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Preformulation for Lung Delivery

Welcome to My Blog series in preformulation for drug development

In this seventh blog on preformulation, I will talk about preformulation for lung delivery. The airways are the port of entry of viruses and bacteria, but also the route of administration of medicines. The major lung diseases are Asthma, COPD, and Cystic Fibrosis. To develop a drug product (DP) for lung delivery one needs to understand the physiology of the lung and the requirements for stabilization and aerodynamics of DP in that environment. Stay tuned for more blogs and follow

Physiology of the lungs

The lungs have the largest surface area in the human body (~100 m^2 of the gaseous exchange surface of the alveoli). The primary task of the lungs is respiration and metabolism. The pH of the lung is 7.0 – 7.2 (very narrow to maintain respiration) that needs to be taken into consideration when developing a drug product for this route of administration. There are four buffer equilibria that occur in the lung, hemoglobin, oxyhemoglobin, phosphoric acid, and carbonic acid ionizations. All ionized forms dissociate according to their equilibrium constants. Ionized hemoglobin picks up an oxygen molecule in erythrocytes and dissociate to liberate oxyhemoglobin and a proton. The ionized oxyhemoglobin, by liberating a proton, will move the equilibrium of the formation of carbonic acid to the left, to release carbon dioxide, which will pass through the alveolar lumen and exhaled through respiration.

The lungs have low buffering capacity that is important to maintain respiration. The lining fluid volume of a 70 kg human is 10 – 30 mL. The epithelium fluid thickness is 7 – 70 nm. This is important for the development of formulations for respiratory diseases, especially when you need to achieve a dissolution of a solid formulation in that layer of fluid. There are a multitude of respiratory diseases including inflammatory, obstructive, restrictive, respiratory track infections, pleural cavity, pulmonary vascular, and neonatal diseases.

Each of these diseases need a different approach for formulation development. The strategy is to develop a stable and a biopharmaceutical suitable dosage form that meet regulatory requirements. Many guidelines are stricter than for other route of administration like the limit for heavy metals.

Physicochemical properties relevant to lung delivery


The solubility of the API is one of the most important physicochemical properties that need to be taken into consideration when developing a drug product. The inhalations drug delivery uses either solid particles in aerosol formulations or nebulizers. In either of them the aim is to maintain the API in the desired physical state, solid state or in solution. Therefore, the target formulation is different.

As mentioned in the previous blogs, solubility can be defined as an apparent or equilibrium solubility. The crystal modifications play an important role and thus, the importance of polymorph screening in early stage of drug development.

The concept of solubility product, Ksp defined as the molar product of the ion species is used to desolubilize the API by adding common ions in the formulation by lowering the Ksp. For nebulizers, where you need the API in solution, the main emphasis is on the stability in solution for the final formulation. The solid-state properties are important only for the storage stability of the API, usually for 6 months.

The feedback to the drug discovery team needs to include the chois of the right pKa and right salt as follows:

· The right pKa for API (pKa (base)>8)

· The counterion should yield a strong crystal; the pKa’ (acid) ≤ pKa - 3

· If the pKa is < 7.0, the (acid) counterion should not yield a pH<2 at the delivered dose; the API could precipitate at pH 7.0> < 2 at the delivered dose that may cause post inhalation cough; the API could precipitate at pH 7.0.

· Do not use methane or benzene sulfonates; there are genotoxic alerts on their methyl, ethyl, and propyl esters (ICH M7).

· Most weak acid APIs are carboxylates (pKa~4.5); Ca-salts are less soluble!

Solid state properties

Due to the importance of the solid-state properties for dry powder inhalers, the analytical methods need to include additional tests and validations. The methods need to include but not limited to:

· Particle size distribution, PSD, where the aerosols DV(50) = 1 – 5 microns

· Differential scanning calorimetry, DSC, where the glass transition temperature, Tg, plays an important role in the drug stabilization. As a rule of thumb, the glass transition temperature should be 20 degrees higher than the spray dryer outlet temperature.

· Thermo gravimetric analysis, DSC for loss of volatiles

· X-ray powder diffraction, XRPD for polymorph and amorphous content

· Scanning electron microscopy, SEM for particle morphology

· Karl Fischer titration, KF for water content

· Dynamic water sorption (gravimetric), DVS for hygroscopicity

Each type of formulation may require different solid-state specifications to achieve the right target product profile. Sometimes it is a compromise between stability and deliverability, but ultimately the performance of the drug product will dictate the final formulation.

Biomolecules as medicines can be delivered by inhalation

Proteins and polynucleotides are administered as medicines. They are mostly derived from recombinant genes expressed in living cells, mammalian or microbial. Biomolecules are highly specific drugs, able to hit disease targets within the body that traditional chemical drugs cannot easily hit. However, the biologics are more sensitive than the small molecules and additional precautions need to be put in place during manufacturing and storage.

The physical instability includes aggregation, denaturation, precipitation, and surface adsorption, whereas the chemical instability is more complex and must address deamidation (Asn and Gln), racemization (Asn), isomerization (Asp), oxidation (Cys, Met, Tyr, Trp, Phe), di-sulfide scrambling (Cys), β- elimination (Cys, Ser, Thr, Lys, Phe), hydrolysis, and glycation. All these liabilities are dependent of the molecule, and some will be more important than the others. To fully understand the API, it is very important to perform forced degradation studies as described in my previous blogs on preformulation. Of most importance is the aggregation of proteins that can cause immunogenicity, highly scrutinized by FDA and other regulatory agencies.

Evolution of dry powder formulations improved lung delivery efficiency

The dry powder formulations evolved from micronized API in lactose blends in the 1970s (still present today), to engineered lactose through passivation or corrosion in the 19080s, to forced controlled additives like leucine, Aerocine (sublimed leucine) and magnesium stearate in the 1990s, to engineered particles like PulmoSphere and PulmoSol and AIR particles in the 2000s. New excipients were added to the family of the dry powder inhalers and the drug performance has significantly increased with the new technologies.

Lung Surfactants

The drug excipient compatibility was addressed in my previous blogs and can be applied to the formulation strategies for inhalation. However, one of the classes of excipients that is specific to the lung delivery is the lung surfactants. They include animal derived surfactants and synthetic pulmonary surfactants.

Animal derived surfactants

· Alveofact - extracted from cow lung lavage fluid

· Curosurf - extracted from material derived from minced pig lung

· Infasurf - extracted from calf lung lavage fluid

· Survanta - extracted from minced cow lung + DPPC, palmitic acid and tripalmitin

Note: Exosurf, Curosurf, Infasurf, and Survanta are currently FDA approved for use in the U.S

Synthetic pulmonary surfactants

· Exosurf - DPPC with hexadecanol and tyloxapol added as spreading agents

· Pumactant (Artificial Lung Expanding Compound or ALEC) - a mixture of DPPC and PG

· KL-4 - composed of DPPC, palmitoyl-oleoyl phosphatidyl glycerol, and palmitic acid, combined with a 21 amino acid synthetic peptide that mimics the structural characteristics of SP-B.

· Venticute - DPPC, PG, palmitic acid, and recombinant SP-C (phospholipoprotein)

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