Studies on the effect of the size of polycaprolactone microspheres for the dispersion of Salbutamol Sulfate from dry powder inhaler formulations

Purpose: To study the effect of the size of the surface-coated polycaprolactone (PCL) microparticle carriers on the aerosolization and dispersion of Salbutamol Sulfate (SS) from Dry Powder Inhaler (DPI) formulations. Methods: The microparticles were fabricated using an emulsion technique in four different sizes (25, 48, 104 and 150 μm) and later coated with Magnesium stearate (MgSt) and leucine. They were characterized by laser diffraction and SEM. The Fine Particle Fraction (FPF) of SS from powder mixtures was determined by a Twin Stage Impinger (TSI). Results: As the carrier size increased from 25 μm to 150 μm, the FPF of the SS delivered by the coated PCL particles increased approximately four fold. A linear relationship was found between the FPF and Volume mean Diameter (VMD) of the particles over this range. Conclusions: The dispersion behaviour of SS from PCL carriers was dependent on the inherent size of the carriers and the increased FPF of SS with increased carrier size probably reflects the higher mechanical forces produced due to the carrier-carrier collisions or collisions between the carrier particles and the internal walls of the inhaler during aerosolization.

Biological responses of human bone marrow mesenchymal stem cells to Sr-M-Si (M = Zn, Mg) silicate bioceramics

Strontium (Sr), Zinc (Zn), magnesium (Mg), and silicon (Si) are reported to be essential trace elements for the growth and mineralization of bone. We speculated that the combination of these bioactive elements in bioceramics may be effective to regulate the osteogenic property of boneforming cells. In this study, two Sr-containing silicate bioceramics, Sr2ZnSi2O7 (SZS) and Sr2MgSi2O7 (SMS), were prepared. The biological response of human bone marrow mesenchymal stem cells (BMSCs) to the two bioceramics (in the forms of powders and dense ceramic bulks) was systematically studied. In powder form, the effect of powder extracts on the viability and alkaline phosphatase (ALP) activity of BMSCs was investigated. In ceramic disc form, both direct and indirect coculture of BMSCs with ceramic discs were used to investigate their biological response, including attachment, proliferation, ALP activity, and bone-related genes expression. Beta-tricalcium phosphate (b-TCP) and akermanite (Ca2MgSi2O7, CMS) were used as control materials. The results showed that the Sr, Zn, and Si (or Sr, Mg, and Si)-containing ionic products from SZS and SMS powders enhanced ALP activity of BMSCs, compared to those from b-TCP. Both SZS and SMS ceramic discs supported the growth of BMSCs, and most importantly, significantly enhanced the ALP activity and bone-related genes expression of BMSCs as compared to b-TCP. The results suggest that the specific combination of bioactive ions (Sr, Zn, Si, e.g.) in bioceramics is a viable way to improve the biological performance of biomaterials, and the form of materials and surface properties were nonnegligible factors to influence cell response.

3D-printing of highly uniform CaSiO3 ceramic scaffolds : preparation, characterization and in vivo osteogenesis

Calcium silicate (CaSiO3, CS) ceramics have received significant attention for application in bone regeneration due to their excellent in vitro apatite-mineralization ability; however, how to prepare porous CS scaffolds with a controllable pore structure for bone tissue engineering still remains a challenge. Conventional methods could not efficiently control the pore structure and mechanical strength of CS scaffolds, resulting in unstable in vivo osteogenesis. The aim of this study is to set out to solve these problems by applying a modified 3D-printing method to prepare highly uniform CS scaffolds with controllable pore structure and improved mechanical strength. The in vivo osteogenesis of the prepared 3D-printed CS scaffolds was further investigated by implanting them in the femur defects of rats. The results show that the CS scaffolds prepared by the modified 3D-printing method have uniform scaffold morphology. The pore size and pore structure of CS scaffolds can be efficiently adjusted. The compressive strength of 3D-printed CS scaffolds is around 120 times that of conventional polyurethane templated CS scaffolds. 3D-Printed CS scaffolds possess excellent apatite-mineralization ability in simulated body fluids. Micro-CT analysis has shown that 3D-printed CS scaffolds play an important role in assisting the regeneration of bone defects in vivo. The healing level of bone defects implanted by 3D-printed CS scaffolds is obviously higher than that of 3D-printed b-tricalcium phosphate (b-TCP) scaffolds at both 4 and 8 weeks. Hematoxylin and eosin (H&E) staining shows that 3D-printed CS scaffolds induce higher quality of the newly formed bone than 3D-printed b-TCP scaffolds. Immunohistochemical analyses have further shown that stronger expression of human type I collagen (COL1) and alkaline phosphate (ALP) in the bone matrix occurs in the 3D-printed CS scaffolds than in the 3D-printed b-TCP scaffolds. Considering these important advantages, such as controllable structure architecture, significant improvement in mechanical strength, excellent in vivo osteogenesis and since there is no need for second-time sintering, it is indicated that the prepared 3D-printed CS scaffolds are a promising material for application in bone regeneration.

Studies on the surface properties of biodegradable polymer carriers in respiratory delivery of drug from Dry Powder Inhaler formulations

Dry Powder Inhaler (DPI) technology has a significant impact in the treatment of various respiratory disorders. DPI formulations consist of a micronized drug (<5ìm) blended with an inert coarse carrier, for which lactose is widely used to date. DPIs are one of the inhalation devices which are used to target the delivery of drugs to the lungs. Drug delivery via DPI formulations is influenced by the physico-chemical characteristics of lactose particles such as size, shape, surface roughness and adhesional forces. Commercially available DPI formulations, which utilise lactose as the carrier, are not efficient in delivering drug to the lungs. The reasons for this are the surface morphology, adhesional properties and surface roughness of lactose. Despite several attempts to modify lactose, the maximum efficient drug delivery to the lungs remains limited; hence, exploring suitable alternative carriers for DPIs is of paramount importance. Therefore, the objective of the project was to study the performance of spherical polymer microparticles as drug carriers and the factors controlling their performance. This study aimed to use biodegradable polymer microspheres as alternative carriers to lactose in DPIs for achieving efficient drug delivery into the lungs. This project focused on fabricating biodegradable polymer microparticles with reproducible surface morphology and particle shape. The surface characteristics of polymeric carriers and the adhesional forces between the drug and carrier particles were investigated in order to gain a better understanding of their influence on drug dispersion. For this purpose, two biodegradable polymers- polycaprolactone (PCL) and poly (DL-lactide-co-glycolide) (PLGA) were used as the carriers to deliver the anti-asthmatic drug - Salbutamol Sulphate (SS). The first study conducted for this dissertation was the aerosolization of SS from mixtures of SS and PCL or PLGA microparticles. The microparticles were fabricated using an emulsion technique and were characterized by laser diffraction for particle size analysis, Scanning Electron Microscopy (SEM) for surface morphology and X-ray Photoelectron Spectroscopy (XPS) to obtain surface elemental composition. The dispersion of the drug from the DPI formulations was determined by using a Twin Stage Impinger (TSI). The Fine particle Fraction (FPF) of SS from powder mixtures was analyzed by High Performance Liquid Chromatography (HPLC). It was found that the drug did not detach from the surface of PCL microspheres. To overcome this, the microspheres were coated with anti-adherent agents such as magnesium stearate and leucine to improve the dispersion of the drug from the carrier surfaces. It was found that coating the PCL microspheres helped in significantly improving the FPF of SS from the PCL surface. These results were in contrast to the PLGA microspheres which readily allowed detachment of the SS from their surface. However, coating PLGA microspheres with antiadherent agents did not further improve the detachment of the drug from the surface. Thus, the first part of the study demonstrated that the surface-coated PCL microspheres and PLGA microspheres can be potential alternatives to lactose as carriers in DPI formulations; however, there was no significant improvement in the FPF of the drug. The second part of the research studied the influence of the size of the microspheres on the FPF of the drug. For this purpose, four different sizes (25 ìm, 48 ìm, 100 ìm and 150 ìm) of the PCL and PLGA microspheres were fabricated and characterized. The dispersion of the drug from microspheres of different sizes was determined. It was found that as the size of the carrier increased there was a significant increase in the FPF of SS. This study suggested that the size of the carrier plays an important role in the dispersion of the drug from the carrier surface. Subsequent experiments in the third part of the dissertation studied the surface properties of the polymeric carrier. The adhesion forces existing between the drug particle and the polymer surfaces, and the surface roughness of the carriers were quantified using Atomic Force Microscopy (AFM). A direct correlation between adhesion forces and dispersion of the drug from the carrier surface was observed suggesting that adhesion forces play an important role in determining the detachment potential of the drug from the carrier surface. However, no direct relationship between the surface roughness of the PCL or PLGA carrier and the FPF of the drug was observed. In conclusion, the body of work presented in this dissertation demonstrated the potential of coated PCL microspheres and PLGA microspheres to be used in DPI formulations as an alternative carrier to sugar based carriers. The study also emphasized the role of the size of the carrier particles and the forces of interaction prevailing between the drug and the carrier particle surface on the aerosolization performances of the drug.

Preparation, characterization and in vitro angiogenic capacity of cobalt substituted β-tricalcium phosphate ceramics

Divalent cobalt ions (Co2+) have been shown to possess the capacity to induce angiogenesis by activating hypoxia inducible factor-1α (HIF-1α) and subsequently inducing the production of vascular endothelial growth factor (VEGF). However, there are few reports about Co-containing biomaterials for inducing in vitro angiogenesis. The aim of the present work was to prepare Co-containing β-tricalcium phosphate (Co-TCP) ceramics with different contents of calcium substituted by cobalt (0, 2, 5 mol%) and to investigate the effect of Co substitution on their physicochemical and biological properties. Co-TCP powders were synthesized by a chemistry precipitation method and Co-TCP ceramics were prepared by sintering the powder compacts. The effect of Co substitution on phase transition and the sintering property of the β-TCP ceramics was investigated. The proliferation and VEGF expression of human bone marrow mesenchymal stem cells (HBMSCs) cultured with both powder extracts and ceramic discs of Co-TCP was further evaluated. The in vitro angiogenesis was evaluated by the tube-like structure formation of human umbilical vein endothelial cells (HUVECs) cultured on ECMatrix™ in the presence of powder extracts. The results showed that Co substitution suppressed the phase transition from β- to α-TCP. Both the powder extracts and ceramic discs of Co-TCP had generally good cytocompatibility to support HBMSC growth. Importantly, the incorporation of Co into β-TCP greatly stimulated VEGF expression of HBMSCs and Co-TCP showed a significant enhancement of network structure formation of HUVECs compared with pure TCP. Our results suggested that the incorporation of Co into bioceramics is a potential viable way to enhance angiogenic properties of biomaterials. Co-TCP bioceramics may be used for bone tissue regeneration with improved angiogenic capacity.

Developing an efficient and reliable dry powder inhaler for pulmonary drug delivery : a review for multidisciplinary researchers

Pulmonary drug delivery is the focus of much research and development because of its great potential to produce maximum therapeutic benefit. Among the available options the dry powder inhaler (DPI) is the preferred device for the treatment of an increasingly diverse number of diseases. However, as drug delivery from a DPI involves a complicated set of physical processes and the integration of drug formulations, device design and patient usage, the engineering development of this medical technology is proving to be a great challenge. Currently there is large range of devices that are either available on the market or under development, however, none exhibit superior clinical efficacy. A major concern is the inter- and intra-patient variability of the drug dosage delivered to the deep lungs. The extent of variability depends on the drug formulation, the device design and the patient’s inhalation profile. This article reviews recent advances in DPI technology and presents the key factors which motivate and constrain the successful engineering of a universal, patient-independent DPI that is capable of efficient, reliable and repeatable drug delivery. A strong emphasis is placed on the physical processes of drug powder aerosolisation, deagglomeration, and dispersion and on the engineering of formulations and inhalers that can optimise these processes.

Dry powder inhaler formulations : effect of carrier size on the drug dispersion

Background: The size of the carrier influences drug aerosolization from a dry powder inhaler (DPI) formulation. Lactose particles with irregular shape and rough surface in a variety of sizes are additionally used as carriers; however, contradictory reports exist regarding the effect of carrier size on the dispersion of drug. We examined the influence of the spherical particle size of the biodegradable polylactide-co-glycolide (PLGA) carrier on the aerosolization of a model drug, salbutamol sulphate (SS). Methods: Four different sizes (20-150 µm) of polymer carriers were fabricated using solvent evaporation technique and the dispersion of SS from these carriers was measured by a Twin Stage Impinger (TSI). The size and morphological properties of polymer carriers were determined by laser diffraction and SEM, respectively. Results: The FPF was found to increase from 5.6% to 21.3% with increasing carrier sizeup to150 µm. Conclusions: The aerosolization of drug increased linearly with the size of polymer carriers. For a fixed mass of drug particles in a formulation, the mass of drug particles per unit area of carriers is higher in formulations containing the larger carriers, which leads to an increase in the dispersion of drug due to the increased mechanical forces occurred between the carriers and the device walls.

Fine-grained Y2Cu2O5 powder from a co-precipitated precursor

A co-precipitation process is utilized to manufacture Y2Cu2O5 precursor powders. Upon calcination at high temperatures, such as 800 degrees C, the co-precipitated powder transforms to Y2Cu2O5. By selective variation of calcination parameters, grain-growth can be controlled to yield different sized Y2Cu2O5 powder, including sub-micron average sizes. ICP analysis, X-ray diffraction, electron microscopy, a.c. magnetic susceptibility and FT Raman are used to characterize phase development, morphology and purity of the powders.

Manufacture of specific BSCCO powder compositions by co-precipitation

A co-precipitation process for large-scale manufacture of bismuth-based HTSC powders has been demonstrated. Powders manufactured by this process have a high phase purity and precisely reproducible stoichiometry. Controlled time and temperature variations are used to convert precursors to HTSC compounds and to obtain specific particle-size distributions. The process has been demonstrated for a variety of compositions in the BSCCO system. Electron microscopy X-ray diffraction, inductively coupled plasma spectroscopy and magnetic-susceptibility measurements are used to characterize the powders.

Shape-formed ceramic superconductors by slip-casting

In order to rigorously test emerging applications using prototypes and pilot designs, high temperature superconductor (HTS) materials must be fabricated into a variety of shapes in an economical manner. We have developed a simple, economical, ceramic slip-casting approach to form complex shaped monolithic HTS articles for which high bulk density has been achieved. The sintered articles exhibit good Meissner signal and consist of phase-pure HTSC phase. A low transport critical current density is observed and is explained on the basis of densification and grain growth. © 1995 The Metallurgical of Society of AIME.

Manufacture of fine-grained Y2BaCuO5 powder by coprecipitation

Quantities of Y2BaCuO5 powder greater than 500g have been manufactured by a co-precipitation process. By suitable heat treatments, the particle size of these powders can be varied from 5µm to less than 500nm. Sub-micrometer size powders may, under some conditions, have a duller green colour which is attributed to <2% unreacted material. However, after re-grinding and re-firing of this powder, high-purity powders can be achieved without significant grain growth. Inductively coupled plasma (ICP) spectroscopy is used to measure the stoichiometry of the powders and X-ray diffraction is used to determine phase purity. In both cases, the bulk composition is consistent with Y2BaCuO5 and phase purity is considered better than 95%.

Interfacial microstructure in Y1Ba2Cu3O7-δ high Tc superconductors

The microstructures of YBa2Cu3O7-δ ceramics prepared from freeze dried powders and containing an excess of CuO have been studied by analytical electron microscopy. Special attention has been paid to the interfacial microstructure. It was found that a liquid phase formed during sintering between 890°C and 920°C and this promoted grain growth and densification. Both clean grain boundaries and boundaries containing an amorphous intergranular film, which was rich in Cu, have been observed. Both CuO and BaCuO2 were present as secondary phases.

Dry powder inhaler formulations-effect of polymer carrier size on the drug dispersion

Background The size of the carrier influences the aerosolization of drug from a dry powder inhaler (DPI) formulation. Currently, lactose monohydrate particles in a variety of sizes are preferably used in carrier based DPI formulations of various drugs; however, contradictory reports exist regarding the effect of the size of the carrier on the dispersion of drug. In this study we examined the influence of the intrinsic particle size of the polymeric carrier on the aerosolization of a model drug salbutamol sulphate (SS). Methods Four different sizes (20–150 lm) of polymer carriers were fabricated using solvent evaporation technique and the dispersion of SS particles from these carriers was measured by a Twin Stage Impinger (TSI). The size and morphological properties of polymer carriers were by laser diffraction and SEM, respectively. Results The FPF from these carriers was found to be increasing from 5.6% to 21.3% with increasing the carrier size. The FPF was found to be greater (21%) with the highest particle size of the carrier (150 lm). Conclusions The aerosolization of drug was dependent on the size of polymer carriers. The smaller size of the carrier resulted in lower FPF which was increased with increasing the carrier size. For a fixed mass of drug particles in a formulation, the mass of drug particles per unit area of carriers is higher in formulations containing the larger carriers, which leads to an increase in the dispersion of drug due to the increased mechanical forces occurred between the carriers and the device walls.