Effect of milling and sieving on functionality of dry powder inhalation products

Alpha-lactose monohydrate is the standard excipient used as diluent or carrier in dry powder inhaler (DPI) formulations. Earlier studies have already revealed that raw materials for the production of inhalation grade lactose have to be carefully selected in order to avoid batch-to-batch variability. In the present study, the effect of milling and milling intensity on the flow properties and the physico-chemical characteristics of lactose crystals has been determined. The milled lactoses were then further processed by sieving to give lactose qualities with identical size distribution data, but different batch history (non-milled and milled at different conditions). These were then used to manufacture low concentration (0.25%) drug blends with the model drugs salbutamol sulphate (SBS) and beclometasonedipropionate (BDP); the blends were analysed with a Multistage Liquid Impinger (MLI) after delivery from an Easyhaler and an Aerolizer device. It could be shown that gentle milling already results in surface defects on the lactose crystal which are further enhanced by using a higher milling intensity. Produced fine lactose particles during the milling process strongly adhere to the lactose surface and cannot be removed by compressed air which is used for the particle sizing. By trend, a higher milling intensity resulted in higher fine particle fractions (FPF) with both devices. Also, SBS was found to generally give higher fine particle fractions than BDP, independent from the device used. In conclusion, lactose pre-treatment by gentle or strong milling affects the carrier surface and thereby the aerosolization properties of drug/lactose blends produced.     

Characterisation and functionality of inhalation anhydrous lactose

The relationships between the physicochemical properties and functionality in dry powder inhaler (DPI) performance was investigated for inhalation grade anhydrous lactose and compared to monohydrate grades. The excipients were characterised using a range of techniques including particle size analysis, moisture sorption and powder rheometry. The inhalation anhydrous lactose grades were readily characterisable. The aerosolisation performance of capsule based DPI formulations containing budesonide (200 μg) and different grades of lactose evaluated using inertial impaction measurements produced fine particle doses of budesonide ranging from 24 to 49 μg. There were no apparent relationships between aerosolisation performance and excipient characteristics, such as particle size and powder density. However, formulations containing lactose grades which exhibit higher powder fluidisation energy values resulted in higher fine particle doses of budesonide.     

Investigations on the Mechanism of Magnesium Stearate to Modify Aerosol Performance in Dry Powder Inhaled Formulations

The potential of the force control agent magnesium stearate (MgSt) to enhance the aerosol performance of lactose-based dry powder inhaled (DPI) formulations was investigated in this study. The excipient-blends were investigated with analytical techniques including time-of-flight secondary ion mass spectrometry and single particle aerosol mass spectrometry (SPAMS), and particle size, morphology, and surface properties were evaluated. Excipient-blends were manufactured either by high-shear or low-shear blending lactose carrier with different amounts of MgSt in the range from 0% to 10% (w/w). Fluticasone propionate (FP) and salmeterol xinafoate (SX) used as model active pharmaceutical ingredients were added by low-shear mixing. The in vitro aerosol performance in terms of aerodynamic particle size distribution and fine particle fraction (FPF) of the FP and SX DPI formulations was evaluated with the Next Generation Impactor and also with SPAMS using a Breezhaler^® inhalation device. The distribution of MgSt on the lactose carrier in the blends was visualized and found to depend strongly on the blending method. This affected drug particle detachment from the carrier and thus impacted aerosol performance for FP and SX. Compared with blends without force control agent, low-shear blending of MgSt increases the FPF of the model drug SX, whereas high-shear blending significantly increased FPF of both SX and FP. The interactions between drug and carrier particles were substantially affected by the choice of blending technique of MgSt with lactose. This allows detailed control of aerosol performance of a DPI by an adequate choice of the blending technique. SPAMS successfully demonstrated that it is capable to distinguish changes in DPI formulations blended with different amounts of MgSt, and additional information in terms of dispersibility of fine particles could be generated.     

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.     

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.     

The use of different sugars as fine and coarse carriers for aerosolised salbutamol sulphate

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.     

The Effect of Engineered Mannitol-Lactose Mixture on Dry Powder Inhaler Performance

Purpose

To co-crystallise mannitol and lactose with a view to obtaining crystals with more favourable morphological features than either lactose or mannitol alone, suitable for use as carriers in formulations for dry powder inhalers (DPIs) using simultaneous engineering of lactose-mannitol mixtures.

Methods

Mannitol and lactose individually and the two sugars with three different ratios were crystallised/co-crystallised using anti-solvent precipitation technique. Obtained crystals were sieved to separate 63?C90???m size fractions and then characterised by size, shape, density and in vitro aerosolisation performance. Solid state of crystallized samples was studied using FT-IR, XRPD and DSC.

Results

At unequal ratios of mannitol to lactose, the elongated shape dominated in the crystallisation process. However, lactose exerted an opposite effect to that of mannitol by reducing elongation ratio and increasing the crystals?? width and thickness. Crystallised ??-lactose showed different anomers compared to commercial lactose (??-lactose monohydrate). Crystallised ??-mannitol showed different polymorphic form compared to commercial mannitol (??-mannitol). Crystallised mannitol:lactose showed up to 5 transitions corresponding to ??-mannitol, ??-lactose monohydrate, ??-lactose, 5??-/3??-lactose and 4??-/1??-lactose. In vitro deposition assessments showed that crystallised carriers produced more efficient delivery of salbutamol sulphate compared to formulations containing commercial grade carriers.

Conclusion

The simultaneous crystallization of lactose-mannitol can be used as a new approach to improve the performance of DPI formulations.     

Influence of carrier on the performance of dry powder inhalers

The aim of this work is to study carriers which can become alternatives to monohydrate lactose in dry powder inhalers and to consider particle parameters that influence adhesion between drug and carrier in dry powder inhalers. Different forms of mannitol, lactose and maltitol were mixed with either terbutaline sulphate or formoterol fumarate. The blends were submitted to different adhesion tests where drug detachment from the carrier was obtained either through mechanical vibration or by aspiration. Parameters like particle shape, roughness, amorphous content and cristalline form may affect interactions between drug and carrier. In our case, crystallized forms of the carrier offered lower adhesion but better release of the active ingredient than spray-dried forms. The crystallized mannitol produced maximal fine particle dose. The blends of the mannitols and the two active ingredients gave different results. The two techniques used to assess the adhesion of drugs to carrier particles provide complementary information about drug/carrier interactions and detachment. The mechanical sieving allows to assess blend stability and the air-jet sieving makes it possible to determine how easily the drug separates from carrier. For the drugs tested, the results of fine particle doses are in agreement with the Alpine air-jet sieve results. The tests used are helpful for the choice of a new carrier in the field of the development of new carriers for dry powder inhalers.     

Improving Dry Powder Inhaler Performance by Surface Roughening of Lactose Carrier Particles

Purpose

This study investigated the impact of macro-scale carrier surface roughness on the performance of dry powder inhaler (DPI) formulations.

Methods

Fluid-bed processing and roller compaction were explored as processing methods to increase the surface roughness (R_a) of lactose carrier particles. DPI formulations containing either (a) different concentrations of fine lactose at a fixed concentration of micronized drug (isoniazid) or (b) various concentrations of drug in the absence of fine lactose were prepared. The fine particle fraction (FPF) and aerodynamic particle size of micronized drug of all formulations were determined using the Next Generation Impactor.

Results

Fluid-bed processing resulted in a modest increase in the R_a from 562 to 907 nm while roller compaction led to significant increases in R_a?>?1300 nm. The roller compacted carriers exhibited FPF?>?35%, which were twice that of the smoothest carriers. The addition of up to 5%, w/w of fine lactose improved the FPF of smoother carriers by 60–200% whereas only?<?30% increase was observed in the rough carriers. Analysis of the FPF in tandem with shifts in the mass median aerodynamic diameter of dispersed drug suggested that the finest drug particles were entrapped on rougher surfaces while larger drug particles were dispersed in the air.

Conclusions

The results showed that the processing of lactose carrier particles by roller compaction was immensely beneficial to improving DPI performance, primarily due to increased surface roughness at the macro-scale.

     

Aerosolisation of beclomethasone dipropionate using spray dried lactose/polyethylene glycol carriers.

The aim of this study was to characterize the physical properties of spray dried lactose in the presence of different polyethylene glycols (PEG 400, PEG 3000 and PEG 6000) and to evaluate their performance as carriers for dry powder inhaler (DPI) formulations. The efficiency of spray dried lactose/PEG carriers in aerosolisation of beclomethasone dipropionate (BD), a model hydrophobic drug, was compared to Pharmatose 325 M (L325), spray dried lactose alone (SDL), and also a sieved (< 38 microm) fraction of alpha-lactose monohydrate (SL). In vitro deposition analysis was performed using a twin stage liquid impinger at a flow rate of 60 l/min through a Spinhaler. The deposition profiles of the drug from binary formulations composed of BD and spray dried lactose/PEG carriers were also compared to ternary formulations containing large and fine lactose carriers. Differential scanning calorimetry and X-ray diffraction data showed the presence of alpha-anhydrous lactose in spray dried lactose/PEG crystalline powders. Spray drying of lactose in the presence of PEG 400 resulted in the production of a powder (SDL-PEG400) with lower alpha-lactose monohydrate content, and also smaller particle size distribution than those obtained in the presence of PEG 3000 (SDL-PEG3000) or PEG 6000 (SDL-PEG6000). All formulations showed different deposition profiles, except those containing SDL-PEG3000 or SDL-PEG6000 which exhibited similar data. The fine particle fraction of aerosolised BD varied from 6.26 +/- 1.07 (for L325) to 25.87 +/- 5.33 (for SDL-PEG3000). All deposition profiles of BD aerosolised from SDL-PEG3000 were significantly higher (P < 0.01) than those produced by binary and ternary formulations containing L325, a coarse lactose commercially available for DPI formulations. The differences observed in deposition data for various carriers were interpreted according to their physical properties. It was concluded that particle size distribution, morphology and specific surface texture of SDL-PEG3000 and SDL-PEG6000 were important factors influencing their efficiency as small carriers for DPI formulations.     

Lactose Composite Carriers for Respiratory Delivery

Purpose  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. Methods  Lactose carrier particles were prepared by fusing sub units of lactose (either 2, 6 or 10 μm) in saturated lactose slurry. The resultant composite particles, as well as supplied lactose, were sieve fractioned to obtain a 63–90 μm 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. Results  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. Conclusion  Composite based carriers are a potential route to control drug–carrier adhesion forces and variability thus allowing more precise control of formulation performance.     

Humidity-induced changes of the aerodynamic properties of dry powder aerosol formulations containing different carriers

This paper presents the findings of two related studies. The aim of the first was to study any changes in the aerodynamic properties of salbutamol base powder formulations when different sugars were used as the carriers, after storage at an elevated humidity (75% RH), and whether any such changes (if any) were related to the physical properties of the carriers. The aim of the second was to investigate whether "ageing", i.e. storage of the carrier, drug and blends under desiccation for more than 2 years, affected the aerodynamic properties of salbutamol sulphate powder formulations. Different formulations were prepared, each containing 1.5% (w/w) micronised salbutamol base or sulphate blended with the sieved fraction (63-90 microm) of one of the following sugars: alpha lactose monohydrate, sorbitol, maltose and dextrose. The salbutamol base blends were then stored unprotected at 75% RH (ambient temperature) and salbutamol fine particle fractions (FPFs) were measured by laser diffraction (LD) (% < 5.2 microm) and a multistage liquid impinger (MSLI) (% < 5.3 microm), following aerosolisation at 100 l min(-1) from a model glass inhaler, after storage of each formulation at the elevated conditions for 0, 1 and 6 days. Particle morphology and equilibrium moisture content (EMC) of each formulation prior to and after storage were also evaluated. However, the salbutamol sulphate blends containing either "fresh" or "aged" components were only characterized using LD at 60 l min(-1). Prior to exposure to 75% RH, the lactose blend was found to give the highest FPF of salbutamol (30% by LD and 37% by MSLI), followed by the sorbitol blend (17% by LD and 29% by MSLI), then by the dextrose blend (15% by LD and 25% by MSLI) and finally by the maltose blend (13% by LD and 13% by MSLI). Exposure to 75% RH for 6 days resulted in a small reduction of salbutamol FPF from the lactose blend but drastic diminution of salbutamol FPFs from other blends. After exposure to the high RH, the lactose blend adsorbed ca. 0.4% whilst each of the other sugars took up larger quantities of water (15-40%) and underwent a marked change in the surface texture of the particles. "Ageing" of the carriers and/or formulations did not seem to alter the aerodynamic properties of the drug. "Ageing" of micronised salbutamol sulphate prior to blending, however, was found to improve the FPF of drug. LD was capable of detecting subtle differences between the various formulations and generated FPF results that correlated with those measured by MSLI.     

Modeling dispersion of dry powders for inhalation. The concepts of total fines, cohesive energy and interaction parameters

A range of carrier based dry powder formulations consisting of micronized drug, carrier lactose and, in some formulations, lactose fines were produced and tested for dispersibility, i.e. fine particle fraction (FPF). Two different drugs were used, budesonide (BUD) and beclomethasone dipropionate (BDP). A model based on the total amount of fines (TF) and the cohesive energy (CE) of the formulation is proposed, where TF is the sum of added drug, lactose fines and the fines inherent to the carrier. The expression for CE is derived from regular solutions theory and allows calculation of interparticle interaction parameters. The model was able to describe experimental data well, such as the decrease in FPF when the proportion of drug is increased at a constant TF level and the non-linear effects seen when a cohesive drug is added to carrier. BDP and BUD were found to be 5.3 times and 1.8 times more cohesive than lactose fines respectively. The model hence provides a link between the macroscopic behavior of a dry powder formulation and the interaction between the different species at the particulate level.     

Effects of carriers and storage of formulation on the lung deposition of a hydrophobic and hydrophilic drug from a DPI

The effects of carriers, the drug:carrier ratio and a 1 month storage period of a formulation in permeable polystyrene tube at 40 degrees C/75% RH on the in vitro pulmonary deposition of model drugs from dry powder inhaler (DPI) were evaluated. Budesonide (hydrophobic) and salbutamol sulphate (hydrophilic) were used as model drugs. Mannitol and glucose were used as the carriers. In addition, lactose 110M was used as the carrier for budesonide. The novel multiple dose Taifun was used as a DPI; Taifun is a breath-actuated inhaler that contains the powder formulation in a reservoir chamber. The respirable fractions (RF%) values of the drugs were determined by the "Andersen" sampler. The RF% values of salbutamol sulphate increased with an increase in the drug:carrier ratio before storage, whereas the drug:carrier ratio did not affect the RF% values after storage. In the case of budesonide, the drug:carrier ratio did not affect the RF% values before storage, instead the RF% values of budesonide increased with an increase in the drug:carrier ratio after storage. The RF% values of salbutamol sulphate decreased after storage of the formulation, this was not dependent on the carrier and the drug:carrier ratio. However, with budesonide the effect of the storage on its RF% values was dependent on which carrier was used and also the drug:carrier ratio. Overall, storage had less effect on the RF% values of budesonide than those of salbutamol sulphate. The highest RF% values of budesonide were obtained when mannitol was used as the carrier. Furthermore, the RF% values of salbutamol sulphate tended to be higher when mannitol was used as the carrier instead of glucose.     

Characterisation and Deposition Studies of Recrystallised Lactose from Binary Mixtures of Ethanol/Butanol for Improved Drug Delivery from Dry Powder Inhalers

Dry powder inhaler formulations comprising commercial lactose-drug blends can show restricted detachment of drug from lactose during aerosolisation, which can lead to poor fine particle fractions (FPFs) which are suboptimal. The aim of the present study was to investigate whether the crystallisation of lactose from different ethanol/butanol co-solvent mixtures could be employed as a method of altering the FPF of salbutamol sulphate from powder blends. Lactose particles were prepared by an anti-solvent recrystallisation process using various ratios of the two solvents. Crystallised lactose or commercial lactose was mixed with salbutamol sulphate and in vitro deposition studies were performed using a multistage liquid impinger. Solid-state characterisation results showed that commercial lactose was primarily composed of the α-anomer whilst the crystallised lactose samples comprised a α/β mixture containing a lower number of moles of water per mole of lactose compared to the commercial lactose. The crystallised lactose particles were also less elongated and more irregular in shape with rougher surfaces. Formulation blends containing crystallised lactose showed better aerosolisation performance and dose uniformity when compared to commercial lactose. The highest FPF of salbutamol sulphate (38.0 ± 2.5%) was obtained for the lactose samples that were crystallised from a mixture of ethanol/butanol (20:60) compared to a FPF of 19.7 ± 1.9% obtained for commercial lactose. Engineered lactose carriers with modified anomer content and physicochemical properties, when compared to the commercial grade, produced formulations which generated a high FPF.     

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.     

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.     

Physico-chemical aspects of lactose for inhalation

A dry powder inhaler (DPI) is a dosage form that consists of a powder formulation in a device which is designed to deliver an active ingredient to the respiratory tract. It has been extensively investigated over the past years and several aspects relating to device and particulate delivery mechanisms have been the focal points for debate. DPI formulations may or may not contain carrier particles but whenever a carrier is included in a commercial formulation, it is almost invariably lactose monohydrate. Many physicochemical properties of the lactose carrier particles have been reported to affect the efficiency of a DPI. A number of preparation methods have been developed which have been claimed to produce lactose carriers with characteristics which lead to improved deposition. Alongside these developments, a number of characterization methods have been developed which have been reported to be useful in the measurement of key properties of the particulate ingredients. This review describes the various physicochemical characteristics of lactose, methods of manufacturing lactose particulates and their characterization.     

Pulmonary deposition of lactose carriers used in inhalation powders

Dry powder dosage forms are generally formulated by mixing the micronized drug particles with the larger carrier particles. Lactose is a commonly used carrier. Carriers enhance the flowability of powder mixtures and therefore enable low dosing of active substances. During inhalation, the drug particles are dispersed from the surface of carrier particles. The aim of this study was to compare how different qualities of 99mTc-labelled lactose carrier systems deposit in the lungs. The sizes of the labelled and unlabelled alpha-lactose monohydrate particles were compared by using a laser diffraction method. Distribution of radiolabel between different particle size fractions was determined using the Andersen cascade impactor. The in vivo depositions of lactose carrier systems were investigated in ten healthy men using the technique of gammascintigraphy. In addition, redispersion of budesonide from the carrier materials was evaluated by using the Andersen cascade impactor. According to the validation data the particle size of the lactose carriers remained unchanged during the labelling process. Low pulmonary deposition varying between 2.5 and 3.3% was detected. Only a small amount of lactose was deposited in the lungs, thus pulmonary deposition is not a limiting factor for lactose selection. According to in vitro redispersion data the fine particle fraction of the delivered dose in the impactor varied between 10.3 and 26.0%. Thus, the redispersion of the budesonide particles can be altered by the properties of the carrier system.     

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.