Nanoparticles assembled from poly(D,L-lactic acid)-poly(ethylene glycol) (PLA-PEG) block copolymers may have a therapeutic application in site-specific drug delivery. A series of AB block copolymers based on a fixed PEG block (5 kDa) and a varying PLA segment (2-110 kDa) have been synthesized by the ring-opening polymerization of D,L-lactide using stannous octoate as a catalyst. These copolymers assembled to form spherical nanoparticles in aqueous media following precipitation from a water-miscible organic solvent. 1 H NMR studies of the PLA-PEG nanoparticles in D2O confirmed their core-shell structure, with negligible penetration of the hydrated PEG chains into the PLA core. The influence of the PLA block molecular weight on the hydrodynamic size and micellar aggregation number of the assemblies was determined by dynamic and static light scattering techniques. The hydrodynamic radius of the PLA-PEG 2:5-30:5 nanoparticles was solely dependent on the copolymer architecture and scaled linearly as NPLA 1/3 , where NPLA is the number of monomeric units in the PLA block. The PEG chains of the small PLA-PEG 2:5 and 3:5 assemblies appeared to be fairly splayed as a consequence of their relatively low aggregation number and high surface coverage. However, as NPLA was increased to 6 kDa the area available per PEG chain at the periphery of the shell decreased significantly and then remained fairly constant with further increases in the molecular weight of the PLA block. The aggregation number and hence particle size of nanoparticles produced from copolymers with a PLA block of 45 kDa or more was found to also depend on the concentration of copolymer dissolved in the organic phase during preparation. This suggested that that the PEG chains had little influence on the assembly of the higher molecular weight copolymers.

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Small-angle neutron scattering (SANS) has been used to study the internal structure of poly(lactic acid)−poly(ethylene glycol) (PLA(d)−PEG) block copolymer assemblies, which are being investigated as particulate drug carriers. Three PLA(d)−PEG copolymers with a fixed PEG of 5 kDa and a fully deuterated PLA(d) block of either 3, 15, or 45 kDa were synthesized by the ring opening polymerization of d 8-d,l-lactide, using stannous octoate as a catalyst. These copolymers assembled to form nanoparticles in aqueous media, following precipitation from a water miscible organic solvent. The hydrodynamic radius of the PLA(d)−PEG nanoparticles increased with the molecular weight of the PLA(d) block. SANS data obtained at three different solvent contrasts were analyzed simultaneously using core−shell models, which assumed a homogeneous core of uniform scattering length density and a simple functional form for the scattering length density profile of the shell. The thickness and structure of the stabilizing PEG layer were found to depend on the molecular weight of the PLA(d) block. The splayed PEG chains of the PLA(d)−PEG 3:5 assemblies were characteristic of those found in polymeric micelles. However, as the molecular weight of the PLA(d) block was increased, the PEG brush became more radially homogeneous, in accord with recent Scheutjens−Fleer mean-field theory predictions.

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The purpose of this article is to review the suitability of the analytical and statistical techniques that have thus far been developed to assess the dissolution behavior of particles in the respirable aerodynamic size range, as generated by orally inhaled products (OIPs) such as metered-dose inhalers and dry powder inhalers. The review encompasses all analytical techniques publicized to date, namely, those using paddle-over-disk USP 2 dissolution apparatus, flow-through cell dissolution apparatus, and diffusion cell apparatus. The available techniques may have research value for both industry and academia, especially when developing modified-release formulations. The choice of a method should be guided by the question(s) that the research strives to answer, as well as by the strengths and weaknesses of the available techniques. There is still insufficient knowledge, however, for translating the dissolution data into statements about quality, performance, safety, or efficacy of OIPs in general. Any attempts to standardize a dissolution method for compendial inclusion or compendial use would therefore be premature. This review reinforces and expands on the 2008 stimulus article of the USP Inhalation Ad Hoc Advisory Panel, which "could not find compelling evidence suggesting that such dissolution testing is kinetically and/or clinically crucial for currently approved inhalation drug products."

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GSK961081/FP blend formulation was associated with an increase in FP systemic exposure and greater serum cortisol suppression.

A series of poly(lactic acid)-poly(ethylene oxide) (PLA-PEG) AB block copolymers have been synthesized and used to produce aqueous dispersions of micellar-like nanoparticles. The hydrodynamic radius of the PLA core plus the stabilizing 5 kDa PEG layer, as determined by photon correlation spectroscopy, increased with the molecular weight of the PLA block. PLA-PEG particles have possible application as drug carriers for targeted drug delivery. In addition to particle size, the layer thickness and mobility of the hydrated PEG chains will be important in determining the particle's ability to avoid uptake by the defense system of the body, the phagocytic cells of the reticuloendothelial system. Viscoelastic measurements were used to investigate interparticle interactions in concentrated dispersions of the PLA-PEG nanoparticles. This approach has not previously been used to study how the interactions in dispersions of micellar-like assemblies depend on the copolymer geometry. When the volume fraction of the dispersions, φcore, was increased, the storage modulus, G′, became greater than the loss modulus, G′′, indicating steric interaction between the PEG chains. At higher φcore values, compression of the grafted polymer chains was observed. The critical volume fraction at which overlap of the PEG chains commences, φcore crit (i.e., G′ ) G′′), was used in conjunction with the overall hydrodynamic radius to determine the grafted PEG chain layer thickness. Micellar-like nanoparticles assembled from a PLA-PEG copolymer with a 5 kDa PEG block and a relatively low molecular weight 3 kDa PLA chain had an appreciable steric layer thickness of 6.3 nm. Hence, interparticle interactions in the concentrated dispersion were "soft" in nature as a result of the long-range interactions, as shown by the weak scaling dependence of the storage modulus on the volume fraction. The layer became more extended as the molecular weight of the PLA block was increased from 3 to 6 kDa, and as a consequence the PEG chains became less compressible. By using this method to characterize the PEG layer, it should be possible to rationalize the in vivo performance of the PLA-PEG nanoparticles and therefore aid the design of particulate drug carriers.