Exploring the Possibilities of Delivering Peptides using Inhalation Therapy

Proteins and peptides, including hormones, monoclonal antibodies, cytokines, vaccines, enzymes and nucleotides, constituted nearly 30% of new molecules approved by the US Food and Drug Administration between 2017–2019. These biological drugs with large molecular size and high polarity, are largely administered parenterally due to their poor permeability through the intestinal epithelium and to avoid enzymatic degradation in the gastrointestinal tract. But injectable drugs intended for chronic therapy maybe inconvenient for patients. Many other alternate routes of delivery for biologics have been explored, of which inhalation, in particular has emerged as an attractive one. Although inhalation therapy has been used traditionally to mostly treat respiratory conditions,in recent times the use of pulmonary drug delivery as a non-invasive route for treating systemic diseases has witnessed an increased interest.  

Pulmonary delivery helps bypass the gastrointestinal tract and first-pass metabolism 

allowing fast absorption and is suitable for both local and systemic delivery of macromolecules. It presents a large surface area and an extensive vasculature of the lung. Self-administration and better patient compliance can also be achieved through this route of drug delivery. 


Choosing the Right Inhalation Device 

The various known inhalation technologies include nebulizers, dry powder inhalers (DPIs) and metered dose inhalers (MDIs). Nebulisers have low delivery efficiency, need long administration time, show poor reproducibility and have high costs of device maintenance. MDIs on the other hand use harsh propellants or water (when formulated as aqueous suspension). This can promote protein degradation.  Dry powders on the other hand are significantly advantageous since they are solid and therefore quite stable. Unlike the other inhalation devices, DPI inhalers require minimum patient coordination between breathing and actuation of the device to deliver powder medications. DPIs are, therefore, highly preferred for inhalational delivery of proteins/peptides.  

DPIs are formulated as unit or multi-dose reservoirs and administered using suitable inhalers. However, the possibility of moisture ingress in the enclosed powders due to inefficient sealing between the metering valves in multi-dose reservoirs may render them unsuitable for proteins/peptides as they are prone to degradation in the presence of moisture. In unit-dose approach, individual doses are enclosed in capsules or blisters and in case of capsule based DPIs, further packaging in foil blisters is advocated for enhanced protection. The ease of manufacturing, filling and administration makes the capsule-based DPI a more viable option for protein/peptide delivery. 


Factors to Consider for Developing An Effective Inhalation Formulation  

An effective inhaler system should be capable of reproducible dosing, demonstrate chemical and physical stability, allow controlled inhalation of dose, and contain effective particle size to reach the target region. There are however a few barriers impacting the therapeutic efficacy of inhaled formulations.  

(1) The defence mechanisms of the respiratory system such as the airways, humidity, mucociliary clearance and alveolar macrophages can pose critical challenges to the therapeutic efficiency of inhaled formulations. Especially for systemic therapy, it is necessary for the inhaled biologics to be able to cross the lung epithelium and enter the blood circulation in adequate levels to elicit the desired pharmacological effect.  

(2) The particle size of the drug should be suitable for inhalation. 

(3) Biologic drugs are highly susceptible to degradation even under mild stress conditions which can adversely affect the safety and efficacy of the drug. They should be able to withstand the stress during processing, aerosolisation and transportation.


Anatomical Barriers 

For adequate absorption of the drug, the inhaled particles must dissolve and release the active drug. However, the amount of fluid in the lung for particle dissolution is limited and is estimated to be around 10 to 30 ml. It is therefore difficult to predict the volume of fluid that is available for the dissolution of the inhaled particle after deposition. Moreover, the extensive branching of the lung can also be a barrier to the desired deposition of inhaled particles. As the airways get narrower and become smaller in diameter, the fluid lining layer of the lung becomes thinner until it reaches the alveoli. As a result, particles deposited in the upper airways dissolve faster than those in alveolar space. Once dissolved in the fluid, the drugs either act on the surface of the epithelial cells or are taken up by the cells from where they are absorbed into the systemic circulation. If biological drugs are intended for systemic action, the drug molecules must enter the systemic circulation besides showing adequate particle deposition and dissolution. However, here the pulmonary epithelium becomes a barrier for the transportation of these drugs to the bloodstream. 

Factors that determine the efficiency and the site of deposition of aerosol particles in the lung are their physicochemical properties which include the aerodynamic particle size (Dae), shape, charge, hygroscopicity and density. Generally, particles with Dae between 1 and 5 µm are deposited in the lower respiratory tract. 


Processing Methods 

A suitable method for drying must be employed for biologics to produce particles with good aerosol property while also preserving the integrity of the drugs. Milling, a commonly used technique for producing inhalable dry powders may not be suitable for biologics since they are fragile molecules that are prone to degradation. Spray drying is a single-step particle processing technique in the pharmaceutical industry and has been used to manufacture inhalable dried powders of biologics. In this method, the liquid feed is atomised into a hot drying gas where the solvent is evaporated to produce dried particles. Since thermal stress and high shear force can cause denaturation of proteins, stabilising excipients can be added to retain the structural stability and bioactivity of biologics. Sugars are commonly used as protective excipients in such formulations. Spray freeze drying is another drying technique which combines both spray drying and freeze drying where a liquid is atomised into a cryogen and then lyophilised. This method is not as commonly used as spray drying due to scale-up challenges. 



Enhanced stability and ease of administration makes DPI a suitable delivery approach for therapeutic proteins and peptides. Retaining structural integrity and activity of these biological macromolecules during formulation and processing, choosing the right inhalation strategy and process, are some of the key factors to consider while developing successful, non-invasive inhalation systems for protein and peptide delivery. This can be an opportunity to develop innovative products by using traditional inhalation techniques to repurpose existing biopharmaceuticals. 

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