek insulin pump in the U.S. will not only be able to view their blood glucose data and insulin information on their wireless handheld, but also continuous glucose monitoring readings and trends. This would enable the user to make therapy adjustments from the palm of his hand while operating the pump.
Beyond the traditional leading pharma regions, Russia is growing into a significant diabetes market. During the next few years, the Russian diabetes market is projected to grow more than 7% annually during the next few years. This growth will result from the market launch of several premium-priced diabetes medicines and the rising use of glucagon-like peptide 1 (GLP-1) analogs, dipeptidyl peptidase (DPP-IV) inhibitors and insulin analog mixes.
Two pipeline products belonging to a novel class of sodium glucose cotransporter (SGLT)-2 inhibitors are anticipated to have a strong market impact: Bristol-Myers Squibb Co./AstraZeneca Plc.’s dapagliflozin and J&J’s canagliflozin.
The government reimbursement policy in Russia, which encompasses treatment with most insulins – including the premium-priced long-acting insulin analogs – is expected to increase use of rapid-acting and long-acting branded insulin analogs.