INTRODUCTION:

Inhalation therapies have a rich history, dating back to ancient times, possibly originating with the use of Datura preparations in ancient India around 4,000 years ago^1,2. During the late 18th and 19th centuries, the popularity of earthenware inhalers for inhaling plant-extract-infused air emerged³. The development of atomizers and nebulizers in mid-19th-century France was influenced by the perfume industry and the trend of inhaling thermal waters at spas. By the early 20th century, combustible powders and cigarettes containing stramonium were commonly used to address asthma and respiratory issues^4,5,6.

Following the discovery of the efficacy of epinephrine in treating asthma, hand-bulb nebulizers and early compressor nebulizers were developed⁷. A significant milestone occurred in 1956 with the marketing of the first pressurized-dose inhaler for epinephrine and isoproterenol, marking a crucial step in inhaled drug development⁸. Over the past 50 years, remarkable progress has been made in the technology of devices and formulations for inhaled drugs. Scientific advancements in theoretical modelling, indirect lung deposition measurements, particle sizing, scintigraphic deposition studies, pharmacokinetics, pharmacodynamics, and the 1987 Montreal Protocol (which banned chlorofluorocarbon propellants) have significantly influenced these developments⁹. We are currently witnessing a period of rapid technological advancement in inhaled drug delivery, incorporating aerosol science into various devices, including nebulizers, metered-dose inhalers, and dry powder inhalers (DPIs). These advancements have resulted in improved drug delivery efficiency, increased patient convenience, and better treatment outcomes. The integration of smart technology and connectivity features in inhalation devices has opened up new possibilities for personalized medicine and remote patient monitoring^1,10,11. The objective of this review article is to provide a comprehensive and detailed exploration of the historical evolution and advancements in inhalation therapy¹².

Exploration of early inhalation therapy:

In his 1778 publication, English physician John Mudge described the fabrication of an inhaler with a pewter tank. Dr.Mudge is credited with coining the word "inhaler" and describing how he used his contraption to inhale opium vapor to treat coughs¹⁶. As a result, several porcelain inhaler models influenced by Mudge's design were popular beginning in the nineteenth century. These inhalers worked by pulling air through warm water or an infusion before inhaling. One prominent variant, the Nelson's inhaler, manufactured by S. Maw and Son in London, was mentioned in a Lancet article in 1863. The Nelson's inhaler became widely used and was praised for its effectiveness in delivering medication directly to the lungs. The popularity of porcelain inhalers continued to grow throughout the nineteenth century, with various designs and improvements being made to enhance their functionality and ease of use¹⁷.

Fig 1. Mudge Inhaler

Fig 2. Nelson Inhaler

Historical Evolution of Inhalation Therapy:

Atomizer:

In the mid-nineteenth century, atomizers, also known as nebulizers, were introduced in France as a development influenced by the perfume industry and the prevalent practice of inhaling thermal water at spas. Dr. Auphon Euget-Les Ban is credited with inventing the atomizer in 1849, and later in 1858, Jean Sales-Girons introduced the portable nebulizer. Dr. Sale-Girons was honored with the Paris Academy of Science's silver prize in 1858 for his innovative devices, which incorporated a pump handle to draw liquid from a reservoir and propel it through a nozzle against a plate⁶.

Aerosol:

Throughout the twentieth century, inhaled medicine delivery underwent significant advancements spurred by scientific progress. In the early 1900s, the impetus for research on respiratory tract and particle deposition measurements did not originate from the medical field but rather from chemists investigating toxic aerosols used in warfare during and after World War I¹⁹. Over time, technological improvements and an enhanced understanding of aerosol dynamics have resulted in more precise and targeted delivery methods, thereby enhancing the efficacy of inhaled medications for a range of respiratory conditions^10,20. The researcher uses a basic nine-generation lung model in his work, which purposefully leaves out the upper airway and places emphasis on deposition mechanisms such as Brownian diffusion, impaction, and sedimentation.. Building upon Findeisen's model, Landahl enhances it by introducing features such as a mouth and pharynx, alveolar duct formation, and diverse breathing scenarios ^21,22The MPPD model incorporates upper airways and factors in variables like age, gender, and breathing patterns to estimate particle deposition across various regions of the lung^23,24.

Traditional meter Dose inhaler (MDI’s):

In 1948, Abbott Laboratories introduced the Aerohaler, an inhaler designed for inhaling penicillin-G powder to dispense the powder, users would strike the cartridge, with instructions explicitly cautioning against breathing into the device. Abbott Laboratories also utilized the Aerohaler to administer norisodrine powder as an asthma therapy during the 1950s^6,25,26,27. The landscape of inhaler design underwent a revolutionary transformation with the invention of pressurized metered dose inhalers (pMDIs). In 1955, Dr. George Maison, President of River Lab, spurred by the recommendation of his teenage daughter who suffered from asthma, championed the development of the Pmdi²⁸. This innovation significantly improved ease of use and safety for patients when administering their medication²⁹.

Fig 3. Meter Dose Inhaler (MDIs)

Discovery of Dry powder inhaler (DPI’s):

In 1977, Glaxo introduced the RotaHaler along with albuterol, while Fisons introduced the Spin Haler for chromyl in 1971, representing early examples of dry powder inhalers (DPIs)³⁰. These devices marked a notable advancement in inhalation therapy during that period. In contrast to the success of DPIs, the ultrasonic nebulizer, utilizing a transducer composed of a piezoelectric crystal, did not achieve comparable economic success. The advancements in inhalation therapy during that time period were crucial to improving patient care and overall treatment outcomes^31,32.

Type of dry powder inhaler:

a. Unit Dose Inhaler

b. Multi Dose Inhaler

a. Unit Dose Inhaler:

The technique commonly employed for single-dose Dry Powder Inhalers (DPIs) involves the utilization of a capsule within the DPI containing powdered medication. The apparatus facilitates the opening of this capsule, enabling the inhalation of the powder³³. Subsequent to the inhalation of the powder from the capsule, it is necessary to discard the used capsule³⁴. For the next dosage, a fresh capsule must be inserted into the apparatus, ensuring the continuous and effective administration of medication. This approach is a standard and widely practiced method for the administration of powdered medication through DPIs, allowing for precise and controlled dosing for respiratory conditions³⁵. Overall, this method allows for efficient and accurate delivery of powdered medication for respiratory conditions³⁶.

b. Multi Dose Inhaler:

By oscillating the base of the device back and forth, the drug formulation is dispensed into the dosage chamber from the storage reservoir.

Fig 4. Unit Dose Inhaler andMulti Dose Inhaler

This process occurs after placing the drug formulation into the storage reservoir. In comparison to unit-dose devices that operate at a moderate flow rate and distribute particles containing lactose and carriers, this particular device presents distinct advantages^37,38. Additionally, by minimizing the use of lactose and carriers, this device reduces the risk of potential side effects or allergic reactions for individuals with respiratory conditions^32,39.

Metered Dose Inhalers (MDI’s):

The primary approach to managing acute episodes of asthma and chronic obstructive pulmonary disease (COPD) involves the use of inhaled short-acting beta-agonists^40,41,42. While there is currently no cure for these conditions, the administration of these medications plays a crucial role in controlling acute and intermittent symptoms, ultimately preventing fatalities. Following emergency room (ED) visits, it is recommended that patients receive a prescription for a Metered Dose Inhaler (MDI) along with proper usage instructions. However, the effectiveness of MDIs is contingent on the correct technique, and ED personnel may not always be adequately equipped to educate patients on their proper usage.^43,44,45. Regular cleaning and maintenance are essential for optimal MDI performance⁴⁶.

Challenges with Meter Dose Inhalers (MDI’s):

Managing Metered Dose Inhalers (MDIs) poses challenges, necessitating proper technique coordination between inhalation and device activation. Several major issues related to MDIs include coordination problems, propellant concerns, environmental impact, strength limitations, and incorrect techniques^32,48.

Coordination Issue:

Coordinating inhalation with precise MDI activation can be challenging, leading to inadequate medication delivery.

Propellant Concerns:

MDIs often use environmentally impactful propellants such as chlorofluorocarbons (CFCs) or hydrofluorocarbons (HFCs).

Environmental Impact:

MDI devices contribute to environmental pollution due to canister production and disposal.

Strength Limitation:

Some individuals, especially the elderly, may struggle with the force required to activate the MDI.

Incorrect Techniques:

Regular review and practice of correct usage are recommended.The transition from MDIs to Dry Powder Inhalers (DPIs) addresses coordination challenges, propellant reliance, and environmental concerns^49,50.

Emergence of Dry Powder Inhalers (DPIs):

Dry Powder Inhalers (DPIs) signify a substantial progression in inhalation therapy, providing numerous benefits compared to conventional Metered Dose Inhalers (MDIs).^46,51,52.

Technological Innovation in DPIs:

Dry powder inhalers (DPIs) have been technological innovation focused on improving drug delivery precision, ease of use and patient adherence. Advances include more efficient powder dispersion mechanisms, smart inhalers with. Sensors to track usage, and user-friendly design enhancement for better patient Experience^54,55.

a. Liposome Dry Powder:

Microspheres called liposomes are created from phospholipids. They serve as a slow-release reservoir, contain drug particles, and provide sustained drug release. A lipid bilayer surrounds the aqueous compartments in liposomes (56). In comparison to other drug formulations, liposomal formulations limit the entry of the drug into the systemic circulation, allowing the medicine to be distributed evenly throughout the lungs' airspace. They lead to a reduction in medicine dose frequency. They significantly raise the quality of life and lower medical expenses. In order to create a high-efficiency system for pulmonary drug administration, dry powder inhalers must be carefully constructed^57,58,59.

c. Chitosan Nanoparticle: Polymer Nano particulate systems offer a promising avenue for sustained medication activity and targeted drug delivery to the lungs (60). Effective deposition of substantial doses of inhaled nanoparticles, particularly in the lower lung regions, can be achieved by controlling breathing parameters and particle size. These nanoparticles possess the ability to evade mucociliary clearance and avoid identification by alveolar macrophages. Following pulmonary delivery via a Dry Powder Inhaler (DPI), nanoparticles have demonstrated sustained drug release⁶¹. Chitosan's positive charge has been found to enhance medication absorption by loosening the intercellular tight junctions of the lung epithelium⁶².

d. Microspheres:

The term "micro particles" encompasses three primary categories, namely microspheres (uniformly dispersed spheres), microcapsules (featuring a central core encased in a polymeric membrane), and particles with undefined shapes⁶³. Microspheres, a subtype, can hold both hydrophilic and hydrophobic drug molecules, increasing physicochemical stability by protecting the drug from enzymatic degradation and allowing for continuous drug release⁶⁴. The morphological characteristics of microspheres, including shape and size, are easily modifiable to meet specific requirements.⁶⁵. Certain polymers, such as highly viscous hydroxypropylcellulose (HPC), employed in microsphere formulation exhibit mucoadhesive properties, prolonging lung retention duration and reducing mucociliary clearance.⁶⁶

d. Polymeric Micelles: Polymeric micelles (PMs) have garnered increased attention recently as potential delivery systems for poorly soluble medications. These amphiphilic copolymer-based nanoscopic delivery systems, ranging in size from 10 to 100nm, exhibit a core-shell architecture and hold significant promise for solubilizing and administering hydrophobic drugs in a controlled manner⁶⁷. Many efforts have been made to create novel polymeric amphiphiles; however, the stringent requirements for biocompatibility and biodegradability limit the number of viable polymer amphiphiles for use as drug delivery vehicles⁶⁸.

e. Solid Lipid Nanoparticles: Nanoparticles share characteristics with microparticles, where drug molecules are uniformly distributed on the matrix surface or encapsulated within the nanocarrier's core using biodegradable polymers, whether natural or synthetic. Both drug delivery and diagnostic applications have harnessed the potential of nanoparticle-based drug carriers. The utilization of mucoadhesive polymers in nanoparticle fabrication aims to extend the retention duration within the pulmonary mucosa and mitigate the impact of the mucociliary clearance mechanism, thereby improving bioavailability. Nevertheless, both in vitro and in vivo research has unveiled several limitations associated with polymeric micro- and nanoparticles⁶⁹.

Considerations of Transition⁷⁰:

Patient Education: Successful transition necessitates thorough patient education. Healthcare providers should provide clear instructions on how to use the new inhaler, emphasizing differences in technique and care. Visual aids, demonstration videos, and written instructions can enhance comprehension.

Device Demonstration:

Conducting live demonstrations with placebo devices helps patients practice the correct inhalation technique (71)(54). Reinforce the importance of a forceful, deep inhalation for optimal drug deposition in the lungs.

Cleaning and Maintenance:

Educate patients on the cleaning and maintenance requirements specific to DPIs. While MDIs often require less maintenance, DPIs may need regular cleaning to prevent powder build-up and ensure consistent dosing.

Clinical efficiency across various respiratory conditions:

Assessment of Inhalation Technique:

Regular follow-up appointments allow healthcare providers to assess patients' inhalation techniques, address any concerns, and provide additional education if necessary.

Monitoring Response to Treatment:

Enebuvaluate patients for any changes in symptoms or exacerbations after the transition. Adjustments to the treatment plan may be needed based on the individual's response to the new inhalation device.In the end the transitioning from MDI to DPI involves careful conside ration of patient needs, education, and ongoing monitoring.^72,52.

Advances in Inhaler Devices:

Ideal featureof Inhaler Devices:

As previously observed, dry powder inhalers (DPIs) must meet specific requirements. A study by Kolewe et al. extensively explored aerosol deposition in the upper airways of paediatric subjects, spanning infants to 6-year-old children. This investigation centred on elucidating the interplay between parameters such as particle size, flow rate, and anatomical factors (e.g., glottis-to-cricoid ring diameter ratio, epiglottis angle, and sex) and their impact on aerosol deposition⁷³. The study revealed the significant influence of these parameters on paediatric airway deposition, underscoring the necessity for inhalation devices tailored to paediatric patients to accommodate anatomical and physiological differences⁷⁴. Furthermore, effective drug administration relies on the delivery of particles fine enough to deposit at intended respiratory sites. Consequently, both the powder formulation and the device's model and design play pivotal roles in meeting these requirements.

The optimal inhaler should adhere to specific standards and criteria encompassing ease of use, affordability, portability, and drug stability. Regardless of their designs, DPIs represent a notable advancement in inhalation therapy, fulfilling most criteria. They offer advantages over other inhaler types, achieving higher pulmonary deposition than pressurized metered-dose inhalers (pMDIs). The absence of propellants makes DPIs environmentally sustainable additionally, DPIs generally exhibit superior formulation stability, ensuring medication efficacy throughout their shelf life. However, DPIs face challenges such as variable deposition effectiveness, poor powder de-agglomeration, and dose uniformity issues, contributing to development and manufacturing complexities and higher costs.^35,75

Inhalation Therapy Innovations and Currently Marketed Inhalers:

In recent years, significant advancements have been achieved in inhalation delivery methods to enhance daily treatment routines, improve patient compliance (particularly by reducing dosage frequency), and optimize drug availability and delivery. Progress has been made in manufacturing processes, drug delivery strategies, and device enhancements. Notably, the use of lipid-based or polymer-based carriers in formulations, along with the incorporation of biotechnological drugs, exemplifies these developments. An illustration of this progress is Afrezza®, a dry powder inhaler (DPI) that delivers insulin and is specifically designed for both type 1 and type 2 diabetes.DPIs, as previously mentioned, present a promising avenue for administering biologics, encompassing proteins, nucleic acids, viruses (such as phage’s), and cells (e.g., attenuated bacterial cells like Bacille Calmette-Guérin—BCG for tuberculosis In the ever-evolving landscape of inhalation therapy, numerous DPIs are currently available on the market (Figure 5)⁷⁶.

Fig. 5: Examples of DPI devices that are currently on the market

This advancement results in greater drug deposition, with observations indicating over 50% lung deposition compared to the ≤20% achieved by older inhalers. Notably, certain DPIs are designed to accommodate high doses, as exemplified by Relenza® (zanamivir, 5 mg), Tobi Podhaler® (tobramycin, 28 mg), Bronchitol (40 mg, mannitol), and Osmohale® (mannitol)³⁹.

Challenges and Obstacles in DPI Development:

a. DPI design: The design of dry powder inhalers (DPIs) poses several challenges that need to be addressed(78). Presently available inhalers on the market exhibit efficiencies ranging from less than 10% to between 20% and 40%. However, less than half of the administered dose reaches the intended site of action. Therefore, the ultimate objective is to enhance the efficacy of DPIs and simultaneously reduce the cost associated with these devices⁷⁹.

b. Dry Powder Formulations: Despite years of investigation, the precise mechanisms governing powder cohesion and dispersion remain elusive. However, our understanding of the mixture properties and the intricacies of the mixing processes, which significantly impact the performance of the final formulation, remains inadequate⁸⁰.

c. Pulmonary Vaccination: Currently, the widespread trend in vaccine administration focuses on pulmonary delivery, presenting unique challenges. However, the use of such inhalers can be costly, and any failure in the administration of the dose poses a significant concern⁸¹.

d. Special Patient Groups: Ensuring patient compliance is of utmost importance in the accurate administration of drugs. Specific patient groups, such as small children and the elderly, may require specialized inhalers. Most dry powder inhalers (DPIs) available on the market are approved for children aged six years and older, primarily due to the limited clinical data available for younger children, especially those below the age of six. The feasibility of DPI usage in children under six has not been investigated.³².

e. Target site for inhaled drug: Consequently, a major challenge in the future development of DPIs lies in augmenting peripheral deposition. Addressing this challenge and focusing on improving peripheral depositionwill necessitate the implementation of innovative design strategies and formulation techniques to overcome the existing limitations⁸².

Feature Prospective and Emerging Technologies:

The future of inhalation therapy holds promising advancements across various fronts. In the realm of nanotechnology in drug delivery, prospective use involves harnessing nanotechnology to achieve targeted drug delivery, enhance efficacy, and minimize side effects. This approach is complemented by emerging applications, introducing nano-sized particles that promise improved deposition and enhanced bioavailability within the respiratory system⁷³. Another transformative prospect lies in smart inhalers with connectivity, where integration for real-time monitoring and personalized treatment plans is on the horizon. Continuous advancements in sensors and data analytics emerge as key components in enhancing patient adherence and optimizing treatment outcomes. Furthermore, the expansion of inhalers for delivering biologics and gene therapies represents a prospective breakthrough, with ongoing efforts to develop inhalable gene therapies and vaccines for respiratory conditions⁸¹. Innovations in 3D printing for inhaler design aim at customization, offering tailored devices to meet patient-specific needs for optimal drug delivery and comfort. A shift towards environmentally sustainable propellants is prospective, emphasizing a more eco-conscious approach, while exploring alternative propellant systems with reduced environmental impact is emerging⁸⁰. Artificial intelligence is set to play a crucial role in real-time treatment optimization, analysing inhalation patterns, predicting exacerbations, and suggesting personalized interventions⁸³. Advances in dry powder inhalers (DPIs) are anticipated, with prospective improvements in stability, dose accuracy, and lung deposition. The ongoing evolution of next-generation nebulizers encompasses continued improvements for efficient and targeted drug delivery, with emerging technologies like ultrasonic and vibrating mesh nebulizers offering precise and controlled aerosol generation⁸³.

CONCLUSION:

In conclusion, the presented review provides a thorough examination of the evolution of inhalation therapy, specifically tracing the shift from traditional Metered Dose Inhalers (MDIs) to contemporary Dry Powder Inhalers (DPIs). It emphasizes the significant global threat of respiratory infections to public health and explores the historical development of inhalation devices, ranging from early nebulizers to the challenges and advancements in MDIs, culminating in the emergence of DPIs. The review highlights the advantages of DPIs over MDIs, addressing technological innovations, improved patient experiences, and clinical efficiency across diverse respiratory conditions. Regulatory milestones and market dynamics are analysed, shedding light on changing preferences in the healthcare landscape. Additionally, challenges encountered in DPI development are discussed, offering insights into potential solutions. The article concludes by exploring future prospects in inhalation therapy, including emerging technologies and ongoing research. All aspects considered, this thorough assessment highlights the significant influence of switching to DPIs for respiratory medication delivery, making it an invaluable tool for academics, medical professionals, and business leaders navigating the developing field of inhalation therapy.

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Received on 04.02.2024 Revised on 10.06.2024

Accepted on 03.08.2024 Published on 20.01.2025

Available online from January 27, 2025

Research J. Pharmacy and Technology. 2025;18(1):436-444.

DOI: 10.52711/0974-360X.2025.00067

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

Sr. No.	Advantage	Description
1	Environmental Impact	DPIs address environmental concerns associated with MDIs by eliminating the need for propellants like chlorofluorocarbons (CFCs) or hydrofluoroalkanes (HFAs), providing a more environmentally friendly solution.
2	User-Friendly Design	DPIs are considered more user-friendly, especially for patients who may struggle with coordination. The breath-triggered activation mechanism simplifies usage, reducing the learning curve for patients.
3	Portability and Convenience	DPIs are more portable and convenient due to their compact design and lack of reliance on propellants. This makes them suitable for on-the-go use, promoting better adherence to medication regimens.
4	Coordination Independence	Unlike MDIs, DPIs do not require hand-actuation coordination with inhalation, making them advantageous for individuals with cognitive or motor coordination challenges.
5	Medication Stability	DPIs accommodate a broader range of medications, including those less stable in the presence of propellants. This expands the variety of drugs suitable for inhalation therapy.
6	Consistent Dosage Delivery	DPIs generally provide more consistent and reliable dosage delivery compared to MDIs, being less sensitive to variations in a patient's inhalation technique.
7	Longer Shelf Life	DPIs often have a longer shelf life than MDIs, reducing concerns about medication expiration for patients who use their inhalers less frequently.
8	Reduced Cleaning and Maintenance	DPIs typically require less frequent cleaning and maintenance than MDIs, simplifying overall device management for patients.
9	Variety of Designs	DPIs come in various designs, including single-dose and multi-dose formats, allowing healthcare providers to tailor the choice of inhaler to the specific needs and preferences of each patient.
10	Patient Preference and Adherence	Many patients prefer DPIs due to their simplicity, lack of propellants, and ease of use. Patient satisfaction and comfort with the inhaler device play a crucial role in treatment adherence and overall therapeutic success.
11	Technological Advancements	Ongoing technological advancements in DPI design, such as improvements in particle engineering and the development of smart inhalers, continue to enhance their efficacy for better monitoring and management of respiratory conditions⁵³.

Sr. No.	Type of Inhaler	Sensor System	Therapy Type	Mode of Action
1	Digital Inhaler Health System	Electromechanical sensors and microelectronics	Digital Health Monitoring	Monitors inhaler actuation, logs inhalations, saves patterns for treatment plans
2	Propeller Health Sensor	Attaches to conventional inhalers	Smart Inhaler Transformation	Passively tracks and records medication usage, sends data for analysis and sharing
3	Adherium’s Hailie®	Bluetooth sensors on standard inhalers	Cloud-Based Monitoring	Gathers inhaler use data, provides real-time feedback, aids in adherence monitoring
4	Smart DPIs and associated apps	Digital sensors and mobile health programs	Respiratory Care Enhancement	Real-time monitoring, insights into adherence, improved asthma outcomes
5	Dry Powder Inhalation	-	Drug Delivery Enhancement (Nose-to-Brain)	Improved bioavailability in cynomolgus monkeys, potential for CNS drug delivery Top of Form Bottom of Form

Fig. 5: Examples of DPI devices that are currently on the market

Table No. 2 Advanced Inhaler Technologies79,80

Table No. 2 Advanced Inhaler Technologies^79,80