Engineering spray freeze dried particles for pulmonary delivery of proteins

The thesis has focused on the development of dry powder inhaler (DPI) formulations for pulmonary delivery of antidiabetic peptide and protein drugs such as insulin and glucagon-like peptide-1(7-36) amide (GLP-1). These drugs are generally administered via subcutaneous injection that interferes with the patients’ lifestyle and affects patient compliance and adherence to treatment. The primary goal of the research was to assess the value of insulin and GLP-1 DPI formulations for inhalation use in people with diabetes as an alternative treatment option to injectable antidiabetic medications. The aerosolisation performance of insulin and GLP-1 dry powders from two different types of DPI formulations; carrier free DPI formulations (drug alone) and carrier-based DPI formulations (drug and carrier) were investigated using a next generation impactor. No studies have been reported on the development of carrier free GLP-1 DPI formulations and carrier-based DPI formulations containing excipient free insulin or GLP-1 for pulmonary delivery. Particle engineering such as spray drying and spray freeze drying were employed for the drug and carrier powder preparation, respectively as a formulation strategy to optimise the properties of both drug and carrier particles (e.g., particle size, morphology). In addition, drug particles were prepared in the absence of excipients to minimise the lung safety concern. Mannitol was selected as an alternative carrier to lactose which is the most used carrier in DPI formulations but associated with chemical incompatibility with proteins. Glycine or L-leucine selected as an excipient was added to mannitol carrier to optimise carrier properties (morphology). Spray drying demonstrated to reduce the particle size of insulin and GLP-1 powders to a suitable size range (aerodynamic diameter: ≤ 5 µm) for pulmonary delivery and modified the morphologies. This resulted in high fine particle fraction (insulin FPF: 77.36% ± 18.01%, GLP-1 FPF: 90.73% ± 1.76%) showing feasible for pulmonary delivery of spray dried insulin and GLP-1 dry powders. However, spray dried drug particles for inhalation (≤ 5 μm) were naturally cohesive (high degree of drug-drug agglomeration) due to the small particles associated with high inter-particulate forces between drug particles (drug-drug cohesive forces) therefore exhibited poor powder flow and low drug delivery efficiency (total drug deposition on throat and all impactor stages) from an inhaler device (Handihaler®) (insulin delivered dose: 38.64% ± 3.82%, GLP-1 delivered dose: 32.88% ± 7.00%). Spray freeze drying produced spherical and porous carrier powders with the particle size range between 50 µm and 130 µm suitable as DPI carriers regardless of the inclusion or absence of amino acids. However, surface properties (e.g., morphology and roughness) of spray freeze dried mannitol-based carriers were dependent on the type of amino acid and its concentrations. The novel amino acid-mannitol carriers prepared by spray freeze drying were employed to improve the aerosolisation performance of DPI formulations (e.g., powder flow). Carrier-based DPI formulations containing spray freeze dried glycine-mannitol carrier improved the powder flow of the cohesive drug particles and delivered higher drug dose from Handihaler® compared to drug particles alone in carrier free formulations (insulin delivered dose: from 38.64% ± 3.82% to over 57.0%, GLP-1 delivered dose: from 32.88% ± 7.00% to 45.92% ± 5.84%). This was attributed to the porous powders produced by spray freeze drying. Without the addition of the engineered spray freeze dried carrier to the formulation, spray dried drug particles showed poor flowability. Overall, both carrier free and carrier-based DPI formulations have shown advantages with different challenges for pulmonary administration of insulin and GLP-1. According to an online survey conducted in 2019, patients with diabetes generally accepted the idea of insulin delivery via inhalers as 73.4% of participants were willing to try insulin inhalers. National Health Service availability will have a significant influence on participants’ willingness to try insulin inhalers. The successful inhaled insulin and GLP-1 products will provide an alternative treatment option for people with diabetes by reducing the burden of injection related barriers therefore improve patient compliance and adherence to antidiabetic therapy and quality of life affected by injection treatment

[sup]1H NMR quantification of spray dried and spray freeze-dried saccharide carriers in dry powder inhaler formulations

Quantitative analysis using proton NMR (1H qNMR) has been employed in various areas such as pharmaceutical analysis (e.g., dissolution study), vaccines, natural products analysis, metabolites, and macrolide antibiotics in agriculture industry. However, it is not routinely used in the quantification of saccharides in dry powder inhaler (DPI) formulations. The aim of this study was to develop a 1H NMR method for the quantification of saccharides employed in DPI formulations. Dry powders as DPI carriers were prepared by spray drying (SD) and spray freeze drying (SFD) using three saccharides: namely D-mannitol, D-sorbitol and D-(+)-sucrose. The calibration curves constructed for all three saccharides demonstrated linearity with R2 value of 1. The 1H qNMR method produced accurate (relative error %: 0.184-3.697) and precise data with high repeatability (RSD %: 0.517-3.126) within the calibration curve concentration range. The 1H qNMR method also demonstrated significant sensitivity with low values of limit of detection (0.058 mM for D-mannitol, 0.045 mM for D-(+)-sucrose, and 0.056 mM for D-sorbitol) and limit of quantitation (0.175 mM for D-mannitol, 0.135 mM for D-(+)-sucrose, and 0.168 mM for D-sorbitol). Pulmonary deposition via impaction experiments of the three saccharides was quantified using the developed method. It was found that SFD D-mannitol (68.99%) and SFD D-(+)-sucrose (66.62%) exhibited better delivered dose (total saccharide deposition in throat and all impactor stages) than SD D-mannitol (49.03%) and SD D-(+)-sucrose (57.70%) (p< 0.05). The developed 1H qNMR methodology can be routinely used as an analytical method to assess pulmonary deposition in impaction experiments of saccharides employed as carriers in DPI formulations

The impact of natural and synthetic polymers in formulating micro and nanoparticles for antidiabetic drugs

Diabetes mellitus is one of the long known chronic diseases, today over 400 million people are diagnosed with diabetes. Yet curing diabetes is a challenge. Over the decades, the approaches of treating diabetes mellitus have evolved and polymeric materials have played an integral part in developing and manufacturing anti-diabetic medications. However, injection of insulin remains the conventional therapy for the treatment of diabetes. Oral administration is generally the most preferred route; yet, physiological barriers lead to a challenge for the formulation development for oral delivery of antidiabetic peptide and protein drugs. This present review focuses on the role of different types of biodegradable polymers (e.g., synthetic and natural) that have been used to develop micro and nano particles based formulations for antidiabetic drugs (Type 1 and Type 2) and how the various encapsulation strategies impact its therapeutic effect, including pharmacokinetics studies, drug release profiles and efficacy of the encapsulated drugs. This review also includes studies of different dosage forms such as oral, nasal, inhalation and sublingual for the treatment of diabetes that have been investigated using synthetic and natural biodegradable polymers in order to develop an alternative route to subcutaneous route for a better control of serum glucose levels