Improved Formulations to Enable Stable Delivery of Biologics

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There is a growing demand for biologics spurred by clinical success, favorable safety data, and the ability of biologics to target the underlying cause of disease. Progress in proteins, peptides, nucleic acids, vaccines, and monoclonal antibodies (mAbs) has allowed biologics to advance quickly, especially in recent years. According to an article in Molecules, 25% of new chemical entities approved by FDA between 2015 and 2019 were biologics (1). Perhaps the most striking recent example of the demand for biologics is the rapid scale-up and application of messenger RNA (mRNA) vaccines to treat COVID-19. Though progress has been swift, challenges have created barriers to global adoption due to complications related to formulation, thermostability, and drug delivery. 

Biologics originate from living organisms, have large molecular weights, and generally cannot be chemically synthesized. This means they are vulnerable to the environment and require extreme care to formulate, manufacture, and store (2). As biologics are large molecules with primary, secondary, tertiary, and quaternary structures, they are also sensitive and expensive to produce (3). While biologics are conventionally delivered intravenously in liquid form, liquid formulations exhibit chemical and physical stability problems. Conversely, biologics formulated as a dry powder are more stable and are less prone to degradation, but drug manufacturers must consider shelf stability as well as which excipients and formulation conditions will enable a longer shelf life. Additionally, the chemical and physical properties of the final product must be considered during formulation to fit the route of administration.

This article explores technological innovations that could overcome challenges in formulation and the delivery of biologics—especially for respiratory diseases where inhaled drug delivery offers a significant advantage—to address the need for scale-up of biologics to benefit a broad range of patients.

Overcoming the challenges of oral delivery of biologics

A major issue for respiratory and lung conditions treated via oral therapies is that a lower amount of drug reaches the lung with a higher amount delivered systemically, which can reduce effectiveness and lead to potentially life-threatening toxicities. Vaccines are one example of a biologic that when delivered directly to the respiratory system, rather than through systemic injections, can offer significant advantages and sidestep challenges of oral delivery. The lungs have a large surface area and thin peripheral epithelium, so the administration of vaccines directly to this area allows for faster onset of action (4). Additionally, vaccines administered by inhalation directly into the respiratory system can stimulate the mucosal membrane surface, an advantage for immunity as it triggers the memory T-cell immune response at the site of infection, which can allow for quicker neutralization of the virus and serve as a prevention strategy for infectious diseases (5).

While delivery of respiratory drugs, including vaccines, is a potential route to overcoming the challenges of oral delivery, vaccine formulation has its own challenges and requires appropriate development, manufacturing, distribution, and storage considerations. While vaccines are commonly refrigerated between 2–8 ˚C, they should ideally be stored at ambient temperatures with a long shelf life to reduce cost for both storage and distribution (6). Sensitive vaccines, such as mRNA vaccines, require even colder temperatures to preserve activity. However, vaccines in liquid form cannot be frozen, as this process induces stress to the mixture and can cause irreversible changes to protein shape and therefore function (6). Common vaccine adjuvants, such as aluminum salts, also cannot be frozen and require expensive cold chain storage for distribution (7,8). Excipients and other stabilizers can improve the stability of liquid vaccines, but reformulation via dry powders offers a more elegant solution.

Dry powder formulations can improve thermostability, avoiding or minimizing requirements of cold chain storage; improve aerosol properties for direct-to-lung or nose delivery; and offer greater flexibility for convenient routes of administration, all at a lower dose—thereby improving safety and efficacy. Nebulizers and metered-dose inhalers deliver drugs in liquid form, which can expose biologics to harsh conditions and inconvenience patients with a longer administration time, while dry powder formulations can be delivered using a standard inhaler, intranasally, and/or reconstituted for injection (3,9).

However, formulating biologics into dry powders is no easy task. To maintain activity and potency, biologics must retain their physical and chemical structure, which introduces challenging formulation questions. There is an unmet need for a formulation and delivery technology that can create biologics with aerosolization properties that also maintain structural integrity and stability to improve drug delivery of biologics. Addressing this need could transform the pharmaceutical space and improve the treatment process for millions of patients being treated with biologics.

Current techniques in dry powder development

Research has revealed properties of dry powders that are favorable for aerodynamic delivery to the lungs and other areas, including a highly porous surface area and small, submicron, and micron-sized particles (10). However, depending on the modality of the drug, physical and chemical degradation can occur during the drying process, and the choice of technique must be carefully considered. Techniques to produce inhalable pharmaceutical powders include:

• Spray drying (SD), or spraying solutions into dried hot air. This can be used to produce products for inhalation but is mostly limited to small molecules and proteins that are not thermally sensitive (2).
• Nano-milling is one of the most common processes to improve the bioavailability of poorly water-soluble drugs. The process involves wet milling, or dispersion of particles through impact, to mechanically decrease particle size and increase surface area and has ideal properties for oral, injectable, and inhalable administration (11). Increasing surface area increases dissolution rate and, therefore, increases bioavailability, but conditions can be harsh.
• Shelf freeze-drying (shelf FD)/lyophilization is a common process for producing stable protein particles and dry powder vaccines. The process involves using a freeze dryer known as a lyophilizer to freeze liquid drugs and sublimate the solvent until a powder is formed (3). A disadvantage of shelf FD is that the powder must be further processed by milling to improve particle size and surface area. Unfortunately, for proteins, this causes mechanical stress, resulting in degradation, uneven particle size distribution, and low yield of the expensive biologic (3). Despite this challenge, shelf FD is almost exclusively used for products that are temperature sensitive, but the process can take days, creating inconvenience for manufacturing and distribution (12).
• Spray freeze-drying (SFD) combines the advantages of freeze-drying and traditional spray drying to produce highly porous particles, which is an advantage for inhalation (2). The SFD process involves spraying an aqueous solution through a high-pressure nozzle into a cold gas vapor above liquid nitrogen. The resulting powder has a high surface area, and droplet shape and size can be customized with various atomization nozzles and spray rates (13). Some limitations are the large phase-liquid interface and shear stress, which results in challenges in formulating proteins (2). Also, atomization of the liquid through the high-pressure nozzle causes degradation of surface-active proteins and loss of activity (14).
• Spray freezing into liquid (SFL) involves spraying the liquid formulation directly into a liquid cryogen, a substance used to produce very low temperatures. This has a slower freezing rate than SFD, which results in a lower surface area, improving stability by lowering the risk of water adsorption (3). SFL produces protein powders with better properties than SFD, including less adsorption, aggregation, and denaturation, and higher enzymatic activity (15).

Notably, SFD, SFL, and shelf FD all avoid the use of heat, which can denature proteins (13). Despite the advantages, these technologies offer, the properties of powders produced by SFD, SFL, and shelf FD may not be ideal for inhalation, especially in the context of biologics, as these techniques can cause aggregation—abnormal association of proteins into larger aggregate structures—leading to loss of activity (15).

Thin-film freezing and improving the delivery of biologics

Thin-film freezing (TFF) is an advanced formulation process that can produce stable protein particles of submicron size and is potentially ideal for overcoming some of the challenges described above. The process is described in the following steps:

• A drug, with or without inactive ingredients (excipients), is dissolved in a solvent system.
• The product is applied to a cryogenically cooled surface, typically of a stainless-steel drum (13,16). This flash freezing results in a frozen thin film.
• The frozen solvent system is removed by sublimation, and the collection of the powder produces a high yield—almost 100% compared to 80% with SFD (15).
• The powder is processed to create drugs for targeted administration via inhalation, intranasal delivery, reconstitution for injection, or topically to the skin or eye.

TFF technology was originally developed to improve drugs with poor water solubility and shows advantages over other cryogenic techniques used for preparing biologics, creating unique particle characteristics that are advantageous for inhalation (17,18). The powder is porous with a large surface area and low density that can be aerosolized to facilitate delivery to the lungs, nose, and eyes. TFF has a similar cooling rate to SFL but can form high surface area particles, which is advantageous for inhaled therapies. Additionally, the cooling rate can be more easily controlled (1). TFF has also been shown to maintain protein stability and bioactivity and to cause less denaturation compared to other techniques (14,18,19).

TFF is especially convenient for the development of vaccine formulations. Repeated freezing and thawing of a dry powder vaccine containing aluminum salts formulated using TFF did not show aggregation following reconstitution (8). TFF can also maintain drug activity after high-temperature storage. The immunogenicity of a TFF dry powder vaccine was preserved after storage temperatures as high as 40 ˚C for up to three months, which is a major advantage for cold chain logistics (20).

TFF technology is being applied to multiple therapies, including biologics, currently in preclinical and clinical development and holds relevance for delivery of respiratory treatments, as it allows for targeted delivery of therapy to the lungs with a faster onset of action and reduced systemic side effects. One application where TFF technology can provide a significant advantage is the use of dry powder mAbs for COVID-19. TFF has been shown to produce better aerosol properties of mAbs compared to shelf FD, and a dry powder version of a mAb tested in vivo successfully neutralized SARS-CoV-2 infection and reduced viral load (21,22). Delivery of the TFF dry powder COVID-19 antibody to infected hamsters resulted in a dose-dependent reduction of viral load when the administration was initiated 24 hours after infection with SARS-CoV-2 (21). TFF is also being applied to improve the delivery of non-biologic antiviral therapies for COVID-19, including remdesivir and niclosamide, and could offer a promising alternative for outpatient COVID-19 treatment (23).

The future of biologics drug delivery

Lessons learned in recent years, including during the rapid deployment and production of mRNA vaccines to prevent COVID-19, have made the need for innovative technologies that optimize drug formulation, delivery, stability, administration, and distribution of biologics apparent. Processing methods and excipients must be considered for different routes of administration to develop characteristics that can overcome biological barriers and improve delivery. Non-invasive therapies that are stable at room temperature could eliminate the need for ultra-cold chain refrigeration and reduce logistics costs, making medicines more accessible globally. More targeted delivery for biologics could also improve the efficacy of these therapies, especially for respiratory diseases.

While dry powder formulations offer a logical solution to overcome the challenges of liquid delivery of biologics, not all conventional dry powder techniques are amenable to biologics formulation and delivery. TFF technology has emerged as a promising particle engineering technique for developing dry powders for pharmaceuticals, which overcome the challenges of other techniques when it comes to temperature stability, water solubility, and absorption. TFF has been successfully applied to prepare dry powders of proteins and biological products, which subsequently maintain their structure and functional activity with optimal aerosol performance and improved thermostability, overcoming cold chain storage limitations. Other dry powder technologies continue to emerge, including the use of microwave energy as the heat source for sublimation to enable uniform drying and the use of LyoSphere, which can form small beads for easy-to-dispense doses (2). Additional processes such as aseptic spray-freeze drying, aseptic spray drying, and radiant energy vacuum technology are being studied in an effort to overcome formulation and manufacturing challenges of biologics (2).

As researchers continue to advance biologics to treat diseases, further development of dry powder technology will be essential to scale up and improve the delivery of these therapies to better support access, convenience, and efficacy for patients.

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About the author

Robert O. Williams III, PhD, is the division head and professor of molecular pharmaceutics and drug delivery at The University of Texas at Austin, College of Pharmacy; the Johnson & Johnson centennial chair in pharmacy at the University of Texas at Austin, College of Pharmacy; editor-in-chief of the AAPS PharmSciTech scientific journal; and the technology inventor/special advisor for TFF Pharmaceuticals.

Article details

BioPharm International
Volume 35, Number 7
July 2022
Pages: 46–49

Citation

When referring to this article, please cite it as R. Williams, “Improved Formulations to Enable Stable Delivery of Biologics," BioPharm International 35 (7) 46–49 (2022).