DRUG DEVICES – A Next-Generation Inhaled Dry Powder Delivery Platform


INTRODUCTION

Drug developers have long sought effective pulmonary delivery of therapeutics to treat diseases inherent to the respiratory tract. Indeed, inhaled therapies are certainly favored over oral or intravenous therapies for respiratory and other diseases. Pulmonary drug delivery offers superior direct targeting to the site of action, higher lung doses, and lower systemic drug concentrations, opening the potential for higher therapeutic index with an overall benefit of lower total body dose and reduced potential for adverse events.1 Delivery of drug to the deep lung can also offer improved access to the systemic circulation with several advantages, including rapid onset of action, avoidance of first-pass metabolism, and convenience as compared to injection.

Traditional inhaled drug delivery has used a number of technologies, including pressurized metered dose inhalers (pMDIs), nebulizers, and dry powder inhalers (DPIs). While delivery of drugs via these first-generation inhaled drug systems provides great advantages over oral or intravenous delivery, these systems also have inherent limitations. The limitations of these systems create a tremendous opportunity for next-generation inhaled delivery platforms that can overcome the shortcomings of today’s approaches.

PRESSURIZED METERED DOSE INHALERS (PMDIS)

Pressurized metered dose inhalers (pMDIs) contain drug suspended or dissolved in a volatile propellant that is atomized for inhalation. The propellants that were originally used, chlorofluorocarbons and hydrofluoroalkanes, emit environmentally unfriendly gases. Moving away from these propellants has proven to be difficult with certain drugs and formulations, reducing the number of therapeutics that can be formulated in this way. pMDIs are also characterized by low lung deposition efficiency and require breath coordination for effective delivery.

NEBULIZERS

Nebulizers deliver atomized aqueous drug solution by air jet or ultrasonic mechanisms. Nebulized drugs are typically delivered continuously over multiple breaths. Used mostly for elderly, infant, or critically ill patients, nebulization is typically considered to be a lessconvenient delivery system in terms of portability and delivery time, and is also characterized by low lung deposition efficiency. Nebulizers possess limitations in terms of the formulation of drugs that are degraded by shear and air-water interfaces.

DRY POWDER INHALERS (DPIS)

Dry powder inhalers (DPIs) have traditionally used micronized powdered medication blended with a large quantity of lactose-based carrier, limiting the amount of drug that can be delivered. With no propellant, DPIs generally rely on the force of patient inhalation for delivery, which has limited their use in patient populations with potentially compromised lung capacity, such as children and the elderly. These lactose blends are typically composed of more than 80% to 90% lactose with microgram quantities of drug, resulting in a low drug mass-to-volume of powder ratio that limits their use primarily to high-potency drugs. These powders are also generally highly flow rate-dependent with respect to their dispersibility, have poor delivery efficiency with typically less than 20% of drug making it to the lung, and have high patient-to-patient variability. Secondgeneration DP delivery based on particle engineering approaches (rather than active devices) have included production of porous particles and coating of particles with hydrophobic force-modifying excipients, such as magnesium stearate. Porous particles allow for aerosolizable powders with good dispersibility over a wide range of inspiratory flow rates, however, the inherent low particle density results in a low drug mass-to-volume of powder inhaled. The reduction in amount of drug per unit volume can make porous particles unsuitable for large molecule drugs or drug combinations that often require higher effective drug mass loadings per dose.

Limitations of existing inhaled drug delivery methods have created the opportunity for a new approach to DP inhaled drug delivery technology. Moving forward, trends in the industry indicate that this significant opportunity is growing as more pharmaceutical and biopharmaceutical companies pursue the following product and formulation objectives:

“¢ using pulmonary delivery for a range of small-to-large drug molecules, spanning both existing and new drug entities;

“¢ increasing the dosage of active drug molecules in inhaled therapeutics, specifically increasing the drug mass to inhaled volume;

“¢ seeking to commercialize drug combination formulations, including two, three, and higher numbers of drugs combined into a single inhaled product; and

“¢ pursuing reproducible delivery across a range of patient populations, including pediatrics, the elderly, and those with generally compromised lung function.

A new dry powder formulation approach has been developed that overcomes the limitations of traditional inhaled delivery and has the potential to expand therapeutic options, disease targets, and patient populations for pulmonary drug delivery.

NEW PLATFORM FOR DPI THERAPEUTICS ADDRESSES LIMITATIONS, BROADENS SCOPE

Based on research to address the limitations of existing inhaled dry powder formulations, Pulmatrix has developed iSPERSETM, a novel, proprietary inhaled dry powder delivery platform for use in the pulmonary delivery of drugs. iSPERSE particles can be engineered for localized therapeutic applications in the lungs, or for systemic delivery of therapeutics in which the goals include rapid onset of action, avoidance of first-pass metabolism, and convenience as compared to injection.

iSPERSE powders are characterized by small particle size, relatively high density and flow rate-independent dispersibility, along with the ability for low or high drug loading of single or multiple drugs. iSPERSE represents a next-generation pulmonary delivery platform with significant potential as iSPERSE’s properties yield drug delivery capabilities superior to (and indeed not feasible with) conventional dry powder technologies that rely on the use of lactose blending or low-density, porous particles.

Pulmatrix, a clinical-stage biotechnology company discovering and developing a new class of therapies for respiratory diseases, developed this new approach to inhaled drug delivery as part of the development process for the company’s own novel, proprietary inhaled medicines, some of which are already in human clinical trials for a range of diverse diseases, such as asthma and chronic obstructive pulmonary disease (COPD).

CUSTOMIZABLE DRUG-TOCARRIER VOLUME

iSPERSEuses proprietary salt-based formulations optimized for inhalation to create a robust and flexible platform that can accommodate low or high drug loads of a range of molecule types. iSPERSE particles (Figure 1) are routinely prepared by a singlestep spray-drying process from either aqueous or organic systems. Small hydrophilic, small hydrophobic, and large molecules have all been incorporated successfully into iSPERSE formulations. These iSPERSE powders can contain as little as 5% excipients, which compares favorably to the greater than 80% to 90% lactose that is typical of commercial lactose blend DPI formulations.

This fundamental formulation difference of iSPERSE, along with the powder property of relatively high density, maps directly into drug dose, creating feasible drug doses in a unit of up to 100 mg for iSPERSE.2 Additionally, iSPERSE inherently offers the potential of a strong safety profile, as, in addition to drug molecules, iSPERSE dry powders exclusively contain excipients that are generally regarded as safe (GRAS).

DYNAMIC FLOW RATE EFFICACY

iSPERSE powders allow for the highly efficient delivery of reproducible aerosols to the lungs with mass median aerodynamic diameters (MMAD) typically ranging from 2 to 5 microns and respirable fine particle fractions routinely greater than 50%. The iSPERSE particles also possess the desirable property of being highly dispersible across a wide range of dispersion energies in spite of their small geometric particle size. Across flow rates from 15 through 60 liters per minute (LPM), the percent of powder emitted from a passive dry powder inhaler (DPI) using iSPERSE formulated DPs is high and remains primarily unchanged (Figure 2), delivering drugs to the lung much more efficiently and with far less energy on the part of the patient.

iSPERSE powders improve upon the delivery efficiency limitations of lactose blends, in particular allowing for a reduction in nominal dose. This expands the potential therapeutic applicability of iSPERSE as it could be appropriate for the broadest patient populations, including effective inhaled drug delivery to patients with normal or impaired lung function, using simple and convenient commercially available inhaler devices, such as passive capsule or blister-based DPI devices. Furthermore, iSPERSE formulations can be readily made in both clinical trial and commercial quantities using the proven and scalable spray-drying process capable of high and consistent yields.

MULTI-DRUG COMBINATIONS

The properties of iSPERSE have meaningful therapeutic and patient benefits, including the potential for single formulations that contain multiple drugs. In fact, preclinical data have shown the potential of the iSPERSE platform to enable the aerosol delivery of drug combinations that include triple drug combinations or higher. For example, in in vitro and preclinical studies presented recently, an iSPERSE fluticasone and salmeterol combination was matched to commercially available Advair® Diskus®, which contains the fluticasone and salmeterol combination blended with lactose to enable pulmonary delivery.3 A triple iSPERSE combination of Advair components and an additional anticholinergic bronchodilator was also demonstrated. Highlights from these data include:

“¢ iSPERSE demonstrated improved delivery efficiency over Advair Diskus, as iSPERSE was shown to deliver over 2 times more lung dose of the active pharmaceutical ingredients than Advair Diskus. This improved delivery efficiency may offer two primary benefits: reduced off-target drug exposure and oral deposition, which potentially could reduce side effects such as thrush (oral candida) and other infections and reduced nominal dose (dose sparing), which lowers cost of goods.

“¢ iSPERSE showed flow rate-independent performance in terms of dose and particle size distribution, which could enable iSPERSE applicability across a broad range of patient populations, expanding applications beyond patients with normal lung function to also include those having lower or impaired lung function, including pediatric, elderly, and those with compromised lung function.

“¢ The iSPERSE particle size distribution that would reach the lungs is consistent with an Advair Diskus particle size distribution (MMAD between 3.1 and 3.2 microns for iSPERSE comparable to 3.0 microns for Advair Diskus).

“¢ iSPERSE showed excellent agreement in size distribution for both drugs (fluticasone and salmeterol) and, even with the addition of a third drug, iSPERSE was able to maintain comparable size distribution, flow rate independence, and other powder properties desirable for inhaled delivery.

“¢ Consistent delivery of dual and triple combination components was achieved, with all components of iSPERSE in both dual and triple combinations retaining expected in vivo activity, as demonstrated by reduced lung inflammation and airway hyper-responsiveness in a murine model of allergic asthma.

INHALED DELIVERY OF DIVERSE CLASSES OF DRUGS

The potential of iSPERSE technology has been validated not only with small molecule drugs, but also macromolecule drugs (proteins, peptides, antibodies) at therapeutically relevant doses well in excess of those achievable by traditional dry powder lactose blend technologies. In vivo efficacy has been demonstrated with small molecules for the treatment of asthma and COPD, antibiotics in mouse models of bacterial infection, as well as lung and systemic delivery of macromolecules.

POTENTIAL APPLICATIONS FOR ISPERSE

The attributes of iSPERSE give this proprietary novel delivery platform the potential to (1) deliver high drug payloads, (2) deliver low potency drugs, (3) offer flexible formulation options, (4) reduce side effects, (5) facilitate straightforward manufacturing, (6) support the formulation of small and large molecule drugs (proteins and peptides), and (7) support drug combinations (including triple drug combinations or higher).

Expanding the viability of dry inhaled powder delivery beyond select small molecules to include proteins, peptides, and antibodies at therapeutically relevant doses as well as triple, quadruple, or higher drug combinations will enable development of simple, convenient inhaled therapies for a new and expanded range of disease targets and patient populations. As such, iSPERSE has the potential to be the pulmonary delivery platform of choice for a number of first-in-class and best-in-class inhaled therapeutics.

Commercially, Pulmatrix is seeking iSPERSE partnerships as well as advancing its own iSPERSE-based drug formulations. In terms of diseases that are likely near-term candidates for iSPERSE clinical initiatives, a number of proprietary iSPERSE drug formulation candidates are now being advanced, including small molecules, combinations, and biologics in a variety of therapeutic areas, including COPD, cystic fibrosis, asthma, idiopathic pulmonary fibrosis (IPF), and non-CF bronchiectasis.

To support the development of its own pipeline as well as the iSPERSE partnering programs, Pulmatrix has developed a complete range of pulmonary drug formulation capabilities that are integral to the successful commercialization of the iSPERSE platform, including

“¢ dry powder formulation and manufacturing,
“¢ dry powder physicochemical properties optimization,
“¢ aerosol characterization and method development,
“¢ dry powder inhaler selection and testing,
“¢ preclinical efficacy/safety testing (in vitro and in vivo), and
“¢ clinical program operation and management.

These platform and formulation  optimization capabilities will be offered to  iSPERSE partners.

REFERENCES

1. Patton and Byron, Inhaling medicines: delivering drugs to the body through the lungs. Nature Reviews Drug Discovery, 2007;6:67-74.
2. Sung et al. iSPERSETM: formulation and in vitro characterization of a novel dry powder drug delivery technology. Respiratory Drug Delivery Europe. 2011;2:411-414.
3. Sung et al. Pulmonary Delivery of Combination Drug Products via a Novel Dry Powder Delivery Technology.Paper presented at the 11th US-Japan Symposium on Drug Delivery Systems. Lahaina, Hawaii, December 15-20, 2011

Dr. Jean C. Sung is the Director of Pharmaceutical Development at Pulmatrix, a clinical-stage company discovering and advancing novel respiratory therapeutics and drug delivery technologies. She is responsible for Pulmatrix’s formulation, process, and analytical development functions. With prior experience at Alkermes, Inc. and AIR, Inc. (Advanced Inhalation Research), Dr. Sung has spent more than a decade developing novel particle engineering and formulation technologies to advance respiratory dry powder drug delivery. Dr. Sung earned her PhD and MS in Engineering Sciences with a focus on Biomedical Engineering from Harvard University and her SB in Chemical Engineering from Massachusetts Institute of Technology.