Templated Open Flocs of Nanorods for Enhanced Pulmonary Delivery with Pressurized Metered Dose Inhalers

Abstract

Purpose

A novel concept is presented for the formation of stable suspensions composed of low density flocs of high aspect ratio drug particles in hydrofluoroalkane (HFA) propellants, and for subdividing (templating) the flocs with aerosolized HFA droplets to achieve high fine particle fractions with a pressurized metered dose inhaler.

Methods

Bovine serum albumin (BSA) nanorods, produced by thin film freezing (TFF), were added to HFA to form a suspension. Particle properties were analyzed with an Anderson cascade impactor (ACI), static and dynamic light scattering and optical microscopy.

Results

The space filling flocs in HFA were stable against settling for one year. The pMDI produced high fine particle fractions (38–47%) with an emitted dose of 0.7 mg/actuation. The atomized HFA droplets break apart, that is template, the highly open flocs. Upon evaporation of HFA, capillary forces shrink the templated flocs to produce porous particles with optimal aerodynamic diameters for deep lung delivery.

Conclusions

Open flocs composed of nanorods, stable against settling, may be templated during actuation with a pMDI to produce optimal aerodynamic diameters and high fine particle fractions. This concept is applicable to a wide variety of drugs without the need for surfactants or cosolvents to stabilize the primary particles.

Appendix

Bruggeman mixing rule

For porous particles or suspensions with a BSA particle volume fraction ϕ, the effective refractive index n _e and dielectric constant ɛ _e can be calculated from the following Bruggeman mixing relationships

$$\left( {1 - \phi } \right)\frac{{n_{\text{A}} ^2 - n_{\text{e}} ^2 }}{{n_{\text{A}} ^2 + 2n_{\text{e}} ^2 }} + \phi \frac{{n_{\text{B}} ^2 - n_{\text{e}} ^2 }}{{n_{\text{B}} ^2 + 2n_{\text{e}} ^2 }} = 0$$

(9)

$$\left( {1 - \phi } \right)\frac{{\varepsilon _{\text{A}} - \varepsilon _{\text{e}} }}{{\varepsilon _{\text{A}} + 2\varepsilon _{\text{e}} }} + \phi \frac{{\varepsilon _{\text{B}} - \varepsilon _{\text{e}} }}{{\varepsilon _{\text{B}} + 2\varepsilon _{\text{e}} }} = 0$$

(10)

where ϕ can be either ϕ _g or ϕ _f, the subscript A denotes air or HFA 227, and B denotes BSA.

Attractive van der Waals equations

The Φ _vdw is directly proportional to the Hamaker constant A ₁₂₁ for one particle interacting with another (subscript 1) across solvent, such as HFA 227 or acetonitrile, (subscript 2) as a function of the particle geometry (74). The Hamaker constant A ₁₂₁ may be approximated by

$$A_{121} = \left( {\sqrt {A_{11} } - \sqrt {A_{22} } } \right)^2 $$

(11)

where A ₁₁ and A ₂₂ are the pure Hamaker constants for BSA and the suspending media interacting across a vacuum, respectively. These values were calculated from Lifshitz theory (74,75). To determine A ₁₁ for porous BSA particles in HFA 227, ɛ _e and n _e were calculated with the Bruggeman mixing rule (Eqs. 9 and 10) at ϕ = 0.5 in HFA 227 (40,62). The van der Waals attractive potential between identical spherical particles (74)

$$\Phi _{{\text{vdw}}} {\text{ = }} - \frac{{A_{121} R}}{{12h}}$$

(12)

which has an attractive force F _vdw given as

$$F_{{\text{vdw}}} = \frac{{A_{121} R}}{{12h^2 }}$$

(13)

where R is the spherical particle radius and h is the separation distance between the particle surfaces and for identical hollow spheres with solid shells (76)

$$\Phi _{{\text{vdw}}} = - \frac{{A_{121} R}}{{12}}\left( {\frac{1}{{h + 2t}} - \frac{2}{{h + t}} + \frac{1}{h}} \right) - \frac{{A_{121} }}{6}\ln \left( {\frac{{h(h + 2t)}}{{(h + t)^2 }}} \right)$$

(14)

where t is the shell thickness. For identical rods, E _vdw can be calculated for parallel

$$\Phi _{{\text{vdw}}} = - \frac{{A_{121} LR^{1/2} }}{{24h^{3/2} }}$$

(15)

or crossed cylinders

$$\Phi _{{\text{vdw}}} = - \frac{{A_{121} R}}{{6h}}$$

(16)

where L is the cylinder length. The values from Eq. 15 and 16 were averaged to give equal weight to the two orientations (Table III).

Space filling floc derivation

A vial filled with protein particles of total mass m and primary particle density ρ _p into a given volume V of HFA 227 has a volume fraction ϕ _v defined as

$$\phi _{\text{v}} = \frac{{{m \mathord{\left/{\vphantom {m {\rho _{\text{p}} }}} \right.\kern-\nulldelimiterspace} {\rho _{\text{p}} }}}}{V}$$

(17)

The volume fraction of particles in a floc ϕ _f is

$$\phi _{\text{f}} = \frac{{V_{\text{p}} \cdot k}}{{V_{\text{f}} }}$$

(18)

where V _p and V _f are the volume of a spherical primary particle and a spherical floc, respectively, and k is the number of primary particles in a floc.

The volume fraction of flocs in HFA ϕ ^flocs is defined as

$$\phi ^{{\text{flocs}}} = \frac{{V_{\text{f}} \cdot N_{\text{f}} }}{V}$$

(19)

where N _f is the total number of flocs in suspension. N _f = N _p /k where N _p  = m/m _p is the total number of primary particles in suspension and m _p = V _p·ρ _p is the mass of a primary particle. Substitution into Eq. 19 gives

$$\phi ^{{\text{flocs}}} = \frac{{V_{\text{f}} \cdot m}}{{V_{\text{p}} \cdot k \cdot V \cdot \rho _{\text{p}} }} = \frac{{\phi _{\text{v}} }}{{\phi _{\text{f}} }}$$

(20)