载体颗粒表面修饰对其表面能及粉雾剂性能的影响

目的研究载体的表面修饰对粉雾剂性能的影响。方法用不同的润滑剂对乳糖颗粒进行了表面修饰,并利用反向气相法测定了乳糖修饰前后的表面能,考察了表面能对干扰素α-2b粉雾剂沉积性能的影响。结果表面修饰后乳糖颗粒的流动性、表面光滑度都得到较大程度的改善,表面能也相应降低,而粉雾剂的性能得以提高。结论利用反向气相色谱法测定载体的表面能来预测粉雾剂的性能,可以为粉雾剂的处方设计和筛选提供一种快速有力的工具。     

Predicting the quality of powders for inhalation from surface energy and area

Purpose. To correlate the surface energy of active and carrier components in an aerosol powder to in vitro performance of a passive dry powder inhaler. Methods. Inverse gas chromatography (IGC) was used to assess the surface energy of active (albuterol and ipratropium bromide) and carrier (lactose monohydrate, trehalose dihydrate and mannitol) components of a dry powder inhaler formulation. Blends (1%w/w) of drug and carrier were prepared and evaluated for dry powder inhaler performance by cascade impaction. The formulations were tested with either of two passive dry powder inhalers, Rotahaler^® (GlaxoSmithKline) or Handihaler^® (Boehringer Ingelheim). Results. In vitro performance of the powder blends was strongly correlated to surface energy interaction between active and carrier components. Plotting fine particle fraction vs. surface energy interaction yielded an R² value of 0.9283. Increasing surface energy interaction between drug and carrier resulted in greater fine particle fraction of drug. Conclusions. A convincing relationship, potentially useful for rapid formulation design and screening, was found between the surface energy and area parameters derived from IGC and dry powder inhaler performance.     

Dry powder inhaler device influence on carrier particle performance

Dry powder inhalers (DPIs) are distinguished from one another by their unique device geometries, reflecting their distinct drug detachment mechanisms, which can be broadly classified into either aerodynamic or mechanical-based detachment forces. Accordingly, powder particles experience different aerodynamic and mechanical forces depending on the inhaler. However, the influence of carrier particle physical properties on the performance of DPIs with different dispersion mechanisms remains largely unexplored. Carrier particle trajectories through two commercial DPIs were modeled with computational fluid dynamics (CFD) and the results were compared with in vitro aerosol studies to assess the role of carrier particle size and shape on inhaler performance. Two percent (w/w) binary blends of budesonide with anhydrous and granulated lactose carriers ranging up to 300 μm were dispersed from both an Aerolizer? and Handihaler? through a cascade impactor at 60 L min(-1). For the simulations, carrier particles were modeled as spherical monodisperse populations with small (32 μm), medium (108 μm), and large (275 μm) particle diameters. CFD simulations revealed the average number of carrier particle-inhaler collisions increased with carrier particle size (2.3-4.0) in the Aerolizer?, reflecting the improved performance observed in vitro. Collisions within the Handihaler?, in contrast, were less frequent and generally independent of carrier particle size. The results demonstrate that the aerodynamic behavior of carrier particles varies markedly with both their physical properties and the inhalation device, significantly influencing the performance of a dry powder inhaler formulation.     

Effect of separation characteristics between salbutamol sulfate (SS) particles and model carrier excipients on dry powder for inhalation]

Most often dry powder for inhalation are formulated as ordered mixtures of a carrier excipient and a micronized drug substance. In the present study, model powder blends were prepared from a mixture of lactose alpha-monohydrate, micro-crystalline cellulose pellets or synthesized sugar as carrier particles, and micronized salbutamol sulfate (SS). These ordered mixtures were aerosolized by the multidose JAGO dry powder inhaler (DPI) and their in vitro deposition properties were evaluated by a twin impinger (TI). The separation force between SS particles and carrier particles was investigated by the centrifuge method. In addition, the use of the air jet sieve (AJS) method was investigated to assess the separation behavior of drug particles from carrier excipient. Powder blends were sieved through a 325 mesh wire screen of an air jet sieve at an air pressure of 1500 Pa. The amount of drug deposited at the carrier surface was analysed before and after the sieving to calculate the percentage of the drug retained. A relationship was found between in vitro deposition properties (fine particle fraction, FPF) and the separation characteristics obtained by the centrifuge method and by the AJS method. The AJS method might be a suitable alternative for evaluating separation of a drug particle from carrier particles and hence can be used for the formulation screening of the dry powder inhalation.     

Influence of the lactose grade within dry powder formulations of fluticasone propionate and terbutaline sulphate

Dry powder formulations are often composed of fine drug particles and coarser carrier particles, typically alpha-lactose monohydrate. However, the performance of a powder formulation may be highly dependent on the lactose quality and source. This study investigated the characteristics of lactose that influence the drug-to-carrier interaction and the performance of lactose-based dry powder inhaler formulations. The selected lactoses differed in the preparation processes and the content of fine lactose particles. Efficiency testing was done using fluticasone propionate and terbutaline sulphate as model drugs. Inverse gas chromatography was used to determine the surface heterogeneity distribution of different energy sites of the lactose and to understand the mechanism by which the fine carrier particles can improve the performance of dry powder inhalers. To assess the adhesion of respirable-sized drug to carrier particles, a simple method was developed based on aspiration and considering the whole blend as it is used in dry powder inhalers. When the percentage of fine lactose is high, a lower quantity of drug adheres to the lactose and/or the adhesion force is also lower. This was confirmed by the aerosolization assays done in the TSI (twin stage impinger). A correlation was observed between adhesion characteristics and inertial impaction. For both drugs, the fine particle fractions were highest in blends that present a greater proportion of lactose fine particles. A fairly good correlation between the fine particle fractions of both drugs and the peak max value and the AUC (area under curve) were found by inverse gas chromatography. With higher fine particle fraction values, which correspond to higher content of fines, the peak maxima determined by inverse gas chromatography were shifted to higher adsorption potentials, which supports the agglomeration hypothesis.     

The influence of drug morphology on aerosolisation efficiency of dry powder inhaler formulations

The physicochemical properties of two forms of spray dried bovine serum albumin (BSA) have been investigated using particle sizing, surface energy measurement, atomic force microscopy (AFM) and colloid probe microscopy. The BSA powder had similar particle size distributions and surface energy but significantly different morphologies and roughness, classified as smooth and corrugated BSA. Adhesion forces between the corrugated BSA and alpha-lactose monohydrate indicated median adhesion forces were significantly less than for smooth/carrier interaction forces. These observations correlated well with aerosolisation from BSA/carrier blends, where the corrugated BSA particles gave a higher fine particle fraction than the smooth BSA, suggesting reduced BSA/carrier adhesion and increased drug liberation. The use of corrugated drug particle morphology in drug carrier DPI systems may lead to improved aerosol performance through reduced drug carrier contact area.     

Carriers in drug powder delivery

The performance of dry powder inhaler (DPI) systems depends on the design of the powder formulation, the dose-metering system, and the device used to disperse the powder as an aerosol. Multiple factors associated with drug and carrier particles are known to influence dry powder performance. Elucidation of a mechanistic understanding of particulate system properties and how these relate to powder performance and the disruption of inter-particulate forces that cause aggregation has not yet been achieved. However, the complexity of interactions within dry powder formulations has not restricted research in this area. Various strategies of overcoming inter-particulate forces have been devised, ranging from active inhaler designs to powder engineering approaches. The influence of the interactive carrier system’s physicochemical properties (i.e. size, shape, chemical properties, surface roughness, electrostatics, humidity, and ternary excipients) on the performance of carrier-based systems has been examined extensively in the literature. In addition, matrix carriers, which contain drug and functional excipients for promotion of powder performance, control of pharmacokinetics, stability, controlled release of active drug and enhanced control of drug targeting, have also been investigated. Both the interactive carrier and matrix carrier approaches are attempts to develop DPI systems that perform as device-independent formulations and/or provide patient-independent delivery (controlled carrier systems). It seems likely that the future of DPI systems will combine both of these strategies with future developments in device design (formulation independency).     

Lactose modifications enhance its drug performance in the novel multiple dose Taifun DPI

Drug–carrier particle interactions greatly affect the detachment of drug from the carrier in inhalation powders. In this study, a novel multiple dose, reservoir-based Taifun^® was used as a dry powder inhaler, and the effects of carrier physical properties were evaluated on the pulmonary deposition of budesonide, along with physical stability of the inhalation powder. In this study, untreated commercial preparation of -lactose monohydrate, highly amorphous spray dried lactose, crystallized spray dried lactose, Flowlac-100^® and Flowlac-100^® mixed with crystalline micronized lactose were used as carriers. Dry powder formulations were prepared by the suspension method, where the budesonide–carrier ratio was 1:15.1 (w/w). Carriers and formulations were initially characterized, and again after 1 month’s storage at 40 °C/75% RH. The physical properties of the carriers strongly affected the pulmonary deposition of budesonide and the physical stability of the inhalation powder. Initially, amorphous contents of the carriers were 0–64%, but spontaneous crystallisation of the amorphous lactose occurred during storage and, thus all carriers were 100% crystalline after storage. When compared to an untreated -lactose monohydrate, the highly amorphous spray dried lactose and Flowlac-100^® did not improve aerosol performance of the inhalation powder. When crystalline spray dried lactose was used as a carrier, the highest RF% values were achieved, and RF % values did not alter during storage but the emitted budesonide dose was lower than the theoretical dose. When Flowlac-100^® mixed with crystalline micronized lactose was used as a carrier, the emitted budesonide dose was close to the theoretical dose, and high RF % values were achieved but these changed during storage.     

Interparticle forces in binary and ternary ordered powder mixes

An ultracentrifuge technique, previously described by Staniforth et al (1981), has been used to study the adhesion profiles of several binary and ternary ordered powder mixes of pharmaceutical interest. The adhesion profile of an ordered mix provides information about the proportion of drug powder adhering with different forces of attraction to the carrier excipient particle surface. The excipient particle size is shown to affect adhesion between the components of a binary ordered mix-recrystallized lactose formed more stable ordered mixes with drug powder when the carrier particle size was increased. Changes in the adhesion profile of each binary system on adding three different fine-powder excipients to form a ternary ordered mix are also examined. The physical properties of carrier particles and the charge interactions of a third powder component with previously formed binary ordered mixes, are found to influence the physical stability of ternary ordered mixes.     

Inverse gas chromatography: considerations about appropriate use for amorphous and crystalline powders

The use of inverse gas chromatography to assess surface properties of a range of pharmaceutical powders was examined. The powders were two sources of hydroxy propylmethyl cellulose (HPMC), microcrystalline cellulose, magnesium stearate, and acyclovir. These were selected to cover a range for properties from amorphous to crystalline, hydrophilic to hydrophobic, and high to low aqueous solubility. It was found that many powders gave a similar value for the dispersive surface energy, which is surprising given the differences in chemical nature. It is likely that this is due to the use of infinite dilution giving rise to the study of specific regions of the powder surface only. The values obtained for dispersive energies were not influenced by packing mass or flow rate of the carrier gas. The retention of polar probes on the column was a concern for the amorphous HPMC samples. This gave rise to derived values for acid-base nature which varied depending on sample mass and carrier gas flow rate. The data show that care must be taken when studying amorphous samples for which it is possible to obtain diffusion into the material rather than just surface adsorption of probes. Despite these problems, it was still possible to differentiate between the samples (including differences between the two HPMC samples) by use of polar probes. It was also possible to see differences in absorption into the sample, reflecting the different physical forms. For example, microcrystalline cellulose behaved very differently to HPMC. It can be concluded that inverse gas chromatography is a valuable characterization tool, but it must be used with care especially with respect to polar probes on amorphous samples.     

Characterization of physicochemical properties of naproxen systems with amorphous beta-cyclodextrin-epichlorohydrin polymers

Ground mixtures of naproxen with amorphous β-cyclodextrin-epichlorohydrin soluble (βCd-EPS) or insoluble cross-linked (βCd-EPI) polymers were investigated for both solid phase characterization (Differential Scanning Calorimetry, powder X-ray Diffractometry) and dissolution properties (dispersed amount method). The effect of different grinding conditions and of drug-to-carrier ratio was also evaluated. Co-grinding induced a decrease in drug crystallinity to an extent which depended on the grinding time, and was most pronounced for the cross-linked insoluble polymer, particularly in combinations at the lowest drug content. Both cyclodextrin polymers were more effective in improving the naproxen dissolution properties, not only than the parent βCd but also than hydroxyalkyl-derivatives, and their performance was almost comparable to that of methyl-derivatives, previously found as the best carriers for naproxen. Dissolution efficiencies of naproxen from physical mixtures with βCd-EPS, thanks to the high water solubility of this Cd-derivative, were up to three times higher than those from the corresponding products with βCd-EPI. However this difference in their performance became much less evident in co-ground products and tended to progressively diminish with increasing the polymer content in the mixture, according to the better amorphizing power shown by βCd-EPI during the co-grinding process. The 10/90 (w/w) drug–carrier co-ground products exhibited the best dissolution properties, giving dissolution efficiencies about 30 times higher than that of naproxen alone.     

Characterization of the surface properties of a model pharmaceutical fine powder modified with a pharmaceutical lubricant to improve flow via a mechanical dry coating approach

The aim of this study is to investigate the changes in physical and chemical surface properties of a fine lactose powder, which has been processed by a mechanical dry coating approach. A commercially available milled lactose monohydrate powder (median diameter around 20 μm) was dry coated with a pharmaceutical lubricant, magnesium stearate (MgSt). Substantial changes in bulk behavior have been shown previously and the purpose of the current work was to understand the relationship between these bulk changes and physico-chemical changes in the surface. X-ray photoelectron spectroscopy and time-of-flight secondary ion mass spectrometry results demonstrated both qualitatively and quantitatively how the chemical properties of the lactose particle surfaces had been altered. The characterization results indicated that a high-level coverage of a thin coating layer of MgSt has been created through the coating. Inverse gas chromatography was used to probe the surface energetic changes, and at conditions of finite dilution, provided a new insight into surface energy changes. This work demonstrated that the modifications of the surface physical and chemical properties correlated with the reduction in powder cohesion and improvement in powder flow.     

Evaluation of SCF-engineered particle-based lactose blends in passive dry powder inhalers

The objective of this study was to assess the performance of SCF-engineered budesonide and albuterol sulfate powder blends in passive dry powder inhalers (DPI) relative to micronized drug blends. A number of lactose grades for inhalation were screened and the appropriate carrier and drug-to-lactose blending ratio were selected based on drug content and emitted dose uniformity. Aerosol performance was characterized by Andersen cascade impaction. Blend formulations of SEDS (solution enhanced dispersion by supercritical fluids) budesonide and albuterol exhibited a significant drug content uniformity (7-9% RSD) improvement over micronized drug blends (16-20% RSD). Further, the SEDS formulations demonstrated higher emitted dose and reduced emitted dose variability (10-12% RSD) compared to micronized powders (21-25% RSD) in the Turbospin, albeit without significant enhancement of the fine particle fraction. In contrast, SEDS powders exhibited increased fine particle fractions over micronized blends in the Clickhaler; improvements were more pronounced with albuterol sulfate. The performance enhancements observed with the SEDS powders are attributed to their increased surface smoothness and reduced surface energy that are presumed to minimize irreversible drug-carrier particle interactions, thus resulting in more efficient drug detachment from the carrier particle surface during aerosolization. As demonstrated for budesonide and albuterol, SEDS may enhance performance of lactose blends and thus provide an attractive particle engineering option for the development of blend formulations for inhalation delivery.     

Effect of mixing of fine carrier particles on dry powder inhalation property of salbutamol sulfate (SS)

The most commonly used formulations for dry powder inhalations are binary ordered mixes composed of micronized drugs and coarse carriers. An optimal dry powder aerosol formulation should possess an optimal inhalation property and a good flow property. These characteristics are especially important for a multidose dry powder inheler (DPI). In the present study, model powder blend were prepared consisting of synthesized sugar (different particle sized isomalt; IM-PF, IM-FS, IM-F) as a carrier and micronized salbutamol sulfate (SS). These ordered mixtures were aerosolized by the multidose JAGO DPI (SkyePharma AG) and in vitro deposition properties (fine particle fraction, FPF) were evaluated by a twin impinger (TI) at a flow rate of 60 l/min. The separation property between SS and carrier particles was investigated by the centrifuge method and air jet sieve (AJS) method. It was found that FPF decreased with increasing carrier particle size. However, a large carrier particle possesses a good flow property. Therefore, the effect of mixing of fine carrier particles (IM-PF) into the large carrier particles (IM-FS) on dry powder inhalation property was investigated. When the proportion of IM-PF (fine carrier) increase from 0% to 25% of the total carrier powder blend, the FPF also increases from 16.7% to 38.9%. It is concluded that the effect of mixing of fine carrier particles might be a suitable method for improving the dry powder inhalation properties.     

Influence of physico-chemical carrier properties on the in vitro aerosol deposition from interactive mixtures

Interactive mixtures were prepared containing 5% (w/w) salbutamol sulfate using various lactose carrier systems, including sieved fractions and blended mixtures of coarse and fine particles. The solid state and powder properties of the lactose carriers were examined by laser diffraction, differential scanning calorimetry, thermogravimetric analysis, powder X-ray diffraction, vapor sorption gravimetry, rotating drum and atomic force microscopy. The in vitro aerosol deposition was determined using a twin-stage impinger with a Rotahaler at an airflow rate of 60l/min. The fine particle fraction (FPF) of salbutamol sulfate was determined using a validated HPLC assay. All samples were highly crystalline with minimal moisture sorption and the major phase in all samples was alpha-lactose monohydrate. Significant differences in FPF were observed using the various carrier systems. FPF increased with decreasing carrier d(50%) (r(2)=0.919) and increasing proportion of fine carrier particles (below 5 microm) (r(2)=0.841). Carriers consisting of very large proportions of fine particles showed low FPF and did not fit the correlation. The presence of coarse carrier particle fractions was essential to achieve maximum FPF, which occurred when about 10% of fine carrier particles were present in the mixture. Dispersion characteristics may be related to the degree of drug aggregation on the carrier surface.     

Evaluation of the carrier potential for the lipid dispersion system with lipophilic compound

KW-3902 (a newly synthesized adenosine A(1)-receptor antagonist) has potent diuretic and renal protective activities and was formulated in lipid dispersion systems, i.e., lipid emulsions and liposomes. The objective of the present study was to evaluate the carrier potential of these lipid dispersion systems, which is explained here as the ability of the formulation to retain the drug in its dispersed phase. The relative affinity of the drug to the formulation, K(f/b), was defined as a parameter in order to assess the performance of the formulations and was obtained from the in vitro blood component binding study. The results indicated that KW-3902 showed higher relative affinity to the liposome formulation than to the lipid emulsion. Moreover, the total amount of drug retained in the dispersion system depended on both K(f/b) and the dosing volume. The usefulness of the parameter, K(f/b), was discussed as an indicator for a carrier potential to understand the properties of the formulations.     

The impact of low-level inorganic impurities on key physicochemical properties of paracetamol

Trace inorganic impurities in active pharmaceutical ingredients (APIs) while having limited toxicological significance might affect the down stream processing properties of those substances. The level of impurities in paracetamol batches was quantified and mapped using inductively coupled polarization mass spectrometry (ICP-MS) and scanning electron microscopy coupled with energy dispersive X-ray microanalysis (SEM-EDX). The physical form of samples was assessed using X-ray powder diffraction (XRPD) and characterised thermally using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Surface properties were evaluated using inverse gas chromatography (IGC) and moisture sorption. Size distribution was measured using an aerosizer with dry powder dispersion. Physical analysis confirmed that the batches were of the same physical form and particle size distribution was shown to be similar. The SEM-EDX analysis however revealed the presence of aluminium on the surface of particles. This was supported by ICP-MS analysis, which showed different levels of aluminium between batches ranging from 0.1 to 5.6 ppm. IGC indicated that the batches with the highest aluminium content had the highest dispersive free energy. Differences in levels of inorganic impurities typically not considered significant in drug substance specifications correspond with differences in physical properties of APIs, with potential downstream consequences for processing and finished product performance.     

Influence of primary crystallisation conditions on the mechanical and interfacial properties of micronised budesonide for dry powder inhalation

Investigate the influence of primary crystallisation conditions on the mechanical properties and secondary processing behaviour of budesonide for dry powder inhaler (DPI) formulations. Young's modulus of two batches of budesonide crystals (samples A and B) produced using different anti-solvents was determined using nanoindentation. Physicochemical and surface interfacial properties via the cohesive-adhesive balance (CAB) approach to colloid probe atomic force microscopy (AFM) of air-jet micronised budesonide crystals were also investigated. These data were correlated to in vitro aerosolization performance of carrier-based DPI formulations containing either budesonide samples A or B and lactose monohydrate. Young's modulus of budesonide samples A and B crystals was 0.95 and 4.04 GPa, respectively. Sample A crystals with low Young's modulus exhibited poorer micronisation efficiency than sample B. CAB analysis of micronised budesonide samples A and B, suggest that sample B budesonide had a greater adhesion to lactose than sample A. These data correlated with in vitro aerosolisation studies, which showed that the fine particle delivery of budesonide sample A was higher than that of sample B. In conclusion, crystallisation conditions may affect the mechanical properties of budesonide, and therefore secondary processing of the material and their interfacial properties and product performance in carrier based DPI formulations.     

Influence of crystal form of ipratropium bromide on micronisation and aerosolisation behaviour in dry powder inhaler formulations

Objectives This study aimed to investigate the relationship between the mechanical properties of anhydrous and monohydrate ipratropium bromide (IB) crystals, their processing behaviour upon air‐jet micronisation and aerosolisation performance in dry powder inhaler (DPI) formulations. Methods IB monohydrate and anhydrous crystals were produced from seed crystals and supercritical carbon dioxide crystallisation, respectively. Young's modulus of anhydrous and monohydrate IB crystals was determined using nanoindentation. For air‐jet micronised crystals, the physicochemical and surface interfacial properties via the cohesive–adhesive balance (CAB) approach were investigated. These data were correlated to in‐vitro aerosolisation performance of carrier‐based DPI formulations containing either anhydrous or monohydrate IB. Key findings Particle size and Young's modulus of both crystals were similar and this was reflected in their similar processing upon micronisation. Particle size of micronised anhydrous and monohydrate crystals were similar. CAB measurements of the micronised particles of monohydrate or anhydrous forms of IB with respect to lactose were 0.70 (R² = 0.998) and 0.77 (R² = 0.999), respectively. These data suggested that both samples had similar adhesion to lactose, which correlated with their similar in‐vitro aerosolisation performance in DPI formulations. Conclusions Monohydrate and anhydrous crystals of IB exhibited similar mechanical properties and interfacial properties upon secondary processing. As a result, the performance of the DPI formulations were similar.