Early in vitro testing conﬁrms our TFF platform can signiﬁcantly improve the solubility of poorly water soluble drugs, a class of drugs that makes up more than one-third of the major pharmaceuticals worldwide. In the case of some new drugs that cannot be developed due to poor water solubility, our TFF platform has the potential to improve the pharmacokinetic profile of the drug.
Poor Absorption Means Drugs Miss the Target:
Many drugs intended for one organ, especially oral therapeutics intended for lung conditions, often don’t adequately reach their target due to poor absorption. This can cause poor efficacy and severe adverse events. This is true not only for lung conditions but also applies to many other diseases.
Current Technology for Drug Delivery:
Making these drugs inhalable may help address the problem of poor absorption. However, clinical data is not yet available. Biologics, the fastest growing segment of the pharma industry, and combination drugs are especially poorly suited to the inhalable format using today’s technology.
Solubility is an issue that all drugs must address:
No matter how active or potentially active a new drug is against a particular molecular target, if the drug is not available in solution at the site of action, it is most likely not a viable development candidate. According to Lipinski1, 40% of newly discovered drugs have little or no water solubility, and in some therapeutic areas this number can reach 90%, which in most cases will prohibit development.
1Lipinski, American Pharmaceutical Review 5(3):82-85 September 2002
Water solubility can also be an issue for some marketed drugs. According to Kasim2, only two-thirds of the drugs on the WHO Essential Drug List were classiﬁed as high solubility. A marketed drug with poor water solubility can show performance limitations, such as incomplete or erratic absorption, poor bioavailability, and slow onset of action. Effectiveness can vary from patient to patient, and there can be a strong effect of food on drug absorption. Finally, it may be necessary to increase the dose of a poorly soluble drug to obtain the efficacy required, which can lead to adverse side effects, toxicity issues and increased costs.
Some drugs that target lung conditions and diseases have poor solubility that prevent them from being delivered by way of a breath-actuated inhaler and can only be given orally or intravenously. The dry powder inhaler is one of the most effective and convenient forms of breath-actuated inhaler.
The Solution: Thin Film Freezing
Our development of dry powder drugs is enabled by technology licensed to us by the University of Texas at Austin, or UT. Researchers at UT have developed a technology employing a process called Thin Film Freezing, or TFF. While the TFF platform was designed to improve solubility of poorly water soluble drugs generally, the researchers at UT found that the technology was particularly useful in generating dry powder particles with properties targeted for inhalation delivery, especially to the deep lung, an area of extreme interest in respiratory medicine.
The Brittle Matrix Particle
The TFF platform yields particles that are particularly well suited to dry powder inhaler delivery. The process results in a “Brittle Matrix Particle,” which possesses low bulk density, high surface area, and typically an amorphous morphology, allowing the particles to supersaturate when contacting the target site, such as lung tissue. Based upon laboratory experiments the aerodynamic properties of the particles are such that the portion of drug deposited to the deep lung has the potential to reach as high as 75%.
Thin Film Freezing (TFF) Process
The TFF process involves dissolving a drug or drugs in a solvent system, and it will often include agents designed to promote dispersion and avoid clumping and excipients to promote adhesion to the target site. The drug solution is then applied to a cryogenic substrate, such as a liquid nitrogen cooled stainless steel drum. 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, resulting in Brittle Matrix Particles, shown in the photographs below, that are highly porous, large surface area, low-density particles. The process uses industry standard solvents, lung-approved excipients, a custom-made TFF drum and conventional process equipment.
Reformulation of drugs for lung conditions.
Today, many drugs intended for lung conditions are only administered orally due to properties that make them ill-suited for direct delivery by inhalers. Administered by these routes, typically only 10% of the drug reaches the lungs, and these drugs may cause unwanted and even deadly side effects. We believe that our TFF platform for the first time will allow many of these medications to be formulated into the convenient, direct-to-lung dry powder inhaler format providing for delivery of drug directly to the target site.
Biopharmaceuticals (or biologics) are by far the fastest growing sector in the pharmaceutical industry today. Biologics are most commonly delivered intravenously, and they can be an especially challenging class of drugs for formulation into a dry powder. We believe our TFF platform is uniquely suited to meet many of the challenges of biologic formulations, and our UT collaborators have demonstrated via animal model testing and in vitro testing that there is value in investigating the use of TFF’s technology in administering biological drugs, including drugs intended to treat indications other than lung conditions and diseases in future clinical studies.
Combination drugs are products with two or more active pharmaceutical ingredients. In addition to providing for increased patient compliance with multiple medications, some drugs act synergistically and provide an added benefit when given as a combination. However, combining pharmaceutical agents can be challenging, especially for inhalation delivery. Based upon in vitro experiments, our TFF platform has shown the ability to produce fixed dose combinations of many agents.