Engineering nanoparticle agglomerates as dry powders for pulmonary drug delivery

Background: Controlled agglomeration of nanoparticles to micrometer-sized composites (i.e. nanoparticle agglomerates) has been suggested as a particle-engineering approach to combine the advantages of nanoparticles with the aerodynamics of microparticles for pulmonary drug delivery. The aim of this thesis was to engineer nanoparticle agglomerates with properties suitable for inhaler formulation, for drugs with different physicochemical properties. Methods: Nanoparticle agglomerates of three model drugs, namely indometacin, ibuprofen and theophylline, were prepared by coupling wet milling and spray drying. In the case of indometacin and ibuprofen, matrix formers (i.e. mannitol and L-leucine) were added to the aqueous nanosuspensions of the drugs prior to spray drying while for theophylline wet milling was carried out in isopropanol in the presence of mannitol. Nanoparticle agglomerates were characterised with respect to their particle size, morphology, solid state, redispersibility and dissolution, while their in-vitro aerosolisation performance was determined using the next generation impactor. A full factorial design and the fast screening impactor were employed in the case of ibuprofen nanoparticle agglomerates while computational modelling was used to investigate interactions between the crystals of theophylline and mannitol. Results: Nanosupensions of indometacin and ibuprofen stabilised with various polymers/surfactants were successfully prepared by wet milling and were further spray dried. Incorporation of matrix formers before spray drying resulted in nanoparticle agglomerates with improved redispersibility (ability to reform nanoparticles upon hydration), dissolution and higher fine particle fractions compared to those without matrix formers. In the case of theophylline, mannitol acted as a co-milling agent facilitating the size reduction of the drug’s needle-like crystals. Increasing the amount of mannitol led to the formation of smaller, more spherical and porous particles with enhanced aerosolisation performance. For each drug, the nanoparticle agglomerates produced retained the crystallinity of the starting materials ensuring the long-term physical stability of the formulations upon storage. Conclusions: Combining wet milling and spray drying can be used as an industrially feasible particle-engineering platform for dry powders for inhalation. By careful selection of formulation and process parameters, this platform can be applied to a range of drugs with different physicochemical properties

Solidification of nanosuspensions for the production of solid oral dosage forms and inhalable dry powders

INTRODUCTION: Nanosuspensions combine the advantages of nanotherapeutics (e.g. increased dissolution rate and saturation solubility) with ease of commercialisation. Transformation of nanosuspensions to solid oral and inhalable dosage forms minimises the physical instability associated with their liquid state, enhances patient compliance and enables targeted oral and pulmonary drug delivery. AREAS COVERED: This review outlines solidification methods for nanosuspensions. It includes spray and freeze drying as the most widely used techniques. Fluidised-bed coating, granulation and pelletisation are also discussed as they yield nanocrystalline formulations with more straightforward downstream processing to tablets or capsules. Spray-freeze drying, aerosol flow reactor and printing of nanosuspensions are also presented as promising alternative solidification techniques. Results regarding the solid state, in vitro dissolution and/or aerosolisation efficiency of the nanocrystalline formulations are given and combined with available in vivo data. Focus is placed on the redispersibility of the solid nanocrystalline formulations, which is a prerequisite for their clinical application. EXPERT OPINION: A few solidified nanocrystalline products are already on the market and many more are in development. Oral and inhalable nanoparticle formulations are expected to have great potential especially in the areas of personalised medicine and delivery of high drug doses (e.g. antibiotics) to the lungs, respectively

Preparation of respirable nanoparticle agglomerates of the low melting and ductile drug ibuprofen: impact of formulation parameters

Ductile and low melting point drugs exhibit challenging behaviour during both particle size reduction and spray drying as considerable amount of heat is involved in both processes. In this study, a systematic approach was employed to understand the preparation and in-vitro performance of respirable nanoparticle agglomerates by coupling wet milling and spray drying for ibuprofen, which is a drug with a low melting point and challenging mechanical properties. Wet milling in the presence of two stabilizers differing in their thermal properties and subsequent spray drying of the suspensions were employed after the addition of mannitol and/or leucine. The effects of the stabilizer type and the amounts of mannitol (matrix former) and leucine (dispersibility enhancer), on the yield of the process, the particle size, the redispersibility (i.e. reformation of nanoparticles upon rehydration) and the aerosolization (fine particle fraction, FPF%) of the nanoparticle agglomerates were evaluated using standard least squares model and a 23 full factorial design (3 factors at 2 levels plus four centre points). All factors investigated were found to have a significant effect on the yield of nanoparticle agglomerates (p < 0.05). The size of the nanoparticle agglomerates was mainly dependent on the leucine to drug ratio and the type of stabilizer (p < 0.05), while mannitol to drug ratio was the only significant factor affecting the redispersibility of the formulations (p < 0.05). The FPF%, determined using a fast screening impactor, was found to be dependent on both the leucine and mannitol to drug ratio (p < 0.05). This study demonstrates the successful preparation of respirable nanoparticle agglomerates of low melting point and ductile ibuprofen and the usefulness of the design of experiments as a tool to understand the impact of the formulation parameters on their fabrication and in-vitro performance

Preparation of theophylline inhalable microcomposite particles by wet milling and spray drying: the influence of mannitol as a co-milling agent

Inhalable theophylline particles with various amounts of mannitol were prepared by combining wet milling in isopropanol followed by spray drying. The effect of mannitol as a co-milling agent on the micromeritic properties, solid state and aerosol performance of the engineered particles was investigated. Crystal morphology modelling and geometric lattice matching calculations were employed to gain insight into the intermolecular interaction that may influence the mechanical properties of theophylline and mannitol. The addition of mannitol facilitated the size reduction of the needle-like crystals of theophylline and also their assembly in microcomposites by forming a porous structure of mannitol nanocrystals wherein theophylline particles are embedded. The microcomposites were found to be in the same crystalline state as the starting material(s) ensuring their long-term physical stability on storage. Incorporation of mannitol resulted in microcomposite particles with smaller size, more spherical shape and increased porosity. The aerosol performance of the microcomposites was markedly enhanced compared to the spray-dried suspension of theophylline wet milled without mannitol. Overall, wet co-milling with mannitol in an organic solvent followed by spray drying may be used as a formulation approach for producing respirable particles of water-soluble drugs or drugs that are prone to crystal transformation in an aqueous environment (i.e. formation of hydrates)

Pharmaceutical nanocrystals: production by wet milling and applications

Nanocrystals are regarded as an important nanoformulation approach exhibiting advantages of increased dissolution and saturation solubility with chemical stability and low toxicity. Nanocrystals are produced in the form of nanosuspensions using top-down (e.g., wet milling or high pressure homogenization) and bottom-up methods (e.g., antisolvent precipitation). Wet milling is a scalable method applicable to drugs with different physicochemical and mechanical properties. Nanocrystalline-based formulations, either as liquid nanosuspensions or after downstream processing to solid dosage forms, have been developed as drug delivery systems for various routes of administration (i.e., oral, parenteral, pulmonary, ocular, and dermal). In this review, we summarize and discuss the features, preparation methods, and therapeutic applications of pharmaceutical nanocrystals, highlighting their universality as a formulation approach for poorly soluble drugs