Many drugs are poorly soluble and cannot be effectively delivered via oral administration. Vaccines and biologics delivered parenterally also pose logistical challenges stemming from the need for storage and handling at reduced temperatures. Thin-film freezing (TFF) produces drugs that are highly soluble and stable in a powder form, addressing all of these challenges.
A New Powder Production Technology
There is a significant need for new technologies that enhance the solubility of poorly soluble small molecule drugs and increase the stability of biologics/vaccines in order to eliminate the need for a cold chain. TFF, initially developed by Dr. Robert O. Williams III at the University of Texas (UT) at Austin’s Division of Molecular Pharmaceutics and Drug Delivery, is the answer.
The TFF process involves applying a solvent-based solution including the API in inactive ingredients including dispersing agents, agglomeration inhibitors, and excipients that promote adhesion of the target site to a cryogenic substrate, such as a liquid nitrogen–cooled stainless-steel drum. Typically, the TFF process produces high-potency powders that require minimal inactive ingredients, a benefit to drug delivery. When the drug solution contacts the cryogenic surface, it vitrifies, or flash freezes, resulting in a “drug ice,” typically with amorphous drug morphology. The solvent system is removed by lyophilization, which creates highly porous “brittle matrix particles” that have large surface areas and low bulk densities.
During the TFF process, particle morphology may be controlled by manipulating the fluid dynamics and heat transfer properties upon spreading and freezing of liquid droplets on solid surfaces. The properties of the brittle matrix particles allow for drug supersaturation when contacting the target site. Encapsulated TFF powders in dry powder inhalers (DPIs) exhibit aerodynamic properties that enable as much as 80% of the drug to be deposited into the deep lung. Because the API is captured in a highly active state, greater therapeutic effects can also be achieved at much lower doses for many other routes of administration, including intranasal, intraocular, and transdermal.
Biologics and vaccines converted into a powder by the TFF process can be shipped at room temperature and reconstituted at the point of administration, eliminating the cold chain. Animal model and in vitro testing have demonstrated the value of TFF technology for the preparation of biologics and vaccines, including drugs intended to treat indications other than lung diseases.
Because the API is captured in a highly active state, greater therapeutic effects can also be achieved at much lower doses for many other routes of administration, including intranasal, intraocular, and transdermal.
Advantages Over Existing Tech
TFF offers several advantages over other processes that increase solubility and bioavailability (e.g., drying, spray freeze-drying, hot-melt extrusion, and nano-milling). TFF does not present opportunities for thermal degradation or damage due to shear stress or air/water denaturation.
Rather than microparticles, TFF generates nanoaggregates with uniform particle sizes and generally affords higher yields using milder processing conditions. The simple process requires only basic production equipment, is readily scalable, and affords products with higher activities and concentrations.
Leveraging TFF in a Hybrid Strategy
TFF Pharmaceuticals owns the license to the TFF technology and is leveraging its benefits in a hybrid business strategy that includes both internal drug development and external partnerships.
Our initial focus is on diseases of the lung. Today, many such drugs are administered orally, since delivery via inhalation may only result in ~10% of the drug reaching the lungs, as well as unwanted and even deadly side effects.
We believe that our TFF platform will allow many of these medications to be formulated into the convenient DPI format, providing drug delivery directly to the target site. These products are developed following the 505(b)(2) regulatory pathway, enabling us to take advantage of existing dossiers and safety data and accelerate product development.
We also work with a wide range of academic and industry partners on the development of TFF solutions for new chemical entities, biologics, and vaccines.
Two Lead Candidates
We have two drug candidates progressing through the clinic: TFF Vori, an inhalable version of voriconazole for the treatment of invasive pulmonary aspergillosis (IPA), and TFF TAC-LAC, a DPI version of tacrolimus, an immunosuppressive drug used for the prophylactic treatment of lung transplant rejection. In both cases, long-term treatment is often required but can be challenging owing to toxic side effects associated with chronic oral delivery of conventional medications.
IPA is a severe fungal pulmonary disease with a mortality rate that can reach 90% in some patient populations. Voriconazole is generally considered to be the best antifungal drug for the treatment of IPA. TFF Vori provides the drug at the “port of entry” of invasive fungal infections while also reducing or eliminating the unpleasant and potentially devastating side effects associated with orally administered voriconazole and other last-line antifungals. In the summer of 2020, we successfully completed phase I dosing of TFF Vori in healthy subjects in the first clinical study ever of a DPI formulation for the treatment for IPA. Initial results suggest that doses of up to two times higher than those reported to be efficacious in the treatment of IPA appear to be safe.
Tacrolimus, although currently the second most commonly administered immunosuppressive drug used in solid organ transplants, can cause toxicity in the kidneys, particularly at high doses. TFF TAC-LAC delivered using a DPI provides high local lung concentration without the issues associated with oral delivery.
Despite the challenges of the COVID-19 pandemic, we dosed the first patient in our phase I clinical trial for TFF TAC-LAC for the prevention of lung transplant rejection in mid-summer 2020. The U.S. FDA has granted orphan drug designation to TFF TAC-LAC for prophylaxis of lung allograft rejection.
Innovation Through Collaboration
TFF Pharmaceuticals is also excited about our active partnerships, which include the application of TFF to a range of drug types and disease indications. In some cases, clients are working on compounds that could not get to the market without the use of a novel technology like TFF.
As part of a three-year Cooperative Research and Development Agreement (CRADA) with the United States Army Medical Research Institute of Infectious Diseases (USAMRIID), we are exploring the use of TFF technology to formulate dry powder neutralizing antibodies and vaccines for pulmonary delivery.
We are also involved in a research collaboration to formulate dry powder universal influenza vaccines for pulmonary delivery, after which the University of Georgia’s Center for Vaccines and Immunology will evaluate their ability to broadly elicit reactive immune responses and potentially provide longer-lasting protection against a wider variety of influenza viruses.
Most recently, we entered into a worldwide licensing agreement with UNION Therapeutics to accelerate the development and commercialization of dry powder forms of niclosamide — an oral anthelminthic and broad-spectrum antivral1 — as a new potential treatment for COVID-19 and other coronoviruses. While niclosamide exhibits potent antiviral activity against SARS-CoV-2,2 its low aqueous solubility, absorption, and oral bioavailability create challenges for its development as an anti-viral therapy.3 TFF technology can improve the solubility of oral forms of niclosamide and dry powder forms of the drug for delivery directly to the lungs. UNION will use TFF to develop both oral and inhalation versions of niclosamide, as well as other niclosamide-based therapies. Our collaborators at the University of Texas at Austin are also developing inhaled, high-potency forms of remdesivir, a leading therapeutic for COVID-19.
Unbounded Potential
TFF is positioned to bring our disruptive technology to patients around the world. We perceive nearly limitless applications and opportunities with the TFF platform and are focused on developing as many products as possible both internally and through our partnerships to bring more viable and cost-effective drugs to patients in need.
References
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Xu, Jimin, Pei-Yong Shi, Hongmin Li, et al. “Broad Spectrum Antiviral Agent Niclosamide and Its Therapeutic Potential.” ACS Infectious Diseases. 6: 909–915 (2020).
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Jeon, Sangeun et al. “Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs.” Antimicrobial Agents and Chemotherapy. 64: e00819-20 (2020).
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Wu, Chang-Jer, et al. “Inhibition of severe acute respiratory syndrome coronavirus replication by niclosamide.“ Antimicrobial Agents and Chemotherapy. 48: 2693–2696 (2004).