Tuesday, February 7, 2012

New Tools, Old Concerns in Inhalation Therapies

Neil Canavan

The development pathway for inhaled drugs may not be straightforward, but recent advances are making it an easier way to go

Everyone wants to breathe a little easier, have more room to breathe, maybe get a breath of fresh air. Given those truths, it’s a bit surprising that the central importance of the lungs, recognized in metaphor, doesn’t carry over to drug development.
“There’s a general fear of putting something in your lungs that’s not normally there,” said John Patton, PhD, founder and CEO of Dance Pharmaceuticals in San Francisco. “Nobody thinks twice about putting something in the GI tract that’s never been there before.” But put a foreign substance in the lung?
Yet the lungs have evolved numerous mechanisms to clear particulates or prevent their admission. In general this is good, but for drug development, this self-protection presents challenges. The obstacles are:
  • getting the drug where you want it to go (the deep lung);
  • making sure the formulation is appropriate for the lung (the right excipients);
  • attaining the desired efficacy (which may require sustained activity); and
  • getting a rat to take a deep breath (see case study).

Lessons Learned

Before considering the inhalation pathway, take a look at two fair warnings: Pfizer’s Exubera, and Mannkind’s AFREZZA, both inhalable insulins. Dr. Patton was the co-founder of Inhale Therapeutics (later called Nektar), Pfizer’s partner on Exubera. Long story short: The drug formulation worked, the inhalation device was a marketing disaster. “Pfizer got a heap of abuse about the so-called ‘bong,’ ” recalls Dr. Patton of the inhaler’s size and shape.
Marketing blunder aside, Dr. Patton remains impressed by the inroads made by the program, including therapeutic proof of concept. “We achieved identical glycemic control as you get with variable dose injections,” proving that insulin can be effectively administered via the lung; the formulation worked, and the device did, too. Second, insulin, a protein, was successfully formulated with novel excipients (amnnitol, sodium citrate, and glycine) in a combination that created a powder of high glass transition temperature, so it didn’t have to be refrigerated. A further innovation of Exubera’s development was the spray-drying methods, which are becoming industry standards.1,2
As for Mannkind’s AFREZZA, “They used a new excipient, too,” said Dr. Patton, “but an unusual one, and a whole lot of it.” The excipient itself required additional safety tests, which were subsequently passed.3 “If you’re going to use an excipient,” Dr. Patton advised, “use ones that are endogenous, or have already been in other drug products.” Mannitol has long been in use. “And though both glycine and sodium citrate were new, both are endogenous.” He also suggested that, whatever the excipient, use as little as possible. (For a review of endogenous excipients, see Minne, et al. Eur J Pharm Biopharm. 2008.)4
The primary driver for the development of inhaled insulin is patient compliance—no needles, better compliance. Other systemic diseases may also be suitable for this approach; the most compelling reasons to develop inhaled formulations are the diseases of the lung, which can be treated much more effectively, and with less toxicity, using local administration. “There’s a bunch of killer diseases out there,” said Dr. Patton. “Lung cancer, sarcoidosis, pneumonia, pulmonary fibrosis ... the opportunities are broad and significant.”

New Dissolution Method

In the formulation of a drug for pulmonary delivery, a big part of the solution is dissolution. “There is quite a strong, established in vitro/in vivo correlation for orally administered drugs,” said Jason McConville, PhD, assistant professor of pharmaceuticals at the University of Texas, Austin. “Dissolution is performed, and knowing a drug’s solubility and how that effects its rate of uptake is quite well known. But for the lung there isn’t any such dissolution test currently employed for existing therapies.” Dr. McConville, whose research foci include advanced formulation design, set out to change that.
The challenge was significant. “The method I’m proposing is not the perfect answer—it’s impossible to mimic the lung,” he said. “One of the biggest issues is a gigantic surface area of essentially unknown composition—it’s even difficult to know exactly how much water is present.”
For his dissolution method, Dr. McConville adapted a commercially available dissolution device by the incorporation of a membrane-containing cassette. “The cassette was designed to enclose previously air-classified formulations, so that they could be uniformly tested in the dissolution apparatus.” His initial investigation looked at the utility of a composition of a simulated lung fluid dissolution media, the influence of particle size, and the amount of drug loading for a known standard, micronized hydrocortisone.5
“We created a bit of an obstacle for ourselves because we really wanted to simulate the lung, including a recipe for a simulated lung fluid.” The initial concoction, derived from the literature, exhibited an upward drift in pH over time, proving unworkable. Adjustments had to be made.6 “We worried about matching physiological conditions, which in the end proved futile. The best approach we took was just to treat the device as an in vitro comparison test for formulations.” He believes this technique will inform us about future controlled-release inhalable formulations to a degree not previously known.
One application Dr. McConville looks forward to is addressing the issues of drug loading—the subject of a recent paper of his on inhaled chemotherapy—and the potential of proposed sustained-release formulations.7
continued below...
Activaero’s AKITA Jet and AKITA APIXNEB pulmonary drug-delivery devices.
Activaero’s AKITA Jet and AKITA APIXNEB pulmonary drug-delivery devices.

CASE STUDY: A Reliable Ventilator for Human Testing

You’ve got your inhalable formulation in hand and you’re ready for in vivo studies, but there’s a problem. “There are no animals on earth which you can train to breathe in a way that you can optimize drug deposition in the lung,” said Gerhard Scheuch, PhD, founder and CEO of Activaero GmbH.
As soon as it is ethically safe to do so, you need to test in humans. But there’s a problem: Not everyone breathes the same way. “You can imagine if someone is breathing very shallow, then the air is not getting deep and neither is the particle,” Dr. Scheuch said. A healthy subject could be instructed to take a deeper breath (though this is still subject to variation). When testing efficacy in an actual patient, diminished lung capacity may be a defining symptom of their disease.
Because variables of any kind are anathema to the experimentalist, Dr. Scheuch, a physicist and engineer by training, set out to create a type of ventilator that could reliably deliver a controlled inspiration flow and volume of aerosolized particles. The result is the AKITA APIXNEB system that not only controls flow but also, through the use of a vibrating mesh technology, can generate particles from most types of liquid formulations.1
“This is a good technology for early clinical development because you can be assured that you can get the drug into the lungs, and that observed efficacy (and side effects) are not dependent on how the patient is breathing or manipulating an inhaler.”2 It might also be cheaper. The device was initially conceived by Dr. Scheuch while he worked in collaboration with Bayer, to carefully dose a limited, and very expensive, supply of alpha 1 antitrypsin. “Using such a sophisticated inhalation system, you really get pulmonary drug delivery in the order of 80-85%.” And that helps everyone breathe easier. —NC


  1. Watts AB, McConville JT, Williams RO III. Current therapies and technological advances in aqueous aerosol drug delivery. Drug Dev Ind Pharm. 2008;34(9):913-922.
  2. Kirsten A, Watz H, Kretschmar G, et al. Efficacy of the pan-selectin antagonist Bimosiamose on ozone-induced airway inflammation in healthy subjects—A double blind, randomized, placebo-controlled, cross-over clinical trial. Pulm Pharmacol Ther. 2011;24(5):555-558.

Stay on Target

Regardless of the utility of Dr. McConville’s new assay, the true pharmacokinetics of any type of formulation must be established using human testing. For budding inhalation drug developers, this requirement adds an extra high hurdle because of the dearth of related human-derived data in the literature.
“There’s a lot of in vitro data out there for sustained release formulations, but only limited information for in vivo,” said Aliyah Sheth, Pharm D, Department of Pharmacy Practice and Science at the University of Arizona, Tucson, who recently completed a survey on the subject. “Unfortunately, the animal models for inhalation are poor, and much of the work doesn’t translate because of the inability to determine long-term effects.”
That said, there are promising sustained-release formulations, generally of a polymer of liposomal design, being investigated. A few with recent data include:
  • DOTAP-modified PLGA: Inhalable dry powder nanoparticles were loaded with siRNA;8
  • PEG(5000)-DSPE micelles: Polyethylene bubbles containing the chemo-therapeutic paclitaxel exhibited a sustained-­­­­release behavior;9 and
  • Liposomes: A formula for sustained-release budesonide using freeze-dried liposomes is proposed.10
For her part, Sheth suggests investigators stick with phospholipid excipients because they’re endogenous, and polymers for their ease of being aerosolized. “Development of sustained-release formulations may take more time, but in terms of clinical need, the extra effort (and innovation) will be more than worth it.”


  1. White S, Bennett DB, Cheu S, et al. EXUBERA: pharmaceutical development of a novel product for pulmonary delivery of insulin. Diabetes Technol Ther. 2005;7(6):896-906.
  2. Depreter F, Amighi K. Formulation and in vitro evaluation of highly dispersive insulin dry powder formulations for lung administration. Eur J Pharm Biopharm. 2010;76(3):454-463.
  3. Potocka E, Cassidy JP, Haworth P, Heuman D, van Marle S, Baughman RA II. Pharmacokinetic characterization of the novel pulmonary delivery excipient fumaryl diketopiperazine. J Diabetes Sci Technol. 2010;4(5):1164-1173.
  4. Minne A, Boireau H, Horta MJ, Vanbever R. Optimization of the aerosolization properties of an inhalation dry powder based on selection of excipients. Eur J Pharm Biopharm. 2008;70(3):839-844.
  5. Son YJ, McConville JT. Development of a standardized dissolution test method for inhaled pharmaceutical formulations. Int J Pharm. 2009;382(1-2):15-22.
  6. Davies NM, Feddah MR. A novel method for assessing dissolution of aerosol inhaler products. Int J Pharm. 2003;255(1-2):175-187.
  7. Carvalho TC, Carvalho SR, McConville JT. Formulations for pulmonary administration of anticancer agents to treat lung malignancies. J Aerosol Med Pulm Drug Deliv. 2011;24(2):61-80.
  8. Jensen DK, Jensen LB, Koocheki S, et al. Design of an inhalable dry powder formulation of DOTAP-modified PLGA nanoparticles loaded with siRNA [published online ahead of print Aug. 12, 2011.]. J Control Release.
  9. Gill KK, Nazzal S, Kaddoumi A. Paclitaxel loaded PEG(5000)-DSPE micelles as pulmonary delivery platform: Formulation characterization, tissue distribution, plasma pharmacokinetics, and toxicological evaluation. Eur J Pharm Biopharm. 2011;79(2):276-284.
  10. Parmar JJ, Singh DJ, Hegde DD, et al. Development and evaluation of inhalational liposomal system of budesonide for better management of asthma. Indian J Pharm Sci. 2010;72(4):442-448.

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