Search

OBJECTIVE: This study aimed to investigate the effects of ticagrelor on myocardial microcirculation, cardiac function, and adverse cardiovascular events in ST-segment elevation myocardial infarction (STEMI) patients after percutaneous coronary intervention (PCI). PATIENTS AND METHODS: A total of 80 STEMI patients admitted to our hospital from February 2020 to March 2023 were selected and included in the retrospective study, all receiving PCI treatment. They were randomly and retrospectively divided into a control group (40 cases) and an observation group (40 cases), and treated with clopidogrel and ticagrelor, respectively. The clinical effects were compared. RESULTS: The starting perfusion time of the contrast agent in the myocardial infarction area in the observation group was 2.22±0.27 s, and the peak perfusion time was 2.62±0.27 s, which was lower than those in the control group (2.51±0.29 s and 3.21±0.39 s, t=4.629, 7.867, p=0.000). The ratio of peak perfusion intensity between the two groups was significantly different (t=2.363, p=0.021). Left ventricular ejection fraction, stroke volume index, and cardiac index in the observation group were higher than those in the control group (55.03±6.03 vs. 52.33±5.13; 57.39±6.81 vs. 51.11±6.31 L/min·m-2; 3.49±0.45 vs. 3.12±0.38 mL/m2, t=2.157, 4.278, 3.973, p<0.05). The observation group had lower levels of brain natriuretic peptide and C-reactive protein compared to the control group (425.35±55.71 vs. 589.36±70.24 pg/mL; 15.13±1.03 vs. 21.64±2.74 mg/L; t=11.570, 14.066, p=0.000). There was no statistical significance in the incidence of adverse cardiovascular events between the two groups (2.50% vs. 7.50%, 2=1.920, p=0.166). CONCLUSIONS: The use of ticagrelor can regulate myocardial microcirculation and improve cardiac function in STEMI patients undergoing PCI. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The optimal time to start renal replacement therapy (RRT) for acute kidney injury (AKI) remains controversial. We aim to compare the effects of early vs. delayed RRT initiation on clinical outcomes in adult patients with AKI. MATERIALS AND METHODS: PubMed, Embase, Cochrane Library, Web of Science, Chinese Biomedical Literature Database, ClinicalTrials.gov, and the International Clinical Trial registry platform were systematically searched from inception to 7 August 2022. The review included randomized clinical trials (RCTs) comparing early and delayed initiation of RRT in AKI patients. The selected primary outcomes were short-term and long-term mortality. Secondary outcomes included RRT dependency, intensive care unit (ICU) length of stay, hospital length of stay, mechanical ventilator-free days, vasoactive agents-free days, RRT-free days, and adverse events. RESULTS: Overall, 15 RCTs, including 5,625 patients, were analyzed. Early RRT showed no survival benefit when compared to the delayed therapy (28-or 30-day mortality: RR, 1.01, 95% CI: 0.94- 1.08, p = 0.87; 60-day mortality: RR, 0.87, 95% CI: 0.71-1.06, p = 0.16; 90-day mortality: RR, 1.00, 95% CI: 0.88-1.13, p = 0.97; in-hospital mortality: RR, 1.05, 95% CI: 0.88-1.24, p = 0.58; ICU mortality: RR, 1.00, 95% CI: 0.91-1.10, p = 0.98). The delayed RRT did not lead to a higher risk of RRT dependency, ICU, or hospital length of stay than the early RRT. Similarly, early initiation of RRT did not lead to longer ventilator-free, vasoactive agent-free, and RRT-free days. However, early RRT initiation was associated with more adverse events. CONCLUSIONS: Our study suggested that early RRT initiation was not associated with survival benefits or better clinical outcomes and increased the risk of RRT-associated adverse events. Current evidence does not support the use of early RRT for AKI patients without urgent indications. [ABSTRACT FROM AUTHOR]

By exposing floating gates of EEPROM memory cells with frontside sample preparation, scanning nonlinear dielectric microscopy (SNDM) succeeded in reading back the data stored in the memory cells with a 250 nm node size. At an optimized voltage bias of AC = 3 V and DC = 1 V, a clear signal contrast between programmed and erased cells is obtained. The high resolution SNDM signal reveals the details of bowling-pin shape structure of memory cells, providing high confidence in data assignment during forensic applications. Such high resolution also makes SNDM a promising technique for newer generation devices with smaller node size. [ABSTRACT FROM AUTHOR]

A custom-built gas cluster ion source with an energy up to 20 keV is constructed. Ar, CO2, N2, and O2 are used as the working gases. The clusters are formed by metal conical nozzles with critical diameters of 65−135 um and a cone angle of 14°. To facilitate evacuation of the chambers we use the pulse mode of nozzle feeding. This allows an increase in the gas pressure in the stagnation zone (inlet pressure) up to 15 bar. The current of the clusters with an energy of 20 keV is 20 µA; the maximal current density is 3 µA/cm2. The mass spectra of the argon clusters formed at different pressures and electron ionization energy are studied by time-of-flight spectroscopy. The inlet pressure dependence of the mean cluster size is considered as a function of the condensation parameter Г*. An argon cluster beam is used to smooth the surface of the titanium coating and pressed silicon nanopowder. The roughness of the Ti coating surface decreases from 3.7 to 0.8 nm; the removal of microparticles from the surface is also observed. In the case of the surface of Si, besides the smoothing effect the formation of 100 nm craters is observed. [ABSTRACT FROM AUTHOR]

This study proposes the generality of surface air temperature ( SAT)-atmospheric circulation feedback during high-temperature weather in late July 2003 over East China by using the Advanced Research Weather Research and Forecasting model ( WRF; Version 3) simulations with a succession of 24-h integrations, i.e. on a daily scale, the SAT increase leads to a weakened ridge of the western Pacific subtropical high in the lower troposphere (i.e. negative feedback), whereas it leads to a strengthened ridge in the upper troposphere (i.e. positive feedback) and vice versa. Additionally, using the balance equation of temperature, the feedbacks are clarified from the diurnal-variation perspective. This shows many complex details, e.g. the changes in geopotential heights are more complex than those in air temperatures, and the overall daily feedback appears to be dominated by the feedback during the phase with intense daytime surface heating. All of the WRF-modified land surface conditions can lead to large changes in the maximum, minimum, and average SATs over the mean diurnal scale, with generally larger differences induced by land surface schemes than those induced by initial soil moisture, suggesting that the SAT-circulation feedback can be greatly reduced (or amplified) by different land conditions over the diurnal weather scale and that diurnal variations could substantially contribute to longer timescale climate. [ABSTRACT FROM AUTHOR]

The Sichuan-Chongqing area in China has complex basin topography and is known for its extremely hot summer weather. In this paper, the mesoscale model WRF version 3.6.1 was used to simulate a period of 1–10 days in advance of the hot weather that occurred in Sichuan-Chongqing on August 10, 2006, to investigate the effect of six different land surface schemes (LSSs) (SLAB, RUC, PX, NOAH, NOAH_MP, and CLM4) on short- and medium-range simulations of high temperatures. The simulated surface air temperatures (SATs) are sensitive to the LSSs and simulation lengths. Specifically, all of the LSSs except PX generally reproduce the observed high temperatures, with CLM4 SATs at 06 UTC (SAT06) the most consistent with measurements whereas the short-range (medium-range) results from NOAH_MP (NOAH) are the worst. Detailed explanations were given in terms of surface fluxes and physical processes. RUC soil moisture initialization appears poor and the LSS reflects too strong gravity drainage. When the LSSs with increased numbers of soil layers are used, the simulated high temperatures are found more consistent with measurements. Additionally, regional sensible heat flux (SHF) does not show high consistency with SAT. The results that differ from the previous studies are partly due to the complex geography and the LSS deficiencies. [ABSTRACT FROM AUTHOR]

AKT pathway has a critical role in mediating signaling transductions for cell proliferation, differentiation and survival. Previous studies have shown that AKT activation is achieved through a series of phosphorylation steps: first, AKT is phosphorylated at Thr-450 by JNK kinases to prime its activation; then, phosphoinositide-dependent kinase 1 phosphorylates AKT at Thr-308 to expose the Ser-473 residue; and finally, AKT is phosphorylated at Ser-473 by several kinases (PKD2 and others) to achieve its full activation. For its inactivation, the PH-domain containing phosphatases dephosphorylate AKT at Ser-473, and protein serine/threonine phosphatase-2A (PP-2A) dephosphorylates it at Thr-308. However, it remains unknown regarding which phosphatase dephosphorylates AKT at Thr-450 during its inactivation. In this study, we present both in vitro and in vivo evidence to show that protein serine/threonine phosphatase-1 (PP-1) is a major phosphatase that directly dephosphorylates AKT to modulate its activation. First, purified PP-1 directly dephosphorylates AKT in vitro. Second, immunoprecipitation and immunocolocalization showed that PP-1 interacts with AKT. Third, stable knock down of PP-1α or PP-1β but not PP-1γ, PP-2Aα or PP-2Aβ by shRNA leads to enhanced phosphorylation of AKT at Thr-450. Finally, overexpression of PP-1α or PP-1β but not PP-1γ, PP-2Aα or PP-2Aβ results in attenuated phosphorylation of AKT at Thr-450. Moreover, our results also show that dephosphorylation of AKT by PP-1 significantly modulates its functions in regulating the expression of downstream genes, promoting cell survival and modulating differentiation. These results show that PP-1 acts as a major phosphatase to dephosphorylate AKT at Thr-450 and thus modulate its functions. [ABSTRACT FROM AUTHOR]

In this paper, we strengthen some of Leindler's results from [L. Leindler. Embedding relations of Besov classes. Acta Sci. Math. (Szeged), 73(2007)133-149.] under GBV condition. First, we discuss embedding relations between two Besov classes. Next, we give an equivalent estimate for the k-order modulus of continuity of f (x) in Lp norm under GBV condition. Finally, we give the condition to ensure a function f ∈ Lp have Fourier coefficients of GBV belongs to the Besov class. [ABSTRACT FROM AUTHOR]

The aim of the study was to investigate the interdependence of carrier particle size, surface treatment of the carrier, and inclusion of fines on the drug delivery from dry power inhaler formulations. Two size fractions (< 63 and 63-90 microm) of alpha-lactose monohydrate were subjected to treatment with 95% (v/v) ethanol to introduce small asperities or cavities onto the otherwise smooth surface without substantially changing the particle shape. After blending with albuterol sulfate [ALB; volume median diameter (VMD), 1.9 microm; geometric standard deviation (GSD), 1.5], the solvent-treated lactose produced a fine particle fraction (FPF; < 6.18 microm) and dispersibility of the drug that was significantly (ANOVA p < 0.01) lower than that which resulted from formulations containing untreated lactose of a similar size fraction, after aerosolization at 60 L min(-1) via a Rotahaler. The two size fractions of the treated lactose resulted in similar deposition profiles of ALB. The effects of such surface asperities or cavities of lactose were offset by introducing a small amount (5% w/w) of smaller-sized lactose (5-10 microm) to the powder formulations. The fine lactose increased the FPF and dispersibility of ALB to such a level that all lactose batches, regardless of particle size or whether solvent treated, produced a similar fraction of aerosolized ALB. The inclusion of recrystallized needle lactose (5-15 microm) was superior to micronized lactose in improving the aerosolization of ALB. The findings of this study indicate that the presence and characteristics of the finer fraction of lactose carrier particles dominate over the particle size and surface smoothness of the carrier particles in determining dispersion and deaggregation of drugs from dry powder formulations for inhalation., (Copyright 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association)

The purpose of the present study was to investigate the effects of molecular weight (MW) of polyvinylpyrrolidone (PVP) on glass transition and crystallization of sucrose. Thus, sucrose was co-lyophilized with 2.5 and 5.0% w/w PVP of different molecular weights, which were characterized using gel permeation chromatography. Freeze drying was carried out for 48 h at a shelf temperature of -40 degrees C and a pressure of about 36 Pa. The samples were then dried in a vacuum oven at 24 degrees C for 12 h before drying for a further 12 h at 40 degrees C. Differential scanning calorimetry (DSC) was employed to measure the glass transition temperature (Tg), dynamic crystallization temperature (Tc) and isothermal crystallization induction time (tc) at 85 degrees C of sucrose. Isothermal water vapour sorption of each sample was also measured at different relative humidities. Tg values of sucrose varied from 48.3+/-0.8 degrees C for freeze-dried (FD) sucrose alone to 58.8+/-0.8 degrees C for the mixture containing 5.0% PVP of nominal MW 300 K. PVP increased sucrose T(g) significantly (ANOVA P<0.05). Although there was no significant difference (P>0.05) in Tg of the mixtures containing 2.5% w/w PVP of different MW, samples with 5.0% PVP of MW 300 K produced a significantly higher (P<0.05) Tg than the other mixtures. All mixtures were shown to possess higher (P<0.01) Tc than FD sucrose alone, which exhibited a T(c) of approximately 85 degrees C. PVP of MW 300 K consistently induced a significantly (P<0.05) higher Tc of sucrose than PVP of smaller MW. Increasing PVP concentration from 2.5 to 5.0% also resulted in a substantial increase in sucrose Tc. Using isothermal water vapour absorption, sucrose tc was found to increase up to over 10 times when it was co-lyophilized with 2.5% PVP, the actual value of tc being dependent upon the MW of the PVP. For example, PVP of MW 300 K resulted in a sucrose tc at 85 degrees C (89.1-95.6 min), which was approximately seven times higher than that of 2.5% PVP of MW 24 or 40 K. A longer tc of sucrose was also observed for mixtures containing PVP of MW 300 K than when sucrose was mixed with PVP of smaller MW. Thus the effect of PVP on sucrose Tg, Tc and tc was found to be dependent upon MW. PVP of higher MW was more efficient in inhibiting sucrose crystallization and by stabilizing glassy structures of the sugar, these polymers may improve the stability of co-lyophilized proteins and peptides.

The aim of this study was to investigate the dispersion and deaggregation of a model drug, salbutamol sulphate (SS), using lactose, mannitol or sorbitol as coarse and fine carriers. Binary and tertiary formulations containing micronised salbutamol sulphate (SS) and sieved (63-90 microm) coarse sugar crystals or salbutamol sulphate (SS) with a mixture of coarse and fine sugar particles were prepared. Factorial design was employed to investigate the effects of three variables, i.e. the chemical entity of the coarse sugar carrier, the chemical entity of the fine sugar and the concentration of fine sugar, on the dispersion and deaggregation of salbutamol sulphate after aerosolisation at 60 l/min via a Rotahaler(R) into a twin stage liquid impinger (TSI). The binary formulations containing the different sugar entities produced differences in the fine (<6.4 microm) particle fraction (FPF) of SS in a decreasing order of mannitol >sorbitol >lactose, but failed to produce efficient dispersion of SS since the FPF was <10%. Adding fine sugar particles and increasing their concentration to the binary mixtures generally resulted in an increase in the FPF of salbutamol sulphate. The chemical nature of the fine carriers was found to play a less important role in determining respirable fraction of the drug than the coarse carriers. In conclusion, other sugars such as mannitol or sorbitol, besides lactose, may be employed as coarse and/or fine carriers for incorporation into dry powder aerosol formulations to increase FPF.

We have investigated the interdependence of various factors (particle size, surface smoothness, carrier particle shape, inhalation flow rate) on the deposition of a model drug (salbutamol sulphate) after aerosolization from a model inhaler device (Rotahaler). Different batches of alpha-lactose monohydrate were prepared to have different particle size, particle shape and surface smoothness. Each batch of lactose was then mixed separately with salbutamol sulphate in a ratio of 67.5 : 1 (w/w), under similar conditions. Drug deposition from each formulation was investigated using a 4-stage liquid impinger after aerosolization at 28.3, 60.0 and 96.0 L min(-1) via a Rotahaler. At a flow rate of 28.3 L min(-1), a large portion of drug particles was not emitted from the inhaler, the % emission varying from 29.6% to 66.6% for all formulations investigated. Drug emission tended to increase with particle size of the carrier whilst fine particle fraction, fine particle dose and dispersibility appeared to increase with decreasing particle size but increasing elongation ratio of the carrier particles. Increasing the flow rate to 60.0 L min(-1) was shown to increase drug emission since > 75% total dose was found to be emitted from the inhaler. Again, smaller or more elongated lactose particles resulted in a higher fine particle dose or fine particle fraction of salbutamol sulphate than the coarser carrier, although they produced a similar (analysis of variance P > 0.05) drug emission. Increasing the flow rate to 96.0 L min(-1) did not increase drug emission. Increasing the flow rate resulted in an increase in the fine particle fraction and fine particle dose of salbutamol sulphate from all formulations. The flow rate of the airstream appeared to play the most important role, followed by particle size and elongation ratio of the carrier particles, with the surface smoothness relatively less significant in determining the deposition of salbutamol sulphate from the Rotahaler.

Purpose: To crystallize lactose under static conditions with a view to preparing crystals of well-defined morphology., Methods: et-Lactose monohydrate was crystallized from neutralized Carbopol 934 gels. When the majority of crystals had grown to maturity, the gels were acidified using diluted hydrochloric acid and the crystals were harvested by filtration or centrifugation and washed with ethanol-water mixtures., Results: Crystals prepared from the gel had a consistently narrower size distribution than control crystals, prepared from solution under constant stirring. If crystallization was effected in the gel without sedimentation of the crystals, then the resultant crystals had smooth surfaces without visually detectable surface roughness or asperities viewed by optical microscopy. The crystals from Carbopol gels also exhibited the uniform shape of an elongated tomahawk regardless of the crystallization conditions, in contrast to crystallization under constant stirring, where the crystal shape of lactose changed with crystallization conditions especially as a function of the initial concentration of lactose. All batches of lactose crystals prepared from Carbopol gels existed as alpha-lactose monohydrate, which showed better flowability than the controls of a similar particle size., Conclusions: Crystallization from Carbopol gel produces lactose crystals of uniform size, regular shape, smooth surface, and improved flowability.

Lactose has been widely used as a carrier for inhalation aerosols. The carrier morphology is believed to affect the delivery of the drug. The aim of this study was to investigate the effects of crystallization conditions on the morphology of alpha-lactose monohydrate intended for use as the carrier for dry powder aerosols. The crystallization of lactose was carried out from aqueous solutions at different supersaturations, temperatures, different stages of crystallization and in the presence of different water-miscible organic solvents. The majority of lactose crystals were found to be either tomahawk-shaped or pyramidal after crystallization at an initial lactose concentration between 33-43% w/w, but these became prismatic if the lactose concentration was increased to 50% w/w. A further increase in the lactose concentration to 60% w/w led to the preparation of elongated cuboidal crystals. Higher initial lactose concentrations tended to result in the crystallization of more elongated particles. Crystallization at 40 degrees C was shown to prepare lactose crystals with a more regular shape and a smoother surface than those crystallized at 0 degrees C. Lactose particles generated during the later stage of crystallization were found to be more regular in shape with a smoother surface than those prepared in the earlier stage. The addition of 10% (v/v) methanol or ethanol or acetone to the mother liquor increased the growth rate of lactose particles whereas addition of propanol or glycerine inhibited the rate of crystal growth. Lactose crystals prepared in the presence of glycerine were more regularly shaped with a smoother surface than those prepared in the presence of ethanol or acetone. All the resultant crystals were shown to comprise alpha-lactose monohydrate. Lactose crystals could be prepared with a precisely defined morphology by means of carefully controlling the crystallization conditions.

Alpha-lactose monohydrate was prepared to have different morphological features but with similar particle size. The crystal shape and surface smoothness of lactose were quantified by a number of shape descriptors and these were supported qualitatively by the visual examination of scanning electron (SE) micrographs of the crystals. All batches of lactose were subjected to a similar history of processing before blending separately with micronised salbutamol sulphate (SS) in a ratio of 67.5:1, w/w, using similar procedures. In vitro deposition of SS from these formulations was investigated after aerosolisation of the formulations at 60 l min(-1) via the Rotahaler and the Cyclohaler into a twin stage liquid impinger. The formulations prepared using the different batches of lactose produced different deposition profiles of SS. The fine particle (< 6.4 microm) fraction (FPF) of aerosolised SS varied from 12.6 +/- 2.4 to 25.6 +/- 1.5% after aerosolisation from the Cyclohaler whilst it changed from 15.0 +/- 2.2 to 24.4 +/- 0.8% after aerosolisation from the Rotahaler. The fine particle dose (FPD) and dispersibility of SS followed a similar trend to the change in the FPF of the drug. No significant difference (ANOVA P > 0.05) was observed for the deposition profiles of SS after aerosolisation from the Rotahaler and the Cyclohaler. The FPF and dispersibility of SS increased with either the surface smoothness (P < 0.01) or elongation ratio (P < 0.01) of lactose crystals. The t-ratio values of FPF and dispersibility of SS generated by changes in the surface smoothness were similar to those resulting from changes in elongation ratio. Increasing either the surface smoothness or the elongation ratio of lactose crystals will increase the potentially respirable fraction of SS from dry powder formulations for inhalation.

Dry powder formulations for inhalation usually comprise a mixture of coarse lactose (CL), employed as a carrier, and micronized drug. It was the aim of this study to determine the effects of fine lactose (FL), blended as a tertiary component on the mixing homogeneity and dispersibility of a model hydrophobic drug, beclomethasone dipropionate (BDP). BDP particles (volume median diameter (VMD) 4.6 microm) existed mainly as agglomerates, the majority of which were not dispersed into primary particles after aerosolization at a high shear force (4.7 psi). The resultant particle size distribution of BDP was multi-modal with VMD varying between 4.7 and 30.2 microm. Ternary interactive mixtures were prepared to consist of CL, FL and BDP with a fixed ratio of lactose to BDP of 67.5:1 w/w, but two concentrations of FL, i.e. 2.5 and 5%, w/w. The mixing was carried out using different sequences of adding the three components for two mixing times (15 and 60 min). Binary mixtures composed of CL and BDP were prepared for both mixing times as the controls, and these exhibited a coefficient of variation (COV) in BDP content <= 5%. Addition of FL to the binary formulations greatly reduced the content uniformity of BDP if the final powder were prepared by first mixing CL with FL before mixing with the drug (COV>20%, after mixing for 15 min). However, the mixtures, prepared using other mixing sequences, had a similar uniformity of BDP content to the binary mixtures. All ternary mixtures containing 2.5% FL consistently produced a significantly higher (ANOVA P<0.01) fine particle fraction (FPF, 3.1--6.1%) and fine particle dose (FPD, 13.6--30.1 microg) of BDP than the binary mixtures (FPF, 0.3-0.4%; FPD, 1.6-2.1 microg) after aerosolization at 60 l min(-1) via a Rotahaler into a twin stage liquid impinger. The mixing sequences exerted a significant (P<0.05) effect on the dispersion and deaggregation of BDP from the formulations prepared using a mixing time of 15 min but such an effect disappeared when the mixing time was lengthened to 60 min. The dispersibility of BDP was always higher from the ternary mixtures than from the binary mixtures. BDP delivery from dry powder inhalers was improved markedly by adding FL to the formulation, without substantial reduction in the content uniformity of the drug.

Five different grades of lactose namely, anhydrous lactose, medium lactose, regular lactose, lactose crystals and foremost lactose were fractionated under similar conditions to obtain a size range of 63-90 microm and were characterised using laser diffraction and time-of-flight particle sizing techniques, scanning electron microscopy, optical microscopy image analysis, thermal gravimetric analysis and differential scanning calorimetry. Each of these lactose fractions were then blended separately with micronised salbutamol sulphate in a ratio of 67.5:1 (w/w). The mixing uniformity and percentage recovery of salbutamol sulphate in the powder blends were analysed using a validated HPLC method. The deposition profiles of the drug were determined using a 5-stage liquid impinger after aerosolisation at 60 l min(-1) via a Rotahaler. Despite the identical processing conditions, the lactose fractions were shown to differ in particle size, size distribution and concentrations of fine particles. The particles from each fraction also exhibited different surface textures and dissimilar DSC thermograms. However, all the blends of the lactose with salbutamol sulphate were found to have a relatively high uniformity of salbutamol sulphate content, as suggested by a coefficient of variation of less than 3.2%. Anhydrous and medium lactose produced a more efficient delivery of salbutamol sulphate when aerosolised from the Rotahaler in comparison to other grades of lactose. For example, the fine particle fraction (FPF) and fine particle dose (FPD) of drug from formulations containing anhydrous lactose were 13.4+/-4.2% and 57.3+/-17.6 microg, respectively, which were approximately two times higher than the respective values of the formulation containing regular lactose. Medium lactose resulted in drug FPF (7. 9+/-2.7%) and FPD (32.4+/-11.8 microg), which were significantly (ANOVA P<0.05) higher than the same parameters obtained using lactose crystals, foremost lactose and regular lactose. More efficient drug delivery from anhydrous lactose may be partly attributed to the relatively higher concentration of fine lactose in this grade of carrier, although it showed a rougher surface than the other grades of lactose. However, the relatively high FPF of the drug from medium lactose may have been due to the relatively small mean particle size and smooth surface of the particles. Therefore, the source and grade of lactose may have a substantial effect on drug delivery from dry powder inhaler formulations and care should be taken in establishing appropriate quality control parameters when selecting an appropriate grade of carrier.

Ternary mixtures composed of coarse lactose (CL) (90.8 microm), salbutamol sulphate (SS) (5.8 microm) and either micronised lactose (ML) (5 microm) or intermediate sized lactose (IML) (15.9 microm) in a ratio of 66.5:1:1 w/w were prepared using different mixing sequences of the various components. In addition, a binary mixture composed of CL and SS (67.5:1 w/w) was also prepared as the control. The in vitro deposition of SS was measured using a twin stage impinger after aerosolisation at 60 and 90 l min-1 via a Rotahaler. The aerodynamic particle size distribution of both the aerosolised SS and lactose was further analysed using an Andersen cascade impactor at 60 l min-1. All ternary mixtures produced a significantly higher (analysis of variance, P<0.01) fine particle fraction (FPF) and fine particle dose (FPD) of SS than the control after aerosolisation at either 60 or 90 l min-1. Formulations containing the ML produced significantly (P<0.05) higher FPF and FPD of SS than those containing the IML at both aerosolisation flow rates. Different mixing sequences were also shown to result in different deposition profiles of both SS and lactose after aerosolisation of the ternary mixtures containing ML at 60 l min-1. The formulation prepared by first blending ML with CL before mixing with SS produced a higher FPF and FPD of SS but a lower FPF of lactose than the same formulation in terms of composition but prepared using different mixing orders of the three components. In contrast, the formulations containing IML produced a similar deposition profile to SS, regardless of the mixing sequences, and so did the formulations containing ML aerosolised at 90 l min-1. These results suggest that the effect of mixing sequences on drug deposition may become more prominent at lower aerosolisation flow rates and by reducing the size of any added fine lactose.