I have previously talked about spray-drying nucleic acids and their role in gene therapy , which is used to create effective delivery systems for pDNA and siRNA therapy. Gene therapy is achieved by transfecting cells with an encapsulated plasmid DNA (pDNA) that must enter the nucleus to replace a defective gene. RNA is also used to silence harmful genes whereby the siRNA travels to the cytoplasm and induces degradation of its complementary mRNA to prevent the synthesis of a targeted protein. Most of the research on producing effective delivery systems for gene therapy and numerous other medicines focuses on inhalable dry powder for lung delivery. Today I would like to focus on the importance of inhalable drugs and talk about the role spray-drying plays in their creation. There’s a lot to absorb, so take a deep breath and read on!

There’s little I enjoy more than hiking in the mountains and getting a lung full of fresh air. More than a lung full, in fact, as the average person inhales 7 to 8 liters of air per minute, which equates to about 11,000 liters per day. This unconscious process of inhalation and exhalation is vital to our health and ensures that the body’s cells receive the oxygen they need to function. The lungs absorb oxygen through a process called gas exchange which takes place in the millions of tiny air sacs in the lungs known as alveoli. There are so many alveoli that if you were to spread them out flat, they would cover an area nearly the size of a tennis court. When we inhale, air travels down our trachea (windpipe) and into our lungs via two tubes called bronchi, which branch out into smaller bronchioles and end in tiny clusters of alveoli. Each alveolus is surrounded by a network of tiny blood vessels called capillaries. The walls of the alveoli are about 1/50^th the thickness of a human hair, allowing gases to pass through them into the blood in the capillaries. The oxygen that enters the blood binds to the hemoglobin and is transported by the heart to all the cells in the body. Drug manufacturers have exploited this efficient and effective transportation system by creating inhalable dry powder drugs (generally less than 5 micrometers in diameter) small enough to pass through the upper respiratory tract and the bronchial tubes. After the particles have been deposited in the lungs, they need to dissolve in the thin layer lining the alveoli, where they can then be absorbed into the bloodstream. Once in the bloodstream, it can be transported to its target site, and eventually, the drug is metabolized and eliminated from the body, often through the liver and kidneys.

 

“Inhalable dry powder drugs (generally less than 5 μm in diameter) are small enough to pass through the upper respiratory tract before dissolving in the thin layer lining the alveoli, where they can be absorbed into the bloodstream”.

 

As I’m sure you can imagine, creating particles small enough to traverse this network of tubes is no simple task; however, several advantages to this delivery system make it worth the effort. The lungs are the ideal transportation system for problems that need immediate remedy, such as an asthma attack. Drugs that are taken orally have to pass through the digestive system before becoming effective; there is also a loss of active ingredients during this process. There are delivery systems that are easier to design and manufacture, but they come with drawbacks. Viral delivery systems are simple, and their biggest advantage is their high transfection efficiency in human tissue; however, the toxicity of viruses can trigger immune responses, and pre-existing antibodies can neutralize the delivery system and the molecules it carries, reducing the efficiency of the therapy. Non-viral delivery systems have been used to circumvent these issues. Lipid-, polymer-, and peptide-based systems can be modified to improve biocompatibility, increase internalization, and tailor the exact requirements for drug delivery. These types of materials are used in the formulation of drug particles and used to encapsulate or carry the drug, protect it from degradation, and enhance its absorption in the lungs, playing the role the virus does in viral delivery systems. One of the most common excipients for dry powder lung delivery is lactose.

 

“Lipid-, polymer-, and peptide-based systems can be modified to improve biocompatibility, increase internalization, and tailor the exact requirements for drug delivery”.

 

Lactose has several advantageous material properties that make it ideal for inhalable drugs. It is an FDA-approved carrier due to its non-toxic and readily degradable properties after administration. Other FDA-approved carriers include leucine, mannitol, glucose, trehalose, and sucrose. Lactose is ideal as it is less sticky than other sugars and has a higher glass transition temperature, enabling an easy-flowing powder when spray-dried. Aerosolization is used to create a range of inhalable powders, including peptides, antibiotics, vaccines, and biodegradable carrier particles. These drugs can target ailments all over the body, but they can be particularly beneficial for lung-specific applications to treat cystic fibrosis, asthma, chronic pulmonary infections, lung cancer, and tuberculosis. The creation of inhalable drugs using the spray-drying technique involves preparing aqueous solutions by dissolving an active ingredient (drug, nanoparticles) and an excipient (lactose or others) in water at different solid concentrations. Occasionally ethanol is added to the solution to enhance evaporation. The resultant spray-dried powder is separated by a cyclone and collected in a vessel. There are several commonly applied analytical methods used to characterize spray-dried powders, such as:

 

SEM                                       Particle morphology and size

Laser Diffraction                Particle size

Anderson Impactor           Fine particle fraction

X-Ray Diffraction                Amorphous/crystalline state

DSC                                        Glass transition temperature

Gas adsorption                   Mass specific surface area

Karl Fisher                           Moisture content

 

“The creation of inhalable drugs using the spray-drying technique involves preparing aqueous solutions by dissolving an active ingredient (drug, nanoparticles) and an excipient (lactose or others) in water at different solid concentrations”.

 

There are other means of creating inhalable drugs for pulmonary applications, such as freeze-drying and jet-milling; however, spray drying has many advantages over these methods. It is possible to generate highly dispersible powders without the need for the carrier particles required when freeze-drying. The jet milling process creates flat particles with poor flow properties. Jet-milled lactose has a crystalline structure, whereas spray-dried lactose is amorphous. Amorphous composites are attributed to the rapid drying process that leaves little time for evaporation and solid phase formation. The spherical particles made possible with spray-drying have a low contact area and homogeneous particle size distribution resulting in an increased respirable fraction. Spray drying is also a cost-effective one-step process going directly from liquid to dry formulations with high scale-up capability.

 

“The spherical particles made possible with spray-drying have a low contact area and homogeneous particle size distribution resulting in an increased respirable fraction”.

 

Four strategies exist for creating dry powder formulations. The first is small carrier-free drug particles, which are aerosol powders ranging from 1 to 5 μm and the optimum size for deposition beyond increasingly narrow airways. Such small particles, however, often stick together and are very cohesive with poor flow properties. This is overcome by using small drugs and larger carrier particles that improve flow through the inhaler. As already mentioned, lactose is the most commonly used carrier, often designed to have a size of 50 μm to 80 μm. During inhalation, the smaller particles separate from the carrier particles and are deposited in the alveoli. The third strategy was a breakthrough in inhaled dry powder aerosol research and involved large porous drug particles (>5 μm) with low mass density (<0.4 g/cm). Designed as an alternative to the first strategy, these larger particles aggregate and disaggregate more easily, have better flowability, and can evade the phagocytic clearance mechanism in the lungs. The last strategy is to use encapsulated nanoparticle drugs in carrier particles, and has become the subject of a wealth of research. Nanomedicine is an emerging field in the biomedical sciences, and the proposal for pulmonary administration has been suggested due to the aforementioned benefits of lung drug delivery. The small particle size, however, limits lung deposition causing them to be exhaled from the lungs after inhalation. Incorporating nanoparticles into carrier particles through spray-drying makes their use for pulmonary drug delivery viable. The versatility of spray drying and the high degree of control over the method make each strategy possible, and given the advantages of inhalable drugs over other, more invasive means of delivery, I look forward to seeing what the future brings.

Till next time,