The rapid recognition of intravenously injected colloidal carriers, such as liposomes and polymeric nanospheres from the blood by Kupffer cells, has initiated a surge of development for "Kupffer cell-evading" or long-circulating particles. Such carriers have applications in vascular drug delivery and release, site-specific targeting (passive as well as active targeting), as well as transfusion medicine. In this article we have critically reviewed and assessed the rational approaches in the design as well as the biological performance of such constructs. For engineering and design of long-circulating carriers, we have taken a lead from nature. Here, we have explored the surface mechanisms, which affords red blood cells long-circulatory lives and the ability of specific microorganisms to evade macrophage recognition. Our analysis is then centered where such strategies have been translated and fabricated to design a wide range of particulate carriers (e.g., nanospheres, liposomes, micelles, oil-in-water emulsions) with prolonged circulation and/or target specificity. With regard to the targeting issues, attention is particularly focused on the importance of physiological barriers and disease states.

Long-Circulating and Target-Specific Nanoparticles: Theory to Practice

On the importance and mechanisms of burst release in matrix-controlled drug delivery systems

This review covers recent developments in the area of particle engineering via spray drying. The last decade has seen a shift from empirical formulation efforts to an engineering approach based on a better understanding of particle formation in the spray drying process. Microparticles with nanoscale substructures can now be designed and their functionality has contributed significantly to stability and efficacy of the particulate dosage form. The review provides concepts and a theoretical framework for particle design calculations. It reviews experimental research into parameters that influence particle formation. A classification based on dimensionless numbers is presented that can be used to estimate how excipient properties in combination with process parameters influence the morphology of the engineered particles. A wide range of pharmaceutical application examples—low density particles, composite particles, microencapsulation, and glass stabilization—is discussed, with specific emphasis on the underlying particle formation mechanisms and design concepts.

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Pharmaceutical particle engineering via spray drying.

The mechanisms of drug release in poly(lactic-co-glycolic acid)-based drug delivery systems--a review.

The present invention relates to engineered multivalent and multispecific binding proteins, methods of making, and specifically to their uses in the prevention, diagnosis, and/or treatment of disease.

Dual variable domain immunoglobulins and uses thereof

https://onlinelibrary.wiley.com/doi/pdf/10.1021/js9604117

A Theoretical Model of Erosion and Macromolecular Drug Release from Biodegrading Microspheres

Purpose. Relatively large (>5 µm) and porous (mass density < 0.4 g/cm3) particles present advantages for the delivery of drugs to the lungs, e.g., excellent aerosolization properties. The aim of this study was, first, to formulate such particles with excipients that are either FDA-approved for inhalation or endogenous to the lungs; and second, to compare the aerodynamic size and performance of the particles with theoretical estimates based on bulk powder measurements. 
Methods. Dry powders were made of water-soluble excipients (e.g., lactose, albumin) combined with water-insoluble material (e.g., lung surfactant), using a standard single-step spray-drying process. Aerosolization properties were assessed with a Spinhaler TM device in vitro in both an Andersen cascade impactor and an AerosizerTM.. 
Results. By properly choosing excipient concentration and varying the spray drying parameters, a high degree of control was achieved over the physical properties of the dry powders. Mean geometric diameters ranged between 3 and 15 µm, and tap densities between 0.04 and 0.6 g/cm3. Theoretical estimates of mass mean aerodynamic diameter (MMAD) were rationalized and calculated in terms of geometric particle diameters and bulk tap densities. Experimental values of MMAD obtained from the AerosizerTM most closely approximated the theoretical estimates, as compared to those obtained from the Andersen cascade impactor. Particles possessing high porosity and large size, with theoretical estimates of MMAD between 1−3 µm, exhibited emitted doses as high as 96% and respirable fractions ranging up to 49% or 92%, depending on measurement technique. 
Conclusions. Dry powders engineered as large and light particles, and prepared with combinations of GRAS (generally recognized as safe) excipients, may be broadly applicable to inhalation therapy.

Formulation and physical characterization of large porous particles for inhalation.

Particles incorporating a surfactant and/or a hydrophilic or hydrophobic complex of a positively or negatively charged therapeutic agent and a charged molecule of opposite charge for drug delivery to the pulmonary system, and methods for their synthesis and administration are provided. In a preferred embodiment, the particles are made of a biodegradable material and have a tap density less than 0.4 g/cm3 and a mass mean diameter between 5 νm and 30 νm, which together yield an aerodynamic diameter of the particles of between approximately one and five microns. The particles may be formed of biodegradable materials such as biodegradable polymers. For example, the particles may be formed of poly(lactic acid) or poly(glycolic acid) or copolymers thereof. Alternatively, the particles may comprise a therapeutic, prophylactic or diagnostic agent and a material selected from the group consisting of surfactant and a molecule having a charge opposite to the charge of the agent and forming a complex thereto. The particles have a tap density less than 0.4 g/cm3 and a mass mean diameter between 5 νm and 30 νm. Exemplary surfactants include phosphoglycerides such as dipalmitoyl phosphatidylcholine (DPPC). The particles are administered to the respiratory tract to permit systemic or local delivery of a wide variety of therapeutic agents. Aggregation of particles before or during administration to the respiratory tract results in particles having an aerodynamic diameter larger than that of the fully dispersed particles. Aerodynamic diameters between three and five microns are advantageous for delivery to the central airways.

Large porous particles emitted from an inhaler

Method and apparatus for producing dry particles. Two liquid components are combined in a static mixer (230, 630), atomized into droplets, and the droplets dried to form dry particles. Use of the static mixer (230, 630) enables incompatible liquid components to be rapidly and homogeneously combined. The present invention optimizes process conditions for increasing and controlling particle porosity. The present invention also allows for optimization of particle size in real-time during particle production.

Method and apparatus for producing dry particles

The invention generally relates to formulations having particles comprising phospholipids, bioactive agent and excipients and the pulmonary delivery thereof. Dry powder inhaled insulin formulations are disclosed. Improved formulations comprising DPPC, insulin and sodium citrate which are useful in the treatment of diabetes are disclosed. Also, the invention relates to a method of for the pulmonary delivery of a bioactive agent comprising administering to the respiratory tract of a patient in need of treatment, or diagnosis an effective amount of particles comprising a bioactive agent of any combination thereof in association, wherein release of the agent from the administered particles occurs in a rapid fashion.

Richard P. Batycky

Papers

A Theoretical Model of Erosion and Macromolecular Drug Release from Biodegrading Microspheres

Formulation and physical characterization of large porous particles for inhalation.

Large porous particles emitted from an inhaler

Method and apparatus for producing dry particles

Particles for inhalation having rapid release properties