Investigation of Spray Drying Parameters to Formulate Novel Spray-Dried Proliposome Powder Formulations Followed by Their Aerosolization Performance

Introduction

The pulmonary system is a non-invasive and historically used route for inhalation therapy. It offers a highly vascularized, large surface area (circa 100 m2), facilitating rapid absorption [1,2]. Recently popularized for both localized and systemic delivery, this route has allowed for the delivery of water-soluble active compounds with associated poor bioavailability when administered via alternative routes [3]. In the localized treatment of pulmonary diseases, formulations can be deposited directly onto the lung epithelium; this facilitates rapid onset of action, potentially negating drug degradation and resulting in lower dosing requirements. Beclomethasone dipropionate (BDP) is a synthetic steroidal drug delivered via inhalation for the prophylaxis of asthma symptoms. As a model drug, it has been employed in a myriad of micro- and nanoformulations. Recently, these formulations have gained popularity in encapsulating therapeutically active compounds for their delivery to the pulmonary system. These offer drug loading ability, biocompatibility, and biodegradability, preventing drug degradation and ensuring sustained release and formulation stability. Various lipid-based formulations offer these characteristics, delivering drugs to the pulmonary system, including transfersomes and protransfersomes [4], niosomes and proniosomes [5,6], liposomes and proliposomes [7,8], solid lipid nanoparticles [9], hybrid nanoparticles [10,11], microspheres [12], and nanostructured lipid carriers [13].

Liposomes have been extensively employed as a carrier system for delivering hydrophilic drugs (entrapped in the central core) and lipophilic drugs (entrapped in the vesicle’s concentric bilayers) [14]. However, it is established that liposomes are associated with instability during storage, commonly resulting in the leakage of entrapped drugs, vesicle aggregation, and fusion [15,16]. This instability is attributed to the oxidation and hydrolysis of liposomal phospholipids, which may curtail the shelf-life of liposome formulations. To curb the observed stability issues and capitalize on the potential of liposomes, proliposome formulations have been developed [17]. Proliposomes are powdered formulations comprising carbohydrate carriers (e.g., sucrose, sorbitol, lactose, and mannitol) loaded or coated with phospholipid, and can generate liposomes upon hydration. Production of proliposomes can be achieved through a plethora of methods, including the particulate-based slurry method, fluidized-bed coating [18] and freeze drying. However, these methods suffer from numerous drawbacks, including extended production times, as well as being associated with potential phospholipid and drug loss during the proliposome formulation process. The manufacture of spray-dried proliposome (SDP) [2,19,20] formulations offer select advantages, such as minimized wastage of drug and excipients. SDP formulations containing micronized particles can be delivered effectively via dry powder inhalers (DPIs).

Since 1970, DPIs have been commercially available for drug delivery targeting the pulmonary system [21]. DPIs are essentially breath-actuated devices and do not require a combination of coordinated press-and-breathe efforts. During inhalation or when using an artificial model, inspiratory air generates high turbulence from DPIs, resulting in the dry powder formulation being carried into the lungs. However, deposition of powder formulations using DPIs differs from device to device, as well as from formulation to formulation. There are also additional factors which can affect the dose of drug, including inspiratory flow rate, formulation flow properties, particle size, shape, and density, and inter-particulate interaction.

In this study, novel spray-dried (SD) formulations were developed, optimized, and characterized based on the ideal parameters employed via spray drying in order to identify and specify parameters for small to large scale manufacturing as well as their ideal deposition in the pulmonary system for better patient outcome. These SDP formulations were prepared using beclomethasone dipropionate (BDP) as a model drug. Mannitol, trehalose, and LMH carriers were investigated for their potential use as carbohydrate carriers in a unique combination of spray drying parameters, including inlet temperatures, airflow rates, and pump feed rates; this was followed by characterization, namely of production yield, particle size, moisture content, particle morphology, particle nature (crystalline/amorphous), and entrapment efficiency. Additionally, following optimization, the novel SDP formulations were studied for their aerosolization performance using a DPI in combination with an artificial lung model (i.e., a next-generation impactor; NGI) to assess drug deposition. The full illustration of the study is provided in Scheme 1.

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Materials

Mannitol, trehalose dihydrate, Tween 20, and beclomethasone dipropionate (BDP) were purchased from Sigma Aldrich, Gillingham, UK. Lactose monohydrate (LMH) was acquired from VWR Chemicals, Lutterworth, UK. HPLC-grade methanol and ethanol were purchased from Fisher scientific, Loughborough, UK. Dimyristoylphosphatidylcholine (DMPC) was procured from Lipoid, Steinhausen, Switzerland. Hydroxypropyl methylcellulose (HPMC) capsules (size 3) were gifted by Qualicaps, Madrid, Spain. Dry powder low-resistance inhalers (RS01; 4 kPa at 100 L/min) were a generous gift from Plastiape, Osnago, Italy.

Khan, I.; Edes, K.; Alsaadi, I.; Al-Khaial, M.Q.; Bnyan, R.; Khan, S.A.; Sadozai, S.K.; Khan, W.; Yousaf, S. Investigation of Spray Drying Parameters to Formulate Novel Spray-Dried Proliposome Powder Formulations Followed by Their Aerosolization Performance. Pharmaceutics 2024, 16, 1541. https://doi.org/10.3390/pharmaceutics16121541

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