Increasing Duration Of Therapeutic Action The Case For Nanoparticles

Various attempts to achieve sustained drug action in the lungs following drug deposition via aerosol have led to promising results in animals but so far disappointing results in humans. These include the use of liposomes [19], polymers [20], and surfactants [21] and the modulation of particle size through the lowering of particle density [22]. Among the factors working against long action of drugs in the lungs are natural clearance mechanisms related to airway mucocilia and macrophages that remove drug particles within less than a day after deposition.

A 2002 study [6] that may point the way to solving the lung clearance problem involved the production of dry powder aerosol particles of aerodynamic diameter 1-5 microns that dissolve in the lungs into polymeric nanoparticles capable of releasing drug over long periods of time. The goal of the "Trojan" particles (i.e., particles designed to efficiently deliver to the lungs particles possessing dimensions and mass too small to otherwise deposit effectively in the lungs) is to aerosolize effectively from a simple inhaler in a dry powder form and then to release particles whose dimensions are sufficiently small to avoid mucociliary and phagocytic clearance until the particles have delivered their therapeutic payload. The hypothesis of this new drug delivery system is that, since nano-, or "ultrafine", particles, once deposited, often remain in the lung-lining fluid until dissolution (assuming they are soluble), escaping both phagocytic and mucociliary clearance mechanisms [23,24], deposition of drug-bearing nanoparticles in the lungs may offer the potential for sustained drug action and release throughout the lumen of the lungs.

The particles were made by spray-drying of an ethanol-water cosolvent into the form of large porous particles, characterized by geometric sizes greater than 5 mm and mass densities around 0.1g/cm3 or less, this physical structure having achieved recent popularity as carriers of drugs to the lungs for local and systemic applications [25].

Figure 2 illustrates the kinds of particles made in this study. Here, polystyrene nanoparticles (170-nm diameter) were prepared in an ethanol cosolvent and spray-dried to produce large thin-walled particles with a wall thickness of approximately 400 nm, or 3 layers of nanoparticles. The study showed that such particles aerosolize effectively from a small inhaler and redisperse into nanoparticles once in solution. Nanoparticle aggregates were made with a variety of different materials and through many different spray-drying conditions, suggesting that these large porous nanoparticle systems are robust and functional as aerosols.

Figure 2 A hollow "Trojan" particle formed of polystryrene nanoparticles that spontaneously assemble into ordered arrays following spray-drying from a colloidal suspension. This particle, shown at two different magnifications, is sufficiently large and massive to enter the lungs and deposit prior to exhalation. Upon deposition, the particle can dissolve into nanoparticles, which by virtue of their small size can avoid the lungs' natural clearance systems (phagocytosis and mucociliary clearance). Such "large porous nanoparticle" (LPNP) aggregates may provide an important new drug delivery system for the sustained release of drugs for diseases such as asthma, chronic obstructive pulmonary disease, and tuberculosis. (From Ref. 6.)

Figure 2 A hollow "Trojan" particle formed of polystryrene nanoparticles that spontaneously assemble into ordered arrays following spray-drying from a colloidal suspension. This particle, shown at two different magnifications, is sufficiently large and massive to enter the lungs and deposit prior to exhalation. Upon deposition, the particle can dissolve into nanoparticles, which by virtue of their small size can avoid the lungs' natural clearance systems (phagocytosis and mucociliary clearance). Such "large porous nanoparticle" (LPNP) aggregates may provide an important new drug delivery system for the sustained release of drugs for diseases such as asthma, chronic obstructive pulmonary disease, and tuberculosis. (From Ref. 6.)

The authors did not, however, incorporate drug into their particles or examine drug delivery properties in an animal model, thus it remains to be seen how effective these particles will be at actually achieving sustained drug release in the lungs. It is probable that the "noncleared" lifetime of the particles following deposition in the lungs will be highly dependent on the actual size of the nanoparticles; i.e., that smaller nanoparticle size will translate into longer potential lifetime in the lungs. However, achieving sustained drug release from very small particles is extremely challenging, particularly given the relative shortness of diffusion path lengths involved. Moreover, high drug load will also work against sustained release of drugs. Thus these large porous nanoparticle delivery systems will almost certainly have an optimal "duration of action" window, driven largely by nanoparticle size and drug load, though lacking experimental release data it is hard to know what this window of duration will actually be.

In any case such novel "Trojan" particle systems open up a new avenue of material property research for inhaled drug delivery systems and may help progress the goal of achieving long-action therapies through inhalation, for important diseases such as tuberculosis and diabetes.

Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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