Development and characterization of an Indacaterol/Tiotropium Bromide composite dry powder inhalation formulation for COPD

Abstract

As a major public health issue, chronic obstructive pulmonary disease (COPD) causes approximately 2.7 million deaths worldwide each year and has a significant negative impact on patients’ health. We have developed a novel long-acting fixed-dose combination dry powder inhalation formulation with synergistic therapeutic effects, containing indacaterol maleate (IND, a long-acting β₂ agonist) and tiotropium bromide (TIO, a long-acting muscarinic receptor antagonist), aimed at improving the clinical management of COPD and providing patients with superior bronchodilator effects. We prepared composite powder formulations using different ratios of fine lactose powder and magnesium stearate, combined with active pharmaceutical ingredients of varying particle sizes. We conducted preliminary studies on the total mixture content, mixing uniformity, delivered dose (DD), and fine particle dose (FPD) of each formulation using high-performance liquid chromatography (HPLC). Further screening and characterization were performed using scanning electron microscopy (SEM), laser particle size analyzers, and powder X-ray diffraction (XRD); simultaneously, we conducted aerodynamic studies and accelerated stability testing on the selected optimal formulation.

This formulation (F7) demonstrated superior performance compared to other formulations. It exhibited excellent mixing uniformity, appropriate content and optimal aerodynamic properties with FPD values near the median standard range. Accelerated stability testing confirmed excellent stability with no significant changes in crystalline form or aerodynamic properties after 6 months. The developed IND/TIO composite inhalation powder represents an innovative dual-bronchodilator DPI formulation. The dual-stage lactose carrier system significantly enhanced drug detachment efficiency and in vitro pulmonary deposition. The introduction of magnesium stearate effectively addressed challenges of poor flowability and particle aggregation in micronized APIs. The formulation exhibits simple preparation process, excellent stability, and superior in vitro pulmonary drug delivery efficacy, making it a promising therapeutic candidate for COPD treatment.

Introduction

Chronic obstructive pulmonary disease (COPD) is a highly prevalent condition with significant morbidity and mortality rates [1], as a respiratory syndrome characterized by progressive, partially reversible airway obstruction and pulmonary hyperinflation [2], [3]. It leads to progressive dyspnea, limitations in daily activities, reduced quality of life, and increased frequency and severity of acute exacerbations, while also imposing a significant burden on healthcare providers and society as a whole [2], [4]. Therefore, in treating COPD, seeking targeted and highly effective medications is particularly crucial.

Inhaled powder medications are widely used to treat lung diseases such as asthma, COPD, or bacterial infections [5], [6], [7]. Unlike oral or injectable formulations, it delivers therapeutic drugs in minute doses directly to the airways, enabling localized effects in the lungs while minimizing unnecessary systemic reactions [6]. The dry powder inhaler (DPI) essentially consists of an air inlet, a capsule/blister/dosing chamber, a cyclonic chamber or dispersion-enhancing component, an air outlet, and a mouthpiece [8], [9]. Patients can control the inhalation flow rate to disaggregate the powdered drug formulation into particles most likely to deposit in the lungs, achieving a delivery rate of up to 40% of the administered dose [10], [11]. DPI formulations contain micronized drug particles with a aerodynamic diameter ranging from 1 to 5 μm. These formulations may also incorporate additional excipients and/or carrier particles to enhance powder flowability and aerosol dispersion, while improving drug stability. They represent an ideal choice for delivering sensitive molecules such as biologics [8], [12].

The primary medications used to treat COPD are bronchodilators, including beta-2 agonists, anticholinergic drugs, theophylline, and corticosteroids [13]. Indacaterol maleate (IND) is a long-acting beta-2 agonist (LABA) that takes effect rapidly within minutes of administration and provides 24-hour bronchodilation for patients. However, monotherapy carries the risk of exacerbating the condition [14], [15]. As a long-acting muscarinic antagonist (LAMA), tiotropium bromide (TIO) can improve lung function and quality of life in COPD patients while reducing the frequency of acute exacerbations [16]. Previous studies have demonstrated that the combination of two bronchodilators with distinct mechanisms of action (LABA + LAMA) not only enhances therapeutic efficacy but also reduces the use of rescue medications in patients previously treated with a single bronchodilator, without significantly increasing adverse effects [17], [18], [19], [20], [21].

Based on the clinical benefits of combining bronchodilators—where 1+1>2—we have innovatively combined IND and TIO to develop a compound dry powder inhalation formulation. We anticipate that this formulation will provide patients with superior bronchodilatory effects, effectively alleviate fluid retention, and offer them additional treatment options. This compound dry powder inhalant combines two active ingredients with lactose as an excipient. In addition to the carrier lactose, a certain proportion of fine-powdered lactose was added. This facilitates the easier dissociation of micronized drugs from the lactose system, promoting drug deposition in the lungs [22], [23]. Compared to the original formulation, we selected magnesium stearate as an additional dispersant for this formulation for the first time, as the finely powdered raw material has poor flowability and tends to form large agglomerates, which could adversely affect the particle size distribution of the DPI[24], [25]. Magnesium stearate enhances powder flowability and improves atomization performance in DPI [26]. Hydroxypropyl methylcellulose(HPMC)capsules have relatively low moisture content, effectively reducing the risk of hydrolysis of the active ingredient. Therefore, HPMC capsules are selected for powder filling [27].

Currently, the development of novel, improved medications for the treatment of COPD is essential. We ingeniously combined two bronchodilators, IND and TIO, and innovatively selected magnesium stearate as a dispersing agent and excipient to prepare a series of novel compound inhalation powders. After comprehensive evaluation, we identified the optimal formulation, F7, which demonstrates superior stability and a well-defined manufacturing process. This formulation represents a novel, highly effective, and safe treatment for COPD.

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Materials

Indacaterol Maleate, Tiotropium Bromide Monohydrate purchased from Shandong Rui Shun Pharmaceutical Co. Ltd. Carrier lactose (Inhalac 140) and fine powder lactose (Inhalac 500) purchased from MEGGLE GmbH & Co.KG. Magnesium stearate (inhalation grade) purchased from Peter Greven Nederland C.V. HPMC Empty Capsule Shells (3#) purchased from Qualicaps Co. Ltd. Sodium dihydrogen phosphate monohydrate (ACS) was purchased from Shengong Bioengineering (Shanghai) Co. Ltd. Phosphoric acid (GR), disodium ethylenediaminetetraacetate dihydrate (AR), acetonitrile (AR), glycerol (AR), and ethanol (AR) were all purchased from Sinopharm Chemical Reagent Co. Ltd.

Xiaobing Wang, Xiaoxi Xu, Chunlei Cheng, Jing Zheng, Wenkun Liu, Yuwen Xu, Jihang Xu, Lihua Wu, Xianhai Sun, Weijian Wang, Hao Fang, Development and characterization of an Indacaterol/Tiotropium Bromide composite dry powder inhalation formulation for COPD, Pharmaceutical Science Advances, 2026, 100136, ISSN 2773-2169, https://doi.org/10.1016/j.pscia.2026.100136.