Frequently Asked Questions

Our formulation research started in the second half of 2018. Numerous novel strategies were tested to achieve the target concentration of 30mg/mL or higher. This research yielded three different promising formulations involving loop diuretics including furosemide.  These are all based on ingredients that are commonly used in pharmaceutical products and are generally considered safe.

In 2022 a patent was issued for the composition of the novel formulation we use with the Infusor.  A patent means it is distinctly different from other formulations before it. The standard  formulation for furosemide is known as Furosemide Injection, USP. This has been, the standard furosemide injection product for human use since 1968. It is almost exclusively used for intravenous administration. Our novel formulation was specifically formulated for subcutaneous infusion by reducing the pH from alkaline to neutral and to increase the concentration.   The benefit of a higher concentration is that a small volume can be administered in a cost-effective manner. We also wanted a product that can be stored outside the refrigerator (room temperature) for 24 months.

Furosemide Injection was first introduced in the 1968. Furosemide is insoluble at the pH of the body and the standard product was made alkaline to prevent precipitation and breakdown. The pH is typically around 9.0, which is fine for intravenous administration (blood flows and is a great buffer). However, when administered subcutaneously, alkaline product may cause a stinging or burning sensation and may cause skin irritation.

In 2012, research began trying to develop a product with neutral pH that could be used for subcutaneous infusion. Numerous buffers were tested, and it was discovered that when tromethamine is used in a particular molar ration to furosemide, the product would be stable at neutral pH. The molar ratio basically means a particular overage of tromethamine in relation to furosemide. Tromethamine at that time was well known and widely used in parenteral products. For example, tromethamine was first introduced with another loop diuretic (torsemide) in 1993 where it acted as a buffer to support the stability of the product. The discovery that tromethamine in higher concentrations can be used to enhance the solubility at neutral pH was unexpected and formed the basis for a patent.

Although the tromethamine discovery enabled subcutaneous infusion for treatment of edema, the concentration is still relatively low. A low concentration means that a relatively large volume needs to be administered for treatment. The typical clinical dose of parenteral furosemide is 80 mg and it would require 8mL of the standard furosemide formulation (10mg/mL) to give 80mg. . Although subcutaneous infusion of 8 or more is not a problem when done slowly (e.g., over 15 minutes or longer), needing 8mL or more limits the choice of delivery systems.

Diabetes and insulin use has driven the development of patch pumps. Insulin is potent and only a small volume is required. To date all patch pumps and cartridges which are in commercial use for diabetes and with other biological drugs have a volume of up to 3-3.5 mL.

To develop a convenient, cost-effective platform one either needed to pursue the development of a new large-volume platform or pursue the development of a higher concentration product so one can leverage the mature and lower-cost drug delivery platforms that exist for 3 mL and smaller. Examples of these are the OmniPod by Insulet (Acton, MA), or the V-Go (Valeritas, NJ)

In the summer of 2018, SQ Innovation initiated research aimed at the discovery of a novel next generation formulation that allowed furosemide concentration of at least 26mg/mL so that an 80 mg clinical dose could be delivered with standard 3 mL cartridges and drug delivery devices. This required a very different formulation that relied on solubilizers never before used with furosemide.

The FDA’s adage for companies developing regulated products is “to meet early and frequently”. The FDA has well-defined processes for these interactions and there is no other regulatory agency in the world that offers this kind of opportunity for early input and dialogue.

We have been working with the FDA since June of 2019 and we have received and incorporated extensive and detailed FDA input.  We met with the FDA in December of 2022 to review our submission plans.   We have submitted our NDA in March of 2023.  FDA review is rigorous for products like these and although we did everything that was expected and more, one never knows if FDA review is successful the first time around or how long this may take.   There are currently no open issues or deficiencies we are aware of.

Products for subcutaneous infusion of drugs require a drug formulation that is suitable for this and a device to deliver it. Although the FDA has several options to regulate these, for new combinations the FDA often decides they want them regulated as a single, combined entity. In this case they are usually regulated as a drug and fall under the New Drug Application process. This is also the case for us. For those familiar with the device regulations this means there is not a separate 510(k) application for the device.

This is different from insulin pump devices. These are usually developed and commercialized independent of a specific insulin product. In this case the device is regulated under the 510(k) device regulations and the insulin products follow the biopharmaceutical regulations.

Even if there is no separate regulatory filing for the device, the FDA requires that the device component be developed, tested and manufactured in accordance with the strict device regulations. The device regulations are very different than the ones that apply to the drug component and companies must setup procedures and systems to support both.

Competition drives innovation. In general, society and the regulatory agencies view competition as beneficial. However, sometimes exclusivity is required and fair to reward the innovator company for doing clinical trials.   These trials are often expensive and it would be unfair if a second company can just use these as evidence of safety or efficacy.  In these cases the company that did these clinical studies (other than PK/bioavailability) may be eligible to receive regulatory exclusivity.  Such exclusivity pertains to using clinical data they paid for.   Our application does not qualify for such exclusivity.   There is no company with regulatory exclusivity for a furosemide product.

For those interested in the details, here are the rules: is the FA may offer a three-year exclusivity for a pharmaceutical company that invests in doing clinical trials to support an indication or use. The FDA grants the company exclusivity for that period before other companies can rely on that specific trial data from the innovator company for their own approval. So, there are two conditions that must be met:

1. The Innovator company (Company A) must have conducted a clinical trial other than a bioavailability/PK study and this clinical study was required for an FDA approval they obtained, and
2. The second company (Company B) seeks the same or similar approval but instead of doing their own study they want to rely on Company A’s study.

In this case the FDA grants company A three years of exclusivity before company B can rely on that study. If you are interested in learning more, you can read the regulation that covers this on the FDA’s website.

We designed to infusor to reuse the electronic components for many successful treatments and the only thing that is thrown away is the Disposable Unit.   The Disposable Unit consist of plastic components and a stainless-steel needle/cannula.   The Disposable Unit houses all components that are in contact with the drug during delivery and are in direct contact with the body.  Therefore the Disposable Unit needs to be sterilized in a similar way as medical syringes and many other medical products are.  Sterilization by radiation is the standard for these products.

Medical devices are sterilized in a variety of ways including using moist heat (steam), dry heat, radiation, ethylene oxide gas, vaporized hydrogen peroxide, and other sterilization methods (for example, chlorine dioxide gas, vaporized peracetic acid, and nitrogen dioxide).

One of the methods that is widely used in medical devices is the called ethylene oxide.   Ethylene oxide.  Unfortunately, Ethylene oxide possesses several physical and health hazards that merit special attention. Ethylene oxide is both flammable and highly reactive. Acute exposures to Ethylene oxide gas may result in respiratory irritation and lung injury, headache, nausea, vomiting, diarrhea, shortness of breath, and cyanosis. Chronic exposure has been associated with the occurrence of cancer, reproductive effects, mutagenic changes, neurotoxicity, and sensitization.   Concerns about Ethylene oxide relates to users who work with ethylene oxide for sterilization and the environment.  The FDA has started a program to promote the use of radiation as an alternative to Ethylene oxide.  The FDA assures that residual levels in approved products are safe so they do not pose a risk to the user.

In the design of the Infusor environmental considerations were important to us.  In line with the consensus opinion about ethylene oxide we wanted to design our product so we did not have to use it and could rely on a safe method without risk for workers or the environment.   We are proud to say we exceeded.  Even if products that use it are considered safe, avoiding ethylene oxide is promoted by the FDA, US Department of Labor and the US Environmental Protection Agency.

For those interested, the following US government websites provide more information:

FDA: https://www.fda.gov/medical-devices/general-hospital-devices-and-supplies/sterilization-medical-devices#why

US Department of Labor (OSHA): https://www.osha.gov/ethylene-oxide

US Environmental Protection Agency (EPA): https://www.epa.gov/hazardous-air-pollutants-ethylene-oxide

The Infusor attaches to the abdominal skin with medical tape.   This is the same kind of tape that is used in hospitals and with the old-style adhesive bandages.   Getting something to stick to the body sounds easy.  However there is much more to it than one might think.  Medical adhesive tapes use a form of glue known as acrylate adhesives.   These have been the standard for decades and are still considered the best for most applications.  Acrylate adhesives bond to the top layer of the skin.   As with other glues, after a short period of drying the bond is irreversible to the top layer of the skin.

Some adhesives have an additive to make the acrylate glue flow deeper into the openings, lines and creases of the skin.   These are called tackified adhesives.   Tackified are typically used for longer term wear – 14 days or longer.  Tackified adhesive are also used when the adhesive needs to hold during swimming or bathing.

Our Infusor is small and light and not to be used during swimming or bathing,   This allowed us to try a gentle adhesive.  We worked closely with 3M to select the most gentle adhesive for our Infusor.  3M is the largest manufacturer of medical adhesives and offers a broad range of medical tapes.  We tested the most gentle version of the series 3M offered.   It is the same adhesive used for other applications where easy removal without skin irritation is important.  The non-tackified medical tape we selected is used for temporary tattoos, under eye patches and medical use such as for around stoma.     All of these applications require minimal risk of irritation, skin damage and removal with the least amount of discomfort.   We know how much most people hate painful removal of medical tape and bandages. We are very pleased the most gentle 3M acrylate adhesive was able to hold the device in place during treatment.  This  avoids or minimizes any discomfort during removal.  This is another benefit of using a small volume and light Infusor.