Baicalin/ambroxol hydrochloride combined dry powder inhalation formulation targeting lung delivery for treatment of idiopathic pulmonary fibrosis: Fabrication, characterization, pharmacokinetics, and pharmacodynamics

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, lung disease associated with the irreversible development of diffuse alveolitis and alveolar structural disorder among middle-aged and elderly individuals [1]. This disease is characterized by abnormal deposition of extracellular matrix molecules, which cause extensive lung remodeling and ultimately promotes pulmonary interstitial fibrosis (PF) [2], [3]. Unfortunately, the pathogenesis of IPF remains unclear. Inflammation and oxidative stress may be important factors involved in the initiation and progression of IPF [4]. Clinical symptoms in the early stages of the disease are imperceptible, presenting as cough and expectoration, whereas symptoms at the later stages include progressive dyspnea accompanied by symptoms of emphysema, copious sputum production, and respiratory failure [5]. The average median survival time after diagnosis is only around 2–3 years, and its survival rate is even lower than that of many cancers. IPF, which has been characterized as a tumor-like disease, has a high mortality rate. The World IPF Association reported that approximately 3.2 million people suffer from IPF and those 1.22 million new patients are diagnosed per year [6]. Lung transplantation is the most direct and effective method for treating IPF [7]. However, given its high cost, few donors, and immunosuppression side effects after surgery, very few patients undergo lung transplantation. Treatment guidelines in 2022 have listed nintedanib and pirfenidone as conditionally recommended drugs for the clinical treatment of IPF [8]. However, nintedanib and pirfenidone only slow but not halt or reverse the progression of IPF, and both have drug tolerability concerns and associated adverse reactions [9], such as gastrointestinal discomfort, liver damage, and skin allergic reactions. Therefore, safe and effective drugs for the treatment of IPF are urgently needed. Theoretically, compound preparation is a relatively suitable approach for treating complex and multi-factorial IPF diseases.

Traditional Chinese Medicine (TCM), which utilizes compounded medicines, has played a vital role in the treatment of chronic and refractory diseases and has been increasingly recognized and widely used. In 2021, a special issue of “Focal Point on Traditional Chinese Medicine” published by Nature magazine [10] reported the therapeutic effects of TCM-derived natural compounds (e.g., artemisinin) and acupuncture on malaria, asthma, liver fibrosis, obesity, etc. Moreover, researcher Tu Youyou, a Nobel laureate in Physiology or Medicine, has proposed a feasible and reasonable plan to address resistance to artemisinin [11], [12], the most effective treatment for malaria at present. In recent years, artemisinin and its derivatives have shown good curative effects in antiparasitic and lupus erythematosus treatment [13]. A multi-center, randomized, double-blind, placebo-controlled study found that berberine [14], the extract of Coptis Chinensis, prevents the development of precancerous lesions that could lead to colorectal cancer and the recurrence of rectal adenoma. TCM has emerged as an important source for promoting drug discovery and uncovering potential treatment.

TCM has shown good effects in IPF treatment through multi-level and multi-target methods [15]. In fact, Baicalin (BA), the extract from Scutellaria baicalensis, has shown positive effects in the treatment of pulmonary fibrosis, IPF, and other lung diseases [16], [17], particularly early PF disease and lung injury [18]. BA also inhibits bleomycin (Bleo)-induced PF by upregulating the adenosine A2a receptor and downregulating the expression of transforming growth factor (TGF-β1) and phosphorylation (p)-ERK1/2 [19]. TGFβ plays an important role in the development and persistence of fibrotic conditions [20]. BA can also exhibit protective and anti-inflammatory effects against alveolar epithelial cell damage induced by cigarette smoke extract by inhibiting the NF-κB pathway [21]. BA [22] can inhibit the proliferation, activation, and migrations of fibroblasts through the signal transduction pathway involved in the process of PF, as well as affect the occurrence and development of PF. These studies indicate that BA has potential for the treatment of IPF.

Ambroxol hydrochloride (AH), the active metabolite of bromexine, has been approved for treatment airway diseases in many countries. AH is used to treat IPF through the following functions [23], [24], [25], [26]. First, AH exerts secretolytic activity by clearing respiratory secretions, and elevating bronchial cilia emptying movement. Second, AH is applied to anti-inflammation and anti-oxidation to balance inflammatory reactions and oxidative stress for symptoms alleviation. AH is the only expectorant and mucolytic agent with anti-inflammatory and anti-oxidant effects. Evidence has shown that drug combination [27] is an effective approach for the treatment of IPF. Therefore, AH exhibits a theoretically synergistic effect with BA for the treatment of IPF through mechanisms such as anti-inflammatory, antioxidant, anti-fibrosis, also improving symptom treatment such as facilitating expectoration and promoting lung functions.

Lung inhalation preparations deliver drugs directly to the lungs, avoiding the first-pass effect and reducing systemic toxicity or adverse reactions. As such, they have been widely used in the treatment of chronic obstructive pulmonary disease, pneumonia, asthma, and other lung diseases [28]. Pulmonary drug delivery has attracted great attention in the treatment of IPF. Inhaled delivery has been the most popular delivery route over the past 6 years [29]. Given the rich capillary network in the alveoli, the thin epithelial cell layer of the alveoli, and the low enzymatic degradation reaction, lung inhalation preparations allow for reduced dosages and have improved drug bioavailability [29], [30]. Lung inhalation preparations may also enable rapid drug absorption and bypasses first-pass metabolism [31]. Such preparations are mainly divided into nebulized inhalations (NEB), metered dose inhalations (MDI), and dry powder inhalations (DPI). Compared to NEB and MDI, DPI has advantage of better drug stability, larger drug delivery dose, more convenient use and portability, and better patient compliance [32], [33]. The spray drying method [34] improves drug atomization performance by reducing powder cohesion and ensures the consistency of aerosol performance of drugs and excipients. L-leucine (L-leu) is mixed with drug, which can improve fluidity, aerosol performance, dispersibility, manufacturability [35], and moisture resistance [36]. In our laboratory [37], [38], DPI prepared with Salvia miltiorrhiza polyphenolic acid or salvianolic acid B using spray drying method had excellent in vitro aerosol performance, uniform structure, and good fluidity.

The current study prepared BA/AH DPIs using TCM-sourced BA and the chemical drug expectorant AH as model drugs, with L-leu as the carrier, using the spray drying method. Thereafter, the characteristics, pharmacokinetics, and pharmacodynamics of the preparation was determined to assess the preparation profile and effect on IPF.

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