A novel platform for DP inhalation drugs

Pulmonary drug delivery offers several advantages for both local and systemic applications. For drugs to treat diseases that are inherent to the respiratory tract, drug delivery via inhalation results in local, direct targeting of the site of action and minimisation of systemic exposure and side-effects.

For systemic applications, the primary advantages of pulmonary drug delivery can include:

• High bioavailability and rapid onset of action
• Avoidance of first pass metabolism
• Elimination of injection with its associated complications and
• Convenience for patients

Current technologies for the inhaled delivery of dry powder (DP) have some fundamental limitations for broad use with existing and novel drug molecules. Traditional DP inhalation delivery utilises lactose blends to deliver respirable micronised drug particles with large lactose carrier particles.

These blends are typically composed of over 80–90% 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 reaching the lung, and have high patient-to-patient variability.

Second-generation DP delivery, based on particle engineering approaches rather than active devices, has included production of porous particles and coating of particles with hydrophobic force-modifying excipients, such as magnesium stearate. Porous particles allow for aerosolisable 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.

Clearly, the opportunity for a new approach to DP inhaled drug delivery exists, driven by the challenges of using current approaches. Moving forward, trends in the industry indicate that this significant opportunity is growing as a greater number of 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 dosage of active drug molecules in inhaled therapeutics, specifically increasing the drug mass to inhaled volume
• seeking to commercialise drug combination formulations, including two, three and higher numbers of drugs combined into a single inhaled product
• pursuing reproducible delivery across a range of patient populations, including pediatrics, the elderly and those with compromised lung function.

Thus, pharmaceutical and biopharmaceutical companies are actively seeking improved DP inhaled technologies across a number of important areas for a variety of strategic, business and therapeutic reasons.

Pulmatrix has developed iSPERSE (inhaled small particles easily respirable and emittable) as a novel inhaled dry powder delivery platform for use in the pulmonary delivery of drugs for local or systemic applications. The powders involved are characterised 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. Their properties yield drug delivery capabilities not feasible with conventional dry powder technologies that rely on the use of lactose blending or low-density, porous particles.

iSPERSE uses proprietary formulations to create a robust and flexible platform that can accommodate low or high drug loads of a range of molecule types. The particles (see Figure 1) are routinely prepared from aqueous or organic systems in a single-step spray drying process. The powders can be formulated to contain as little as 5% excipients, in contrast to lactose blend DPs that typically consist of over 80–90% lactose and therefore contain only small amounts of drug.

This fundamental formulation difference, along with the powder property of relatively high density, maps directly into drug dose, creating feasible drug doses in a unit of up to 100mg for iSPERSE.¹

Additionally, this new platform inherently offers the potential for a strong safety profile as, in addition to drug molecules, these dry powders comprise exclusively generally regarded as safe (GRAS) excipients.

The powders deliver a reproducible aerosol efficiently to the lungs with mass median aerodynamic diameters typically from 2 to 5µm and respirable fine particle fractions greater than 50%. The particles also possess the unique 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 to 60 litres per minute (LPM), the percentage of powder emitted from a passive dry powder inhaler (DPI) is high and remains primarily unchanged across flow rates (Figure 2), offering some pragmatic benefits.

Figure 2: iSPERSE powders are relatively flow rate independent and possess properties suitable for aerosol delivery. Two different powder formulations (A, B) exhibited consistent properties of being geometrically small, dispersible and aerodynamically suitable for lung delivery.

The graphs show capsule emitted powder mass (CEPM) and volume median diameter (VMD) of the powders emitted from an RS01 DPI as a function of flow rate and measured by laser diffraction (mean ± SD; n=4-5).Ref 2

In particular, iSPERSE is potentially appropriate for the broadest patient populations, including effective inhaled drug delivery to patients with normal or impaired lung function, and the use of simple and convenient inhaler devices, such as passive capsule or blister-based DPI devices. Furthermore, the 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.

mutiple drug delivery
The properties of iSPERSE have therapeutic and patient benefits, including the potential for single formulations with multiple drugs. In fact, preclinical data have shown the potential of the platform to enable the aerosol delivery of drug combinations that include triple drug combinations or higher.

The technology has also been exemplified with small molecule drugs and macromolecule drugs (i.e. 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 antibiotics in mouse models of bacterial infection, as well as lung and systemic delivery of macromolecules.

One example from preclinical proof-of-concept work is particularly illustrative. In this work performed by Pulmatrix scientists, the ovalbumin (OVA) mouse model of allergic asthma was used to show the utility of the iSPERSE platform using a well-described inhaled combination, a corticosteroid, fluticasone proprionate (FP), and a long-acting bronchodilator, salmeterol xinafoate (SX).

In these studies, animals inhaled FP/SX iSPERSE formulation or placebo by whole body exposure prior to allergen challenge with OVA. Specific airway resistance was determined by dual chamber plethysmography and was collected at baseline and during methacholine (MCh) challenge following the final iSPERSE-enabled dry powder treatment.

The results are illustrated in Figure 3. Specific airway resistance values were decreased by 33% in this allergen model following MCh challenge. These animals also demonstrated decreased total inflammatory cells marked by reduced eosinophilia assessed by bronchoalveolar lavage. This demonstrates the efficacy of the corticosteroid as well as the long-acting bronchodilator in a mouse model of allergic asthma using the new delivery platform.

Figure 3: Demonstrated efficacy of an iSPERSE ICS and LABA formulation of fluticasone propionate (FP) and salmeterol xinafoate (SX) in an OVA model of mouse allergic asthma. iSPERSE reduced both lung inflammation, in the form of reduced eosinophilia (left) and airway resistance (right) following methacholine-induced airway constriction (Ref 3)

The same effect was seen upon treatment of mice with iSPERSE FP/SX in a house dust mite model of allergic asthma² and in a lipopolysaccharide model of acute lung injury³. These data highlight the potential efficacy of iSPERSE as a novel dry powder delivery technology platform, as aerosol delivery of FP/SX demonstrated reduced inflammation and airway hyper-reactivity.

In conclusion, iSPERSE offers a new platform for dry powder inhaled therapeutics that meets the needs of the next generation of inhaled therapeutics while overcoming many of the challenges with existing lactose blending and other technologies such as porous particle-based technologies. Table 1 summarises the properties and associated benefits of the platform in the context of alternative DP inhaled drug delivery approaches and the evolving needs of pharmaceutical companies seeking DP pulmonary delivery of drugs.

References
1. Sung et al., Respiratory Drug Delivery Europe 2011, Vol 2, pp 411-414, Berlin, Germany, 2011 2. Arold S.P. et al., A Novel Inhaled Dry Powder Delivery Platform; Efficacy of Fluticasone and Salmeterol During Allergic Asthma. 18th Congress of International Society for Aerosols in Medicine, Rotterdam, The Netherlands, June 2011. 3. Arold S.P. et al., Efficacy of Fluticasone and Salmeterol in a Novel Dry Powder Delivery Platform. American Thoracic Society Meeting, Denver, May 2011. Am. J. Respir. And Critical Care Med.