Alternative Routes for Delivering Macromolecules

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Unlike small-molecule drugs, which are chemically synthesized, biologics are produced in living systems such as plant or animal cells, often using recombinant DNA technology. The complexity and size of these macromolecules not only present challenges in the manufacturing step, but also in formulation development. Delivering biologics is not as straightforward as their small-molecule counterparts, and despite their blockbuster success, most biopharmaceuticals are administered by injection--a route that is not considered ideal because it is associated with pain, and therefore, affects quality of life and patient compliance.

There is a lot of interest in oral delivery of biologics because of the convenience it offers both for the patient and manufacturers; however, success has been limited and there is still no proven technology for delivering biologics orally. Alternative routes of administration are now being explored, one of which is the potential of delivering a biologic drug through the skin using microneedles to replace the traditional syringe delivery method; and the other, by developing biopharmaceutical formulations for inhaled or nasal delivery.

Transdermal delivery

“Microneedle delivery can be an alternative to standard syringes and needles or autoinjectors,” says Lisa Dick, PhD, MTS new technology and product development manager, 3M Drug Delivery Systems. Targeting the transdermal route offers the possibility of a faster onset of action compared to subcutaneous administration, she says. “More importantly, for needle-phobic patients, microneedles are less threatening than standard injection needles,” Dick notes. “If you consider microneedle systems where the drug is coated on the microneedle patch, these systems can be virtually painless, easy to apply, and can also be potentially stable at room temperature.”

“For transdermal products, the drug molecule needs to be relatively small (i.e., several hundred atomic mass units) and permeable through the stratum corneum,” Mark Tomai, PhD, head of TLR and MTS Business Development, 3M Drug Delivery Systems, points out. He explains that because most biologic drugs are too large for passive intradermal delivery, microneedle-based delivery systems have been developed. 3M, for example, has developed hollow and solid microneedle systems, which use biocompatible polymeric microneedles to bypass the barrier properties of the stratum corneum.

Hollow microneedle technology. The hollow microneedle technology by 3M is a single-use delivery system designed for self-administration. Liquid formulations are contained in a reservoir and delivered into the skin via a 1-cm² microneedle array. The microneedles can accommodate a range of molecules and drug volumes of up to 2 mL, as long as stability in the liquid form is maintained (1). “For liquid formulations delivered through hollow microneedles, skin tolerability and viscosity are keys considerations during formulation development,” says Tomai.

“Non-viscous formulations flow readily through narrow flow paths in microneedle-based devices, whereas viscous formulations are more prone to plugging in the narrow channels of traditional single-channel devices or require a long delivery time,” Dick observes. According to her, it is possible to deliver more viscous solutions of up to approximately 25 centipoise (cp) with the 3M hollow microstructured transdermal system (hMTS), and there are options for delivery of up to 80 cp solutions in the future.

“The drug product formulation must also be chemically compatible with the microneedle arrays and device, including storage over time,” says Tomai. “Also, drug molecules in a liquid formulation that are delivered using a hollow microneedle injector must be physically able to withstand shear forces when flowing through the device. Such physical compatibility considerations are especially important for biological drugs, which can denature or become inactive.”

Solid microneedle technology. 3M’s solid microneedle technology is based on tiny needles mounted on a wearable patch, which has been designed to deliver proteins, vaccines, or other solid formulations up to 300 mcg (2). “With solid coated microneedles, there are several formulation considerations that need to be taken into account, for example, the balance between chemical stability, the ability to coat onto solid microneedles, and the ability of the formulation to release into the skin,” Tomai highlights. “Chemical stability considerations are similar to those of other dosage forms. The ability to coat a formulation onto solid microneedles is drug dependent and relies on solubility, target dose, and viscosity. For the ability of a formulation to release into the skin, it needs to be released from the microneedle surface through its inherent solubility in the dermal interstitial fluid.” Tomai adds that for every drug molecule, there may be more than one acceptable formulation composition, therefore it is a matter of testing several formulations for manufacturability and the eventual outcome for effective treatment.

Analytical testing of transdermal drug-delivery systems. Analytical testing for transdermal products is phase-appropriate, notes Dick. Fewer tests are carried out during early feasibility investigations and the limits are wider. “However, as more methods are added, the specifications on the results are narrowed,” she continues. 
“The analytical testing of drug product delivered with microneedles is similar in scope to other dosage forms,” Tomai adds. “Regulatory guidance such as the International Council for Harmonization (ICH) Q1, Q3, Q6, and Q8 are consulted in addition to the United States Pharmacopeia (USP). Tests often include the following: drug content, content uniformity, impurities, microbials, and sterility.”

For microneedle products, some device-specific requirements and testing may also be required, according to Dick. “Materials of construction are often USP Class VI and evaluated according to ISO 10993 (3),” she says. “Human factors design and testing are completed at both formative and summative stages. Device performance testing, packaging systems, and sterility controls are also considered as needed for drug products.”

Inhaled or nasal delivery

Another alternative for delivering biologics is the inhaled or nasal route, which has the potential to provide good bioavailability and direct delivery of the drug to the respiratory system (4). “There are two principle drivers towards inhaled or nasal delivery for biologics: firstly, the potential for topical delivery, and secondly, as an alternative systemic delivery route,” explains Mark Parry, technical director, Intertek Melbourn. “Topical delivery allows targeting of the product to the location of action with a potentially lower dose than would be needed for systemic intravenous dosing (e.g., treatment of a lung infection or delivery of a gene therapy to the lungs of a cystic fibrosis sufferer). As an alternative systemic dosing route, inhaled and nasal delivery presents a more patient-friendly alternative to parenteral delivery, as well as potential advantages in pharmacokinetics profiles compared to other options such as subcutaneous injection.”

Device selection. Devices used for delivering biologics by the inhaled or nasal route range from nasal sprays or nasal dry powders, to dry powder inhalers (DPI), pressurized metered-dose inhalers (pMDI), nebulizers, and soft mist devices. “Device selection needs to consider a number of factors that relate to both the properties of the compound being developed as well as the intended usage model of the product,” highlights Ashleigh Wake, director of Biological Services, Intertek Manchester. She adds that there are also related commercial considerations to be factored in.

“Some compounds may need to be present as a solid material because they lack long-term stability in solution, but engineering a DPI formulation requires development of a suitable spray-drying process (or other suitable particle engineering technique), which adds complexity and cost to the product and its development,” Parry explains. “As a result, nebulized and nasal solution and reconstituted solution products tend to dominate the development; however, there are advantages in terms of a simpler, shorter inhaled dosing processes as well as improved shelf lives that can make DPI products more commercially desirable.”

“In terms of device compatibility, one of the early parts of development is to look at the compatibility of the product with the materials and methods of operation of the chosen devices,” says Wake. “For example, the aerosolization of solutions for nebulization can impart significant shear forces as well as increased exposure to oxygen in the air, which must be assessed in order to select an appropriate delivery device.”

Excipients. According to Parry and Wake, the range of excipients proven for use in inhaled and nasal products is more limited than those used for oral formulations. They note that some existing parental formulations contain excipients not used in inhaled products. “This means that the choice of excipients must consider the impact on the required toxicological assessments on any new inhaled excipients,” says Parry.
“Typical developments for aqueous solutions will need to consider tight controls of pH and ionic strength,” Wake explains. “But the use of surfactants is very common in order to control interactions with container and device surfaces.”

Analytical testing of inhaled and nasal products. Besides the typical quality control criteria of assay, purity, and impurities, inhaled and nasal products requires specific testing to look at the product performance, Parry points out. “These tests include measuring the delivered dose (i.e., the actual amount delivered by the device to the patient) and the particle or droplet size, which affects where the product will deposit,” he says. “These parameters are critical for inhaled and nasal product performance as they ensure that the right amount of drug is delivered to the right part of the nose or lungs, and are key stability indicating tests for development and routine testing of these product types.”

Biologics, in general, can suffer from changes in activity and structure when exposed to extremes of condition, as typical of a nebulized or nasal system, observes Wake. “When considering inhaled or nasally delivered biologic materials, it is also necessary to include analytics to ascertain if the delivery mechanism has adversely effected such parameters,” she says.

“Consequently, it is necessary in any quality control program supporting inhaled/nasally delivered biologics to combine chromatographic methods (e.g., reversed-phase size exclusion chromatography [RP-SEC] and/or SEC) used to provide precise and accurate measure of delivered dose with analysis to confirm maintenance of biological activity (typically a cell-based potency assay) and absence of structural change, such as aggregation (SEC/dynamic light scattering [DLS]/analytical ultracentrifugation [AUC]), which can have a detrimental impact on both product efficacy and safety,” Wake explains. “The complexity of biologics analytics in any application often requires the application of multiple techniques to overcome the limitation of any one individual approach.”

References

1. 3M, Drug Delivery Systems-Hollow Microneedle Technology, accessed April 5, 2017. 
2. 3M, Drug Delivery Systems-Solid Microneedle Technology, accessed April 5, 2017.
3. ISO 10993-1, Biological evaluation of medical devices--Part 1: Evaluation and testing within a risk management process (2009).
4. M. Parry et al., Formulation of Biologics for Inhaled and Nasal Delivery, accessed April 5, 2017.

Article Details

Pharmaceutical Technology
Vol. 41, No. 5
Pages: 30–33

Citation

When referring to this article, please cite it as A. Siew, “Alternative Routes for Delivering Macromolecules," Pharmaceutical Technology 41 (5) 2017.