The Preparation And Application Of Large Porous/hollow Microspheres

The lung has gained much attention as a unique portal for drug delivery because of the large surface area for drug absorption,good epithelial permeability,avoidance of hepatic first-pass metabolism,a rich blood supply,relatively lower concentrations of drug-metabolizing enzymes than those delivered orally,and better patient compliance. The lung is a logical site of drug delivery for pulmonary diseases. The advantage of aerosol therapy is that it is simple to administer,yet it delivers the drugs directly to the desired site of action,diminishing side effects. However,this delivery system has been challenged by the loss of efficiency or reproducibility,significant variation between patients and the unsatisfied aerodynamic properties that entails can preclude inhalation as a practical noninvasive human therapy.Dry powder inhalation is a collection of dry microspheres contained in an inhaler device which is widely used in the market. Microsphere products ideal for inhalation should have uniform size distribution,adequate physical and chemical stability , excellent reproducibility , low interparticulate forces,optimal aerodynamic properties,and independence of the type of device and inhalation flow rate. A mean aerodynamic diameter of 1-5μm is considered to be ideal for deposition in the lower airways and thus most useful for pulmonary drug delivery. Therefore,a geat deal of efforts is made to achieve dry microspheres with an aerodynamic diameter of 1-5μm. There are two representative challenges. Microspheres with a geometric diameter in this range are prone to interparticulate interactions resulting in microspheres aggregation. Moreover,microspheres in this size range can be efficiently cleared via mucociliary clearance in the airway and via phagocytosis by the alveolar macrophages in the deep lungs.One inhalable drug delivery system is developed in our lab consisting of microspheres with large geometric diameters and low density,which may partly solve the challenges. Large porous/hollow microspheres,characterized by large geometric diameters (> 5μm) and low density (ρ< 0.4 g/cm3),irregular surface,optimal aerodynamic diameters and desirable lung deposition profiles. We report two processes of making large highly porous/hollow microspheres for local drug delivery to the lungs by inhalation. Because of the small surface-to-volume ratio and less density , the large porous /hollow microspheres are less prone to aggregation,easily dispersed and can be efficiently deliveried to the lungs,as compared with non-porous small microspheres. Microparitcles with an irregular surface have a smaller aggregate strength than a smooth microspheres of the same geometric diameters,because of reduced contact area and reduced interparticulate forces. The large porous/hollow microspheres show a better bioavailability than solid microspheres of the same aerodynamic diameter because of their large geometric diameter beyond 2-3μm,which reduces uptake by alveolar macrophages more efficiently resulting in longer residence time of the microspheres in the lungs.The preparation and application of large porous PLGA microspheres Highly porous large Poly (lactic-co-glycolic acid) (PLGA) microspheres (average diameter,10-20μm) were made by the double emulsion solvent evaporation method. To impart favorable aerodynamic properties, an effervescent salt ammonium bicarbonate (ABC) was included in the internal aqueous phase. ABC in the internal aqueous phase was added to the polymer phase to simply,efficiently improve the aerodynamic properties of PLGA microspheres. ABC produced highly porous structures in the PLGA microspheres and stabilized the emulsion droplets against coalescence during the solvent evaporation process as it escaped as ammonia and carbon dioxide. The aerodynamic properties of the microspheres were greatly improved by increasing the ratio of ammonium bicarbonate to PLGA. Microspheres prepared with 7.5% (ABC/PLGA,w/w,%),3000 rpm had a mass median aerodynamic diameter (MMAD) 4.0±1.2μm and fine particle fraction (FPF) 32.0±9.1%,when tested with Anderson Cascade Impactor (ACI) and Rotahaler. The highly porous large microspheres deposited at the ACI stages corresponding to the trachea and below effectively. The highly porous large microspheres avoided phagocytosis by macrophages , while non-porous small microspheres were quickly taken up by the macrophages. The pore-forming processes of osmogens and oil porogens which widely used as pore-forming agents depend on diffusional mass exchange between discontinuous (polymer droplets) and continuous (external water) phases, during which drug molecules tend to be lost. Unlike methods employing osmogens or oil porogens , the pore formation depends more on effervescence of the decomposition products rather than diffusional mass exchange. In fact,the gas production accelerated solidification of the polymer phase,achieving even higher encapsulation efficiency than non-porous microspheres.Doxorubicin hydrochloride (Dox HCl) was encapsulated in the highly porous large PLGA microspheres. The encapsulation efficiency and aerodynamic properties were evaluated during the experiments. Dox HCl is notoriously difficult to encapsulate in PLGA matrix,with the drug loading efficiency in PLGA microspheres being typically below 1%. To the contrary,the use of ABC enabled > 9% Dox HCl loading (~100% of the drug used for encapsulation) in PLGA microspheres. The enhanced Dox encapsulation is attributed to enhanced solidification of the polymer phase as well as the increased pH of the internal aqueous phase which led to highly soluble in the polymer phase than in the external water phase. This method could encapsulate Dox HCl,with high encapsulation efficiency (~100% for doxorubicin) , in the PLGA microspheres characterized by desirable MMAD (4.6±0.4μm) and FPF (33.8±3.6 %). Fifty two percent of encapsulated Dox was released over 4 days from the highly porous microspheres. This method is an efficient way of making polymeric microspheres for sustained local drug delivery by inhalation. Inhalable antibiotic delivery using dry microspheres co-delivering recombinant deoxyribonuclease and ciprofloxacin for treatment of cystic fibrosisCystic fibrosis (CF) is a common genetic disorder. Thick,tenacious sputum in the CF airway poses a formidable barrier to the effective inhalational delivery of antibiotics,since Pseudomonas aeruginosa and other resident pulmonary bacteria are often insulated from the inhaled antibiotics by a poorly-penetrable sputum layer. To achieve efficient antibiotic delivery to the cystic fibrosis (CF) airway using a single inhalable microspheres co-encapsulating a mucolytic and an antibiotic in hollow microspheres. It is hypothesized that co-delivery of inhaled antibiotics with a mucolytic to decrease sputum viscoelasticity improve the flowability of sputum as well as the antibiotic penetration into the sputum controlling airway infection/inflammation and overcoming the challenges in the CF therapy.Inhalable large hollow dry microspheres containing deoxyribonuclease (DNase) and/or ciprofloxacin (DNase , Cipro , and DNase/Cipro microspheres) were produced by spray-drying with dipalmitylphosphatidylcholine (DPPC),albumin and lactose as excipients. The microspheres containing DPPC and albumin are likely to be safe for human use,because these excipients are endogenous materials present in abundant concentrations in the lungs which should not lead to significant accumulation of these exdogenous materials in the lungs following chronic daily administration. All the excipients are FDA-approved which contribute to the irregular surface shape,large geometric diameter,low density and hollow structure.The Blank,DNase, Cipro, and DNase/Cipro Inhalable dry microspheres were produced by spray-drying. The aerodynamic properties were tested by ACI equipted with Rotahaler. All microspheres showed MMAD below 5μm. Cipro and Cipro/DNase microspheres showed a significantly higher FPF than Blank and DNase microspheres. The addition of ciprofloxacin could improve the aerodynamic properties of the microspheres without significantly changing the microspheres shape. Both drugs were loaded in the dry microspheres without loss. Activity of DNase and ciprofloxacin loaded in the dry microspheres was preserved. The effects to the artificial sputum model (ASM) and antibacterial effects were evaluated using the ASM and artificial sputum. Dry microspheres containing DNase significantly decreased the storage modulus of ASM in less than 30 min. When applied to artificial sputum, Cipro/DNase microspheres showed better antibacterial activity than Cipro microspheres. The higher activity of the Cipro/DNase microspheres is attributable to the mucolytic activity of DNase, which promotes penetration of the dry microspheres into the artificial sputum and efficient dissolution and diffusion of ciprofloxacin.Inhalational delivery of antibiotics to the CF airway can be optimized when the sputum barrier is concomitantly addressed. Co-delivery of antibiotics and DNase using an inhalable microspheres system may be a promising strategy for local antipseudomonal therapy in the CF airway.