1. Introduction
One of the first methods of medication administration identified is respiratory drug delivery [
1]. The beneficial characteristics of the lung enable the administration of larger drug concentrations to the airways for enhanced efficacy and to limit adverse effects. These advantages include avoiding first-pass metabolism and enzymatic inactivation [
2]. The administration is non-invasive, which enhances patient compliance. One of the most widely used methods for treating local respiratory conditions, such as chronic obstructive pulmonary disease, asthma, pneumonia, and chronic pulmonary infections, is pulmonary drug delivery [
3,
4].
Nebulizers, metered dosage inhalers (MDIs), soft mist inhalers (SMIs), and dry powder inhalers (DPIs) are the most frequently utilized pulmonary medication delivery devices. MDIs have a larger carbon footprint than DPIs. DPIs are also cost-effective compared to MDIs [
5]. Hydrofluorocarbon propellants are used in MDIs, which are greenhouse gases that persist in the atmosphere for years. Since DPIs are absent of these propellants and produce 20 g CO
2 equivalent per dose compared to 500 g CO
2 equivalent for MDIs, they have lower greenhouse gas emission potential [
6]. The inhalation helps the active ingredient to enter the respiratory tract. DPIs are also portable tools that make it simple for the patient to administer the formulation. On the other hand, education is essential for the correct usage of the products. Due to their solid form, DPIs have outstanding stability and do not require cold chain storage [
4,
7].
There is an increasing variety of commercially available dry powder inhalers, and these vary significantly in terms of their design, technical features, and other specific features. Some inhalers include properties that make them likely to be effective for a variety of patients, which may offer a certain level of ease for healthcare providers. However, there are numerous factors to take into consideration when choosing the most effective inhaler for individuals with lung disorders. In addition to the type of drug contained in the inhaler, factors such as the degree of clinical evidence supporting its efficacy and safety, doctor and patient preferences, technical features of the various inhalers, and the delivery and deposition of the fine particle dose to the lungs may be crucial to assisting the physician in choosing the best device for each patient in order to optimize their treatment [
8].
Carrier-based and carrier-free systems are the two main categories into which DPIs can be categorized. Applying conventional carrier-based DPIs, drug deposition in the respiratory area is insufficient. The active ingredients in these systems are attached to the surface of a carrier, which is typically lactose. Optimizing the aerosolization of the products is essential since the potential of powders is the appropriate dispersion and deposition in the airways. To improve the therapeutic effect, novel carrier-free DPIs have been developed. In that case, a complex powder is formulated by combining the active pharmaceutical ingredient (API) with appropriate excipients [
9].
The upper respiratory tract, which includes the mouth, larynx, and pharynx, and the lower respiratory tract, which includes the trachea, bronchi, and lungs, are the two primary divisions of the respiratory system. When moving from the trachea to the distal airways, the diameters of the airways decrease as they approach the lower region and alveoli of the lung, and their number simultaneously rises [
1]. Generally, the lower part is the target for orally inhaled medications. Unwanted particle deposition in the upper area might have regional negative effects, such as localized discomfort, coughing, dysphonia, and infections [
10]. Controlling the theoretical aerodynamic diameter at 1–5 µm is required for the successful transport of particles via the pulmonary route to the desired area in the lungs [
11]. In the lower parts, regional deposition is also critical for effective drug delivery [
10]. Extra-fine particles (1–2 µm) are suitable for reaching the deeper areas because they deposit significantly more in the smaller peripheral lung structures than in the upper regions [
12,
13].
Recently, attention has been focused on the inhalable, poorly water-soluble drugs, such as antibiotics and anti-inflammatory and antifungal agents, which would acquire elevated local concentration for improved therapeutic effectiveness. However, a poorly water-soluble drug cannot be efficiently absorbed in the lung since it dissolves slowly in the limited volume of the lining fluid. The undissolved particles may be removed through alveolar macrophage uptake and mucociliary clearance, which leads to a compromised therapeutic effect. Additionally, leftover particles that remain for a long time on the surface of the lung epithelium may cause lung irritation and inflammation [
14].
The development of nano-embedded microparticles for pulmonary application has drawn a growing amount of attention in recent years [
15]. The systems enable the combination of nano- and microparticle benefits. Nanoparticles have advantages for getting through biological barriers [
16]. The overall dosage required is reduced due to the enhanced drug transport in mucus and biofilms [
17]. Problems with pulmonary drug administration may be resolved by using nanoparticle delivery methods [
18]. The application of innovative and effective products that contain nanoparticles may enhance various therapies [
19,
20]. Therefore, DPI formulation with enhanced dissolution and improved absorption is urgently required for the pulmonary delivery of water-insoluble drugs.
One of the most important factors for guaranteeing the safety and efficacy of pharmaceutical medicines is stability [
21]. Drug nanoparticle stability issues, such as crystal formation, sedimentation, and agglomeration, may occur during production, storage, transportation, and application [
22]. In general, liquid formulations are less stable than solid dosage forms. However, the potential of aggregation should be taken into consideration in the case of solid forms while using nanosized API. For efficient therapy, it is necessary to maintain the quality-influencing properties of the products. Proper attention should be given to drug nanocrystal stability difficulties during the development of pharmaceutical products [
23].
In our previous studies, wet milling and nano spray drying were used to prepare a carrier-free DPI product consisting of nanosized meloxicam (MX) [
24]. The “nano-in-micro” DPI can target the smaller airways with the extra-fine particles (<2 μm) and increase the water solubility of the drug. The alveolar section of the lung is where the nano-sized active ingredient may exert its anti-inflammatory effect; therefore, our goal is to deliver a high percentage of the extra-fine particles there. The combined preparation method can create particles under 2 µm with narrow size distribution. The previous investigations of the product revealed that the nanosized MX particles are partially amorphized, improving drug release. In addition, the product demonstrated significant drug deposition in the lung in vitro. The present study focused on the long-term stability of the developed DPI powder that contains nanosized MX. A significant challenge related to the development of formulations in DPIs is their stability. Manufacturing processes, pharmaceutical engineering techniques, and storage conditions can significantly impact the physical and aerosol stability of inhalable particles The physical stability of the DPIs is frequently overlooked in the literature even though they are critical to the quality and performance of the inhalation powders [
4]. As a result of the extensive investigation, we could offer the MX a new, innovative therapeutic application in the management of severe lung inflammation.
4. Conclusions
In this study, the stability test of a carrier-free, novel DPI sample containing nanosized, non-steroidal, anti-inflammatory drug was examined at normal room conditions. After the storage, the formulation presented advantageous characteristics, thanks to the technological steps and the compositions. Wet media milling is one of the most popular methods in the pharmaceutical field to produce stable nanosuspension of poorly water-soluble APIs. To optimize time and cost considerations and accurately predict milling performance at higher scales, a variety of modeling techniques could be used in the industry. The spray-drying technique has also been successfully applied at both laboratory and industrial scales. The advantages of a spray-dried powder include easy use and long shelf-life stability. The development of novel delivery methods can be a strategy for repositioning medications; therefore, it saves money and time for the pharmaceutical industry. The pulmonary route of MX could be an intriguing solution for treating different lung inflammation, which can be caused by SARS-CoV-2 infection, CF and COPD, and NSCLC. The excipients were pulmonary-approved materials. During the testing period, the particle size remained unchanged, while the particle size of MX in the formulation increased but did not differ significantly. Furthermore, the partially amorphous property of MX persisted throughout the stability examination. The outcomes of the dissolution test demonstrated that the initially large amount of drug was released from the samples in the examination time. The results suggest that PVA might inhibit the particles from aggregation and crystallizing. The aerosol performance of the formulated DPIs did not deteriorate. The sample has beneficial FPF and EF results after 12 months. The addition of LEU enhanced the aerosolization of the products. The outcome of this study demonstrates that the “nano-in.micro” DPI can maintain its quality for an extended period. According to ICH guidelines, further stability investigations are required, such as a test of the final package.