When 3M Company (St. Paul, MN, www.3M.com) announced plans to divide and sell its global branded-pharmaceuticals businesses for $2.1 billion to several buyers last November, its strategy included retaining 3M Drug Delivery Systems Division. The division is part of 3M's healthcare business segment, which accounted for roughly 21% of the company's 2005 net sales. The sale of the company's branded-pharmaceutical business, also part of the healthcare business segment, covered regional marketing and intellectual-property rights for 3M's drug portfolio and immune-response platform, but did not include inhalation aerosol products that are sold through licensees. That piece moved to 3M's Drug Delivery Systems Division, which is advancing technology in two principal platforms: inhalation (including inhaled macromolecules) and transdermal (including microneedle or microstructured transdermal systems for vaccines).
Advances in inhalation drug delivery
Inhalation drug delivery is well established, and recent advances by 3M focus on design improvements in pressurized metered dose inhalers (pMDIs) and extending the use of pMDIs to administering macromolecules such as proteins and peptides.
To further enhance product robustness, 3M continues to make improvements in the pMDI container-closure system (CCS).One improvement reduces the potentially problematic deposition of the active drug within the CCS by introducing can coatings (1). The company also is developing new fast-fill, fast-empty valve designs to improve dose-to-dose uniformity as well as to avoid the need for patients to prime the system if only used intermittently (2,3). In addition, 3M recently reported using a novel semipermeable system component to improve the dosing reproducibility of suspension formulations (4).
Ease of use is another important consideration in pMDI technology. Breath-actuation technology is one example. An established product in this area is 3M's "Autohaler," which removes the need for press-and-breathe coordination. More recently, 3M has developed a dose-by-dose counter for inclusion within the pMDI delivery system (5, 6) to meet new guidelines by the US Food and Drug Administration (Rockville, MD, www.fda.gov) on dose-counting mechanisms in MDI products (7) and to help patients manage their therapies. These guidelines detail FDA expectations that all new oral pMDI products contain integrated features to enable patients to track the remaining number of doses. This would prevent the patient from either discarding an inhaler unnecessarily or, more importantly, using the product beyond the number of doses specified in its labeling.
Looking ahead, 3M points to several key trends designed to improve the versatility and flexibility of pMDI-based delivery systems. For future market applications, there will be an increasing need to configure a delivery system containing fewer drug doses while retaining the same performance features. This may be driven by the development of new active drugs with longer durations of action and less-frequent dosing, demand for sample packs, or the future prospect of intermittent systemic therapies or even single-dose vaccine delivery. To this end, 3M has developed and reported on a range of pMDI delivery technologies suitable for reduced- (8) or single-dose product configurations (9).
Using pMDIs to administer macromolecules is another area of active research and development. One example of inhaled delivery of peptide and protein drugs to treat local or systemic disease is "Exubera" (inhaled insulin), recently approved in the United States and European Union.
3M says pMDIs offer several advantages for peptide delivery. First, the hydrofluroalkane (HFA) environment within a pMDI is inert and essentially moisture-free, which provides good stability for macromolecule drugs. Secondly, advances in valve and actuator technology in the pMDI help ensure a consistent and efficient delivery, an important consideration, given the cost and potency of biotech drug substances.
Despite these advantages, there can be formulation challenges in using pMDIs in administering proteins and peptides. Given the low solubility of proteins with HFAs, a suspension–formulation approach is required, which in turn will rely on the effective size reduction of the parent drug into a respirable size, while retaining its tertiary structure and biological activity, explains 3M.
To address these challenges, 3M demonstrated the feasibility of a suspension–formulation approach using particle-engineering technology with a range of molecules that included recombinant human deoxyribonuclease, adenosine deaminase, and salmon calcitonin. The integrity and stability of these molecules for extended storage periods has been demonstrated (10, 11). Molecule stability and pharmaceutical performance in pMDI systems also has been shown: further data generated using salmon calcitonin showed consistent results for in vitro drug purity and respirable fraction on product stability (12), as well as encouraging pharmacokinetic data in a rat model (13).
Also, as part of a strategy to improve delivery of a wider range of molecules via the inhalation route, 3M introduced a range of novel HFA excipients, including oligolactic acids (OLAs). The OLAs show improved functionality such as increasing solubility (14), enhancing suspension stability (15), and providing in vivo sustained release (16) of active ingredients.
Transdermal drug delivery
3M Drug Delivery Systems Division's other key technology platform is transdermal drug delivery (TDD), and microneedle or microstructured transdermal systems for vaccines is an emerging area of interest here. Other advances include improvement in liners, films, and adhesives used as components within TDD systems.
Drug-in-adhesive (DIA) systems are the most prevalent of established TDD designs. DIA systems offer advantages in simplicity, reduced size and thickness, and improved comformability to the application site.
Modified versions of the DIA design, reservoir designs, and, more rarely, matrix patches are other examples of TDD system designs.
"For drugs with a narrower therapeutic window or for which there is need for more temporal control of the delivery profile, systems with a rate-moderating membrane such as the multilaminate DIA or reservoir design are the best option," explains Tim Peterson, US early pharmaceutics and technology manager, 3M Drug Delivery Systems Division. "The multilaminate DIA combines most of the patient friendliness of the simple DIA design with added control over the drug delivery profile," he says. Another transdermal drug delivery type, matrix patches, are seldom used because they require an additional peripheral adhesive to hold the system in place, which in turn increases the overall patch size and thickness.
3M recently developed new components for transdermal drug delivery. These include fluoropolymer-coated release liners for use with new soft adhesives and formulations, ultraviolet blocking films for light-sensitive formulations, and microlayered films that are designed to be soft and occlusive.
In terms of system design for drug delivery, Peterson says the company develops customizable adhesives to improve the adhesion and drug-delivery performance of DIA products. The incorporation of microstructured adhesives is another recent advance that has the potential to improve the performance of DIA patches in several areas, including minimizing skin occlusion and reducing skin irritation (17–19).
Microstructured transdermal system
|Figure 1: Photomicrographs of MTS Arrays Coated with Fluorescent Nanobeads before (top) and after application (bottom). Source: 3M|
3M also is actively developing alternative transdermal delivery methods such as microstructured transdermal systems or microneedles. Microstructured transdermal systems may be used in vaccine delivery, replacing the common approach of using a needle and syringe or in delivering other macromolecules.
A microstructured transdermal system consists of an array of microstructured projections (see Figure 1) coated with a drug or vaccine that is applied to the skin to provide intradermal delivery of active agents, which otherwise would not cross the stratum corneum, explains Peterson. The mechanism for delivery, however, is not based on diffusion as it is in other trandsermal drug delivery products. Instead, it is based on the temporary mechanical disruption of the skin and the placement of the drug or vaccine within the epidermis, where it can more readily reach its site of action.
Much of the work on microstructured transdermal systems is focused on vaccine delivery, in which the system targets the antigen-presenting cells within the skin to reduce pain in administering the vaccine and a more efficient method of vaccination, explains Peterson. Microstructured transdermal systems also may be used for systemic delivery of potent proteins and peptides.
3M's program in microstructured transdermal systems also has provided a basis for the company to develop expertise in coating biomolecules such as proteins and peptides on patch structures. This is a capability that can be extended to other types of active patch delivery systems, which use various forms of energy such as ultrasound, thermal, or laser energy to disrupt the stratum corneum, but still require a patch system containing the active agent to be placed over the treatment area. Active delivery technologies such as these are expected to provide a significant source of growth for transdermal drug delivery markets, as molecules that otherwise could not be delivered through the skin reach the market in these active systems.