An Overview of NanoCluster Powder Formulation Technology - Pharmaceutical Technology

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An Overview of NanoCluster Powder Formulation Technology
The authors describe a technique designed to yield low-density powders with a tailored particle-size distribution over a broad range of respiratory flow rates.


Pharmaceutical Technology
Volume 10, Issue 34, pp. 72-78

Another technique of aerosol generation for pulmonary delivery is thermal or condensation aerosols. Gupta et al. generated deoxycorticosterone, benzil, and phenyl-salicylate aerosols by a thermomechanical process without using propellants (11). The drug and excipients remained in a heated stainless-steel capillary for a short time, were vaporized, and condensed to form a low-velocity, drug-containing aerosol stream. The system can be configured to create various particle sizes from 1 to 5 m, and even nanoparticles smaller than 100 nm (11, 12). In another approach to thermal aerosol generation, a solid thin film of a drug is vaporized under controlled heating conditions, and the vapor mixed with an air stream to form aerosol particles with a MMAD of 1–3 m (13, 14).

Thermally generated aerosols depend upon the volatility of the drug substance. The drug substance should have high vapor pressure when heated so that it vaporizes off the surface before degrading. Degradation through drug pyrolysis or oxidation is a concern with thermally generated aerosols, but it can be mitigated by rapid heating and short exposure to the heating source. Temperature, heating rate, and airflow rate can be controlled electronically by incorporating circuits and sensors into the inhaler. Thus, these devices are more costly than most dry-powder inhalers, particularly for single-dose applications.

Savara Pharmaceuticals's (Austin, TX) NanoCluster technology yields low-density powders with a tailored particle-size distribution and an aerodynamic performance that is consistent over a broad range of respiratory flow rates. NanoCluster powders are produced using standard, commercially available processing equipment, thus offering a simple, scalable manufacturing process. NanoCluster powders have been prepared with less than 5% excipient and, in many cases, can be prepared without excipients.

Formulation

Formulation of particles in the 1–3-m size range previously has required difficult approaches or complex delivery devices. In addition, such particles can be difficult to produce consistently and can require carrier particles because the micronized drug particles have poor flow characteristics. The only currently approved inhalation product capable of being delivered consistently as 1–3-m particles is formulated for delivery by a pressurized metered dose inhaler (pMDI). In a pMDI, the active ingredient is dissolved or suspended in the propellant, and the interaction between the propelled liquid and aerosol valve determines the size of the delivered particle.

An example of such a drug product is Teva's (Petach Tikva, Israel) QVAR (beclomethasone). QVAR, with a particle size in the 1–3 m range, consistently reaches the peripheral lung, thus providing an improved therapeutic outcome (15). In comparison, other products with the same active ingredient but with a particle size of 4–5 m are unable to reach the distal airways (16). In addition, few technologies produce consistent and cost-effective inhalation powders suitable for delivering drugs to the peripheral lung using dry powder inhalers (DPIs) or nebulizers.


Figure 1: The micrometer-sized superstructure of an example NanoCluster (Savara Pharmaceuticals, Austin, TX) is composed of nanosized substructures. ALL FIGURES ARE COURESTY OF THE AUTHORS.
NanoCluster technology produces particles suitably sized and shaped for delivery to the distal airways through nebulizers, DPIs, and pMDIs without the need for carrier particles. The NanoCluster technology uses a bottom-up approach in which individual nanometer-sized drug particles are building blocks that form agglomerates with the desired MMAD (e.g., 1 m for treating distal airways or 5 m for treating upper airways). NanoClusters possess a micrometer-sized superstructure that comprises a nanosized substructure (see Figure 1). By agglomerating nanoparticles under controlled process conditions, scientists can give NanoClusters the desired physical and chemical characteristics. The literature describes solid-state characteristics, morphology, geometric particle size, and MMAD of various NanoCluster formulations (17–19). NanoClusters exhibit customizable aerodynamic sizes and excellent solubility by virtue of their relatively large surface area. In addition, the irregular shape of the NanoClusters decreases their contact area with device surfaces, thus resulting in superior flow properties.


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