Drug-carrier Adhesion Research Articles

The influence of relative humidity on the carrier particle surface characteristics used in dry powder inhalation formulation

Purpose: Investigation of the effect of carrier storage at elevated relative humidities on the carrier surface fines. The resulted effects of this storage conditions on the carrier surface characteristics when mixed with micronized salbutamol sulphate and the subsequent in vitro deposition were investigated. Methods: Lactose (InhaLac120) and mannitol (Pearlitol160) carrier particles (112 µm – 140 µm) were subjected to different relative humidities for 6 weeks period of time in order to get a smoother surface. In vitro deposition carried out for those modified carriers after mixing with salbutamol sulphate using a Next Generation Impactor (NGI). The modified carriers were characterized by scanning electron microscope, Brunauer Emmet and Teller specific surface area determination, differential scanning calorimetry, X-ray powder diffraction and water vapour sorption in comparison with the treated carrier without added fines. Results: The modified lactose and mannitol carriers stored at different relative humidities starting from 35% RH-75% RH show no change in fine particle fraction (FPFs). Subsequently, the carrier storage at 95% RH shows a significant decrease in the in vitro drug release. This probably by increasing drug-carrier adhesion and show a difficult detachment of the drug particles from the carrier surface smoothed at 95% RH. Conclusions: Storage of lactose and mannitol carriers at different relative humidities up to 75% result in un-significant change in drug fine particle fraction using the NGI. Additionally, storage of those carriers at high relative humidity up to 95% RH found to decrease significantly the dispersion of the drug and subsequently the FPF in the in vitro deposition test.

In-Depth Comparison of Dry Particle Coating Processes Used in DPI Particle Engineering.

High-shear mixer coatings as well as mechanofusion processes are used in the particle-engineering of dry powder inhalation carrier systems. The aim of coating the carrier particle is usually to decrease carrier–drug adhesion. This study comprises the in-depth comparison of two established dry particle coating options. Both processes were conducted with and without a model additive (magnesium stearate). In doing so, changes in the behaviour of the processed particles can be traced back to either the process or the additive. It can be stated that the coarse model carrier showed no significant changes when processed without additives. By coating the particles with magnesium stearate, the surface energy decreased significantly. This leads to a significant enhancement of the aerodynamic performance of the respective carrier-based blends. Comparing the engineered carriers with each other, the high-shear mixer coating shows significant benefits, namely, lower drug–carrier adhesion and the higher efficiency of the coating process.

Influence of Added of Fines to the Decanted Carrier Surfaces Used in Dry Powder Formulations

Investigation of the effect of adding carrier fines to the wet decanted carriers and the subsequent effects on the in vitro deposition of salbutamol sulphate. Methods: The wet decantation process used to remove the surface carrier fines carried out nine time for lactose and mannitol carriers. Addition lactose fines up to 8% to decanted lactose. Additionally, mannitol fines up to 16% were added to decanted mannitol. In vitro deposition carried out for those treated carriers after mixing with salbutamol sulphate using the NGI. Results: There were significant increase in fine particle fraction (FPFs). This probably by reducing drug-carrier adhesion and allowing easy detachment of the drugs from the carrier surface. Although this addition of fines could not revert the FPFS to the original value of the untreated carriers. Conclusions: Addition of micronized carriers to decanted carriers found to increase significantly the dispersion of the drug and the in vitro deposition.

Effect of anticoagulants on the protein corona-induced reduced drug carrier adhesion efficiency in human blood flow.

This study addresses the impact of anticoagulant on altering the extent of the previously observed protein corona-induced adhesion reduction of vascular-targeted drug carriers in human blood flows. Specifically, serum blood flow (no anticoagulant) magnifies the negative effect of the plasma protein corona on drug carrier adhesion relative to citrated or heparinized blood flows. Overall, the results from this work suggest that serum better predicts targeted drug carrier adhesion efficiency in vivo compared to anticoagulant containing plasma. Furthermore, this study offers critical insight into the importance of how the choice of anticoagulant can greatly affect drug delivery-related processes in vitro.

Colloidal drug probe: Method development and validation for adhesion force measurement using Atomic Force Microscopy

This study demonstrates a novel technique of preparing drug colloid probes to determine the adhesion force between a model drug salbutamol sulphate (SS) and the surfaces of polymer microparticles to be used as carriers for the dispersion of drug particles from dry powder inhaler (DPI) formulations. Model silica probes of approximately 4μm size, similar to a drug particle used in DPI formulations, were coated with a saturated SS solution with the aid of capillary forces acting between the silica probe and the drug solution. The developed method of ensuring a smooth and uniform layer of SS on the silica probe was validated using X-ray Photoelectron Spectroscopy (XPS) and Scanning Electron Microscopy (SEM). Using the same technique, silica microspheres pre-attached on the AFM cantilever were coated with SS. The adhesion forces between the silica probe and drug coated silica (drug probe) and polymer surfaces (hydrophilic and hydrophobic) were determined. Our experimental results showed that the technique for preparing the drug probe was robust and can be used to determine the adhesion force between hydrophilic/hydrophobic drug probe and carrier surfaces to gain a better understanding on drug carrier adhesion forces in DPI formulations.

Engineered Mannitol Ternary Additives Improve Dispersion of Lactose–Salbutamol Sulphate Dry Powder Inhalations

The aim of this study was to evaluate the influence of novel engineered fine mannitol particles (4.7%, w/w) on the performance of lactose-salbutamol sulphate dry powder inhaler (DPI) formulations to obtain promising aerosolisation properties. The results showed that the more elongated the fine mannitol particles, the weaker the drug-carrier adhesion, the better the drug content homogeneity, the higher the amount of drug expected to be delivered to the lower airways and the higher the total DPI formulation desirability. Linear relationships were established showing that mannitol particles with a more elongated shape generated powders with broader size distributions and that were less uniform in shape. The weaker the drug-carrier adhesion, the higher the fine particle fraction of the drug is upon aerosolisation. It is believed that more elongated fine mannitol particles reduce the number of drug-carrier and drug-drug physical contact points and increase the ability of the drug particles to travel into the lower airways. Additionally, a lower drug-carrier contact area, lower drug-carrier press-on forces and easier drug-carrier detachment are suggested in the case of formulations containing more elongated fine mannitol particles. Ternary 'drug-coarse carrier-elongated fine ternary component' DPI formulations were more favourable than both 'drug-coarse carrier' and 'drug-elongated coarse carrier' binary formulations. This study provides a comprehensive approach for formulators to overcome the undesirable properties of dry powder inhalers, as both improved aerosolisation performance and reasonable flow characteristics were obtained using only a small amount of elongated engineered fine mannitol particles.

Polymer coating of carrier excipients modify aerosol performance of adhered drugs used in dry powder inhalation therapy

The potential of excipient coating to enhance aerosol performance of micronized drugs in carrier excipient-drug blends, used in dry powder inhalers, was investigated. Both EC (ethyl cellulose) and PVP (polyvinylpyrrolidone) were used as coating agents. Carriers were prepared via sieve fractioning followed by spray drying, with and without polymer additive. Each uncoated and coated carrier salbutamol sulphate (SS) blended systems were evaluated for particle size, morphology, drug carrier adhesion and aerosolisation performance, after blending and storage for 24h. All carrier-based systems prepared had similar particle sizes and morphologies. The surface chemistries of the carriers were significantly different, as was drug-carrier adhesion and aerosolisation performance. Particle adhesion between SS and aerosol performance (fine particle fraction; FPF) followed the rank: PVP coated>un-coated>EC coated lactose. This rank order could be attributed to the surface energy measured by contact goniometry and related to the chemistry of lactose and each polymer. Storage did not significantly affect aerosol performance, however a rank increase in mean FPF value was observed for uncoated and EC coated lactose. Finally, the net electrostatic charge across the aerosol cloud indicated that the EC coated lactose transferred less charge to SS particles. The performance of each carrier system could be attributed to the carrier surface chemistry and, in general, by careful selection of the coating polymer, drug-carrier adhesion, electrostatic charge and aerosol performance could be controlled.

Polycaprolactone Microspheres as Carriers for Dry Powder Inhalers: Effect of Surface Coating on Aerosolization of Salbutamol Sulfate

This study reports the factors controlling aerosolization of salbutamol sulfate (SS) from mixtures with polycaprolactone (PCL) microspheres fabricated using an emulsion technique with polyvinyl alcohol (PVA) as stabilizer. The fine particle fraction (FPF) of SS from PCL measured by a twin-stage impinger was unexpectedly found to be zero, although scanning electron microscopy showed that the drug coated the entire microsphere. Precoating the microspheres with magnesium stearate (MgSt) excipient solutions (1%-2%) significantly increased (p < 0.05, n = 5) the FPF of SS (11.4%-15.4%), whereas precoating with leucine had a similar effect (FPF = 11.3 ± 1.1%), but was independent of the solution concentration. The force of adhesion (by atomic force microscopy) between the PCL microspheres and SS was reduced from 301.4 ± 21.7 nN to 110.9 ± 30.5 nN and 121.8 ± 24.6 nN, (p < 0.05, n = 5) for 1% and 2% MgSt solutions, respectively, and to 148.1 ± 21.0 nN when coated with leucine. The presence of PVA on the PCL microspheres (detected by X-ray photoelectron spectroscopy) affected the detachment of SS due to strong adhesion between the two, presumably due to capillary forces acting between them. Precoating the microspheres with excipients increased the FPF significantly by reducing the drug-carrier adhesion.

Agglomerate behaviour of fluticasone propionate within dry powder inhaler formulations

Due to their small size, the respirable drug particles tend to form agglomerates which prevent flowing and aerosolisation. A carrier is used to be mixed with drug in one hand to facilitate the powder flow during manufacturing, in other hand to help the fluidisation upon patient inhalation. Depending on drug concentration, drug agglomerates can be formed in the mixture. The aim of this work was to study the agglomeration behaviour of fluticasone propionate (FP) within interactive mixtures for inhalation. The agglomerate phenomenon of fluticasone propionate after mixing with different fractions of lactose without fine particles of lactose (smaller than 32μm) was demonstrated by the optical microscopy observation. A technique measuring the FP size in the mixture was developed, based on laser diffraction method. The FP agglomerate sizes were found to be in a linear correlation with the pore size of the carrier powder bed (R2=0.9382). The latter depends on the particle size distribution of carrier. This founding can explain the role of carrier size in de-agglomeration of drug particles in the mixture. Furthermore, it gives more structural information of interactive mixture for inhalation that can be used in the investigation of aerosolisation mechanism of powder. According to the manufacturing history, different batches of FP show different agglomeration intensities which can be detected by Spraytec®, a new laser diffraction method for measuring aerodynamic size. After mixing with a carrier, Lactohale LH200, the most cohesive batch of FP, generates a lower fine particle fraction. It can be explained by the fact that agglomerates of fluticasone propionate with very large size was detected in the mixtures. By using silica–gel beads as ball-milling agent during the mixing process, the FP agglomerate size decreases accordingly to the quantity of mixing aid. The homogeneity and the aerodynamic performance of the mixtures are improved. The mixing aid based on ball-milling effect could be used to ameliorate the quality of inhalation mixture of cohesive drug, such as fluticasone propionate. However, there is a threshold where an optimal amount of mixing aids should be used. Not only the drug des-aggregation reaches its peak but the increase in drug–carrier adhesion due to high energy input should balance the de-agglomeration capacity of mixing process. This approach provides a potential alternative in DPI formulation processing.

The influence of physical properties and morphology of crystallised lactose on delivery of salbutamol sulphate from dry powder inhalers

The aim of this work was to investigate the mechanistic evaluation of physicochemical properties of new engineered lactose on aerosolisation performance of salbutamol sulphate (SS) delivered from dry powder inhaler (DPI). Different crystallised lactose particles were obtained from binary mixtures of butanol:acetone. The sieved fractions (63–90μm) of crystallised lactose were characterised in terms of size, shape, flowability, true density and aerosolisation performance (using multiple twin stage impinger (MSLI), Aerolizer® inhaler device, and salbutamol sulphate as a model drug). Compared to commercial lactose, crystallised lactose particles were less elongated, covered with fine lactose particles, and had a rougher surface morphology. The crystallised lactose powders had a considerably lower bulk and tap density and poorer flow when compared to commercial lactose. Engineered carrier with better flow showed improved drug content homogeneity, reduced amounts of drug “deposited” on the inhaler device and throat, and a smaller drug aerodynamic diameter upon inhalation. Aerodynamic diameter of salbutamol sulphate increased as lactose aerodynamic diameter decreased (linear, R2=0.9191) and/or as fine particle lactose content increased (linear, R2=0.8653). Improved drug aerosolisation performance in the case of crystallised lactose particles was attributed to lower drug–carrier adhesion forces due to a rougher surface and higher fine particle content. In conclusion, this work proved that using binary combinations of solvents in crystallisation medium is vital in modification of the physicochemical and micromeritic properties of carriers to achieve a desirable aerosolisation performance from DPI formulations. Among all lactose samples, lactose particles crystallised from pure butanol generated the highest overall DPI formulations desirability.

In vitro characterization of a dual‐receptor targeted drug delivery system for treating vascular diseases

IntroductionDrug delivery systems targeted to the vasculature provide an effective mean for increasing the therapeutic efficacy of various drugs. In this study we present a novel dual‐receptor (selectins and ICAMs) targeting approach to enhance the drug carrier's binding efficiency to the inflamed tissue in vascular diseases.MethodsFlorescent microspheres were prepared by coating the surface with different ratios of antibodies against ICAM‐1 (aICAM‐1) and E‐selectin (aE‐selectin). A flow chamber was used to study the interaction of the microspheres with TNF‐α activated HUVEC under different shear flow conditions.ResultsMicrospheres coated with 2:1 ratio of aICAM‐1 and aE‐selectin had the highest binding efficacy compared to the single antibody coated microspheres. The number of aICAM‐1+aE‐selectin microspheres bound to HUVECs appeared to decrease with increase in wall shear stress in the flow chamber. Moreover, the number of adherent aICAM‐1+aE‐selectin microspheres was significantly higher than the adherent aE‐selectin microspheres under different flow conditions.ConclusionsWe conclude that the adhesion efficiency of the two‐receptor targeting microspheres is significantly higher than the single‐ligand microspheres under various flow conditions and that the drug carrier adhesion ability can be optimized by optimizing the ratio of the two ligands on the surface of the microsphere.

Measuring Surface Roughness of Pharmaceutical Powders Using Vapor Sorption Methods

Particle morphology of pharmaceutical solids has practical importance for several reasons. In particular, surface roughness can influence formulation development and pharmaceutical performance for a wide range of delivery types including oral tablets and dry powder formulations for inhalation. For instance, the surface roughness can influence dissolution, friability, and adhesion of coatings and films for bare tablets (1–5). To illustrate, surface roughness correlated strongly with tablet friability for erythromycin acistrate tablets (3). The surface roughness has also been related to gloss and permeability, such that the reflectivity and surface texture of coated tablets were directly correlated (6,7). The surface roughness of particles also has been correlated to powder flow and powder packing (8), where the smoother particles led to an improvement of powder packing and flow properties. The adhesion of particles to surfaces or other particles can also be greatly affected by surface roughness. This is of particular concern for dry powder inhalation (DPI) formulation development. Dry powder formulations are often composed of small drug particles and inert larger carrier particles. Interactions between these particles can be dominated by physico-chemical properties of the particle, such as size, shape, morphology, contact area, and hygroscopicity (9,10). In particular, it has been shown that the surface roughness of the carrier particles has a significant impact on the adhesion and friction forces between the carrier and drug particles (11,12). Adhesion, blend homogeneity, and stability have been directly related to the surface roughness of the carrier particle (13). The ultimate performance properties of DPI blends as determined by in vitro testing has also been correlated to the primary particle surface roughness (13–15). There is an important balance between the relative scaling in the roughness of the particles and the relative size of the carrier and drug particles when considering the effects of surface roughness on particle–particle adhesion. This was previously described (16) and is illustrated by the schematic in Fig. 1. Assuming no other changes in particle properties (i.e., surface energy, particle size, amorphous content, hygroscopicity, etc.), the rank order of drug-carrier adhesion would obey the following trend in roughness of the larger carrier particle: macro-rough surface (Fig. 1a) > smooth surface (Fig. 1b) > micro-rough surface (Fig. 1c). This trend is strictly dependent on the contact area between drug and carrier. If adhesion is too weak, the active drug may be released during inhalation before the particles reach the deep lung. On the contrary, if adhesion is too strong, the active may not be released at all. This phenomenon has been observed and described in detail for several DPI studies (15–19). Fig. 1 Illustration of macro-roughness (a), smooth surface (b), and micro-roughness (c) affects on particle–particle contact and adhesion In this study, we focus on the measurement of micro-scale roughness using fractal dimensions determined from sorption isotherms with different adsorbates.

Lactose Composite Carriers for Respiratory Delivery

Lactose dry powder inhaler (DPI) carriers, constructed of smaller sub units (composite carriers), were evaluated to assess their potential for minimising drug-carrier adhesion, variability in drug-carrier forces and influence on drug aerosol performance from carrier-drug blends. Lactose carrier particles were prepared by fusing sub units of lactose (either 2, 6 or 10 microm) in saturated lactose slurry. The resultant composite particles, as well as supplied lactose, were sieve fractioned to obtain a 63-90 microm carriers. The carriers were evaluated in terms of size (laser diffraction) morphology (electron microscopy and atomic force microscopy), crystallinity and drug adhesion (colloid probe microscopy). In addition, blends containing drug and carrier were prepared and evaluated in terms of drug aerosol performance. The surface morphology and physico-chemical properties of the composite carriers were significantly different. Depending on the initial primary lactose size, the composite particles could be prepared with different surface roughness. Variation in composite roughness could be related to the change in drug adhesion (via modification in contact geometry) and thus drug aerosol performance from drug-lactose blends. Composite based carriers are a potential route to control drug-carrier adhesion forces and variability thus allowing more precise control of formulation performance.

An investigation into the relationship between carrier-based dry powder inhalation performance and formulation cohesive–adhesive force balances

The inclusion of different carrier materials in a dry powder inhaler (DPI) system can alter formulation performance, which might be attributable to variation in the adhesion between drug and carrier particles. The aim of this study was, therefore, to further examine the relationship between drug-carrier adhesion and performance, by comparing data relating to many different drug-carrier combinations. Four drugs and four carriers were employed, giving a total of 16 combinations. The relative magnitude of the drug-carrier adhesion for each combination was quantified using the cohesion–adhesion balance (CAB) approach to colloidal probe atomic force microscopy. The in vitro inhalation performance of the 16 formulations (1.5% w/w drug) was investigated and found to vary significantly. Plots of fine particle dose against drug-carrier CAB ratio revealed that performance was optimised when the drug-carrier CAB ratio was slightly cohesive. This trend was found to fit with those from similar previous studies, although due to the smaller number of formulations investigated previously, the full extent of this relationship had not been revealed. It was concluded, therefore, that when developing a carrier-based DPI, the selection of a drug-carrier combination with a slightly cohesive CAB ratio might result in optimal performance.

Composite carriers improve the aerosolisation efficiency of drugs for respiratory delivery

The physico-chemical properties and aerosolisation efficiency of a dry powder inhaler (DPI) carrier system constructed from small sub-units (composite carrier) was investigated. Composite carriers were prepared by fusion of 3 μ m mannitol particles. The particles were subsequently sieved to produce a 63 – 90 μ m carrier fraction, which was compared to a sieved as-supplied crystalline material (regular carrier). The carrier particles were studied in terms of morphology (electron, optical and atomic-force microscopy), particle size (laser-diffraction), drug-carrier adhesion (colloid probe microscopy) and in vitro aerosolisation efficiency assessed using a commercially available DPI device (cascade impaction). The composite carriers morphology were similar in size and shape to the regular carrier; however, the variation in surface roughness was reduced while projected topographical surface area increased. Spatial-adhesion measurements of a model drug (salbutamol sulphate) across the surface of the carrier indicated lower variation in adhesion values and lower median adhesion forces, when compared to the regular carrier. Aerosolisation of salbutamol sulphate-composite carrier blends suggested improved drug deposition when compared to the regular carrier (fine particle fractions of 18.5 % ± 1.5 % compared to 5.6 % ± 2.9 % ). This composite approach provides improved carrier homogeneity and reduced drug-carrier adhesion resulting in improved aerosolisation efficiency.