JOURNAL OF AEROSOL MEDICINE AND PULMONARY DRUG DELIVERY Volume 28, Number 0, 2014 ª Mary Ann Liebert, Inc. Pp. 1–14 DOI: 10.1089/jamp.2014.1146
Preparation and Evaluation of Surface Modified Lactose Particles for Improved Performance of Fluticasone Propionate Dry Powder Inhaler Deepak J. Singh, PhD,1 Rajesh R. Jain, MPharm,1 P. S. Soni, PhD,2 Samad Abdul, MVSc, PhD,3 Hegde Darshana, PhD,1 Rajiv V. Gaikwad, MVSc, PhD,3 and Mala D. Menon, PhD1
ABSTRACT
Background: Dry powder inhalers (DPI) are generally formulated by mixing micronized drug particles with coarse lactose carrier particles to assist powder handling during the manufacturing and powder aerosol delivery during patient use. Methods: In the present study, surface modified lactose (SML) particles were produced using force control agents, and their in vitro performance on dry powder inhaler (DPI) formulation of Fluticasone propionate was studied. With a view to reduce surface passivation of high surface free energy sites on the most commonly used DPI carrier, a- lactose monohydrate, effects of various force control agents such as Pluronic F-68, Cremophor RH 40, glyceryl monostearate, polyethylene glycol 6000, magnesium stearate, and soya lecithin were studied. Results: DPI formulations prepared with SML showed improved flow properties, and atomic force microscopy (AFM) studies revealed decrease in surface roughness. The DSC and X-ray diffraction patterns of SML showed no change in the crystal structure and thermal behavior under the experimental conditions. The fine particle fraction (FPF) values of lactose modified with Pluronic F-68, Cremophor RH 40, glyceryl monostearate were improved, with increase in concentration up to 0.5%. Soya lecithin and PEG 6000 modified lactose showed decrease in FPF value with increase in concentration. Increase in FPF value was observed with increasing concentration of magnesium stearate. Two different DPI devices, Rotahaler and Diskhaler, were compared to evaluate the performance of SML formulations. FPF value of all SML formulations were higher using both devices as compared to the same formulations prepared using untreated lactose. One month stability of SML formulations at 40C/75% RH, in permeable polystyrene tubes did not reveal any significant changes in FPF values. Conclusion: SML particles can help in reducing product development hindrances and improve inhalational properties of DPI. Key words: dry powder inhaler, Fluticasone propionate, force control agents, surface modified lactose
Waal’s forces. Under normal circumstances, by allowing the particles to dissipate excess electric charges, and under controlled humidity conditions, the van der Waal interactions are the dominant attractive forces, and create what is called a ‘‘Velcro effect’’ between the particles.(1–3) This results in product development hindrance with regard to flow properties, content uniformity, drug metering, stability, and effective deposition in lung.(4–6) To overcome this, respirable drug
Introduction
M
icronized drug particles used in dry powder inhalers have a relatively high surface area to mass ratio and thus exhibit greater cohesiveness and adhesiveness. They tend to stick together and to inhaler surfaces with which they come in contact. Such cohesive interactions arise from a combination of forces: electrostatic, capillary, and van der 1 2 3
Department of Pharmaceutics, Bombay College of Pharmacy, Mumbai, India. Board of Radiation and Isotope Technology and Medical Cyclotron Facility, Parel, Mumbai, India. Department of Medicine, Bombay Veterinary College, Parel, Mumbai, India.
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particles are adhered to surface of larger carrier particles, such as lactose. a-Lactose monohydrate is the most widely used carrier for dry powder inhalers (DPI) and has been recommended by the FDA as a safe excipient of choice for pulmonary delivery formulations.(7–9) In developing such an interactive blend, the interactions between the drug and carrier particles must be balanced, where they are strong enough to form a stable mixture, but sufficiently weak such that they are readily susceptible to dispersion when entrained. In addition, other factors such as the presence of amorphous content, impurity, specific polar/ nonpolar region on the carrier surface can also influence the drug carrier interactions.(10,11) Drug-to-carrier interaction forces are an important aspect to be considered in DPI formulations. The interactions have to be strong enough to guarantee good mixture stability during handling, but weak enough to enable the separation forces during inhalation to detach a substantial fraction of the drug dose from the carrier crystals.(12,13) Aerosolization process from a DPI to occur is divided into two definable stages or processes, namely: fluidization of the powder bed, followed by drug detachment from carrier particles into respirable sizes; both of these stages are influenced by the adhesion/cohesion of the powder.(14) Many attempts have been made to engineer particles and surfaces with low adhesion/cohesion properties, and hence to control the forces between particles, including between micronized drug particles and between drug and excipient carriers.(14,15) Inadequate drug/ carrier separation is one of the main explanations for the low deposition efficiency encountered with DPIs.(16) Surface morphology is believed to affect particle adhesion by increasing or reducing contact area. Thereby, modifying surface morphological properties may be an effective way to alter cohesion/adhesion, thus, influencing aerosol performance.(17–19) The current methods for overcoming such issues include the production of new lactose carriers with controlled shape and roughness and ‘‘filling’’ the potential active sites by increasing the fine-particle content of the drug or excipient on the carrier surface or pacifying the effects of active sites by surface treatment and/or the addition of force-control agents.(20–22) To reduce surface passivation of high surface free energy sites, some studies using force control agents such as leucine,(23) magnesium stearate,(5,24) and polaxamer(25) have been explored. In the present study surface modified lactose (SML) particles were produced using force control agents, and their in vitro performance on DPI formulation of fluticasone propionate was studied. To improve the performance of powder formulations for inhalation, an attempt was made to reduce surface passivation of high surface free energy sites on the commonly used DPI carrier, a-lactose monohydrate, using various force control agents such as Pluronic F-68, Cremophor RH 40, glyceryl monostearate, PEG 6000, magnesium stearate, and soya lecithin. These are common GRAS pharmaceutical excipients with surface active and lubricant properties, and can be expected to reduce the adhesive and cohesive interactions in fine particle mixtures. Also two different popular DPI Devices in India, Rotahaler and Diskhaler, were compared to evaluate the performance of surface modified lactose formulations of FP. Rotahaler is a single unit dose device in which the DPI capsule is loaded by the patient into
SINGH ET AL.
the device, and during inhalation capsule separation, dispersion and aerosolization of the powder takes place via plastic grid. Diskhaler is a multiunit device in which 4–8 doses in foil blisters are arranged around the rim of the disc that the patient inserts into the device. On actuation, each blister is pierced by a thick plastic needle, followed by dispersion of powder via turbulent airflow path and grid.(26) Material and Methods
Fluticasone propionate (FP) (complying to BP specifications) was kindly supplied by Sun Pharmaceutical Pvt ltd. India. a-Lactose monohydrate (Lactohale-inhalation grade) from Burculo Domo Netherlands, soya lecithin from Lucas Meyer, Hamburg, magnesium stearate from Signet, India, Pluronic F-68, Cremophor RH 40, and glyceryl monostearate from BASF, Mumbai, India were obtained as gift samples. PEG 6000 was purchased from S.D. Fine Chemicals, India. All the excipients were of pharmaceutical grade obtained from reliable suppliers. Preparation of surface modified lactose (SML)
Surface modified lactose (SML) was prepared using a process reported by Young et al.(20) with slight modification. Briefly, the inhalation grade a-lactose monohydrate (Lactohale) was sieved to obtain particles in the range of 63– 90 lm. Pluronic F-68 (PL), Cremophor RH 40 (CRE), glyceryl monostearate (GMS), PEG 6000 (PEG), magnesium stearate (MgSt), and soya lecithin (LN) were used as force control agents to modify the surface of lactose. These force control agents (0.1% to 1.0% w/w) were dispersed in a mixture of isopropyl alcohol, acetone, and water (75:15:10). To this dispersion (30 mL), lactose samples (100 g) were mixed and rotated (200 rev/min) and dried under vacuum for 120 min at 50C, by a high-speed Rotavapour (Superfit India Ltd, India). Samples were reprocessed three times with equivalent volumes (30 mL) of wetting solvent and dried. The treated lactose particles were finally sieved to obtain particles in the range of 63–90 lm; the sieved particles were stored in desiccators with silica gel, and used later as carrier for the DPI formulations. Preparation of dry powder inhaler (DPI) formulations
Powder mixtures of 1% w/w FP were prepared by mixing 0.1 g FP and 9.9 g of surface modified lactose carrier particles (63–90 lm) using a vortex mixer (Remi, India) for 5 min. This mixture was passed several times through sieve (80 # size), and 25 mg quantities were packed into disk of the Diskhaler and hard gelatin capsules (size 3) and stored in a desiccator at 25 – 5C in sealed glass vials. Content uniformity. The DPI powder blends were sampled randomly by taking 10 samples from different locations of the mixing vessel. The samples were dissolved in mixture of water: acetonitrile (40:60) and content of FP in each sample was analyzed by a validated reverse phase HPLC method. The chromatographic system consisted of JASCO PU 980 Intelligent Pump, JASCO UV 975, a UV-VIS detector Version 1.50 Build 15 ( Jasco-BorwinTM, Japan) and Rheodyne injector valve bracket fitted with a 20 lL sample loop. HPLC separations were performed on a stainless steel
SURFACE MODIFIED LACTOSE PARTICLES FOR DPI
Technochrom kromacil; C-18 analytical column (250 mm · 4.6 mm) packed with 5 lm diameter particles. Data was processed using Chromatography Software, Hercule 2000 chromatography interface star 800-interface module interface Version 2.0 ( Jasco-BorwinTM). The composition of the mobile phase was a mixture of water:acetonitrile (40:60). The detection of analyte was carried out at the wavelength of 238 nm. The mean drug content and coefficient of variation were determined. Characterization of surface modified lactose samples In vitro aerosol deposition. A Multistage Liquid Impinger (MSLI) (Copley Scientific, UK) with critical flow controller (Model TPK) was used in this study. At a flow rate of 60 L/min, the cut-off diameters of stages 1, 2, 3, 4, and 5 (filter) are 13, 6.8, 3.1, 1.7, and less than 1.7 microns, respectively. In a five-stage MSLI, the FPF is defined as the percentage of the dose recovered from stages 3 to 5 inclusive, representing particles with an aerodynamic diameter of < 6.8 lm at a flow rate of 60 L/min. A total of 25 mg of blend was filled into a gelatin capsule (size 3) and placed in Rotahaler which was attached to the MSLI. Each stage of the MSLI was filled with 20 mL collecting solvent (acetonitrile: water, 60:40). The MSLI was operated at 60 L/min for 5 seconds. Ten capsules were fired into the MSLI and the collecting solvent at each stage was removed for analysis. The throat, capsule and filter were washed with 20 mL collecting solvents. The rinsed solutions were then diluted appropriately to proper volumes and the drug contents were determined by validated HPLC method. In addition to Rotahaler, the optimized formulation was also assessed by Diskhaler. The fine particle fraction (FPF) values of the DPI formulations were calculated (as percentages of delivered dose), and this formed the basis for selecting the concentration of force control agents, which were taken for investigations. The in vitro deposition study using MSLI was conducted in triplicate for each formulation. Flow properties. The surface modified lactose particles were evaluated to assess flow properties like angle of repose (h) and Carr’s Index. Angle of repose was determined by pouring 4 g of the selected treated lactose sample through a funnel on a sheet of paper in the form of heap. The radius (r) and height (h) of the pile was measured and the angle of repose was calculated.
Angle of repose (h) ¼ tan 1 h=r
[Equation 1]
Carr’s Index (CI) of lactose samples was calculated by following equation. CI ¼ (qtap qbulk )=qtap · 100
[Equation 2]
where qbulk is bulk density and qtap -tapped density. Differential scanning calorimetry. DSC experiments were performed using a differential scanning calorimeter (Shimadzu-Thermal Analyzer DT 40, Japan). An accurately measured amount of each of the selected powders (5–10 mg) was loaded in an aluminum pan with a central pin hole under dynamic nitrogen (purity: 99.999%, supplier: Mars
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Gas Ltd, Mumbai, India) purged at 40 mL/min. An empty aluminum pan was used as reference. Pans were sealed using crimper. The sample was heated from 30–300C at a rate of 10C/min. Measurements were performed in triplicate. X-ray powder diffractometry. The physical state of the lactose after surface modification was assessed by XRPD studies. X-ray powder diffraction patterns of unmodified lactose and surface modified lactose samples were obtained using an X’Pert PRO MPD system with Cu Ka radiation (40 kV, 25 mA) in Bragg-Brentano geometry. The system was equipped with a programmable divergence slit on the incident beam side and X’Celerator detector with antiscatter slit and Ni-filter on the diffracted beam side. 0.04 rad soller slits were used on both sides to limit the axial divergence of the beam. The scanning rate employed was 1/ min over 5–40 diffraction angle (2h) range. Specific surface area. The specific surface areas of the unmodified and modified lactose particles were determined by the Brunauer-Emmett-Teller (BET) adsorption method using a FlowSorb II 2300 (Micromeritics Ltd., USA) instrument determining the quantitative amount of nitrogen adsorption as a single point measurement. Four-g quantities of each sample were degassed at 70C for 2 h under a pressure of 760 Torr in a Flowsorb II 2300 apparatus, using a gas flow composed of a nitrogen/helium mixture 70:30(vol/ vol) (purity for both gases: 99.999%, supplier: Mars Gas Ltd, Mumbai, India). Atomic force microscopy. The AFM measurements were performed in air using a NanoScope Digital Instrument (Santa Barbara, CA) at ambient condition (20–25C/40%– 50% RH). The scans were analyzed with the NanoScope software version 4.22. The mean root mean square roughness value (Rrms) was computed from the AFM height data, from a sample size of 10 lactose particles. Particle morphology. Lactose particles were deposited on small carbon adhesive disk and their structure characterized with an Environmental Scanning Electron Microscope XL-30 ESEM (Philips, France) at 15C, under 3.7Torr pressure and 15-kV voltage. Evaluation of adhesion characteristics
The adhesion characteristics were evaluated by the method reported by Flament et al.(27) Mechanical sieving method. The adhesion forces between drug particles and carrier particles were determined as follows: 5 g of powder blend was placed on a mechanical sieve shaker (Electrolab, India), holding a 63 lm sieve. The assembly with the powder blend was subjected to shakes and shocks, leading to passage of particles with a diameter lower than that of the screen aperture. At periodic intervals of sieving time (5, 10, 20, 30, 60, and 120 sec), 25 mg samples (corresponding to 250 lg FP, n = 5) were taken from the powder bed. The drug concentration in the samples was determined by validated HPLC method as described above.
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Air depression method. The air jet sieve method was used to study the characteristics of separation of the micronized drug from the carrier particles in air steam.(27) Five g of powder blend was kept on 63 lm sieve in a sealed container. Blend was submitted to air flow by a nozzle below the sieve and suspended particles in the air were carried through sieve by aspiration. At periodic intervals of time (5, 10, 20, 30, 60, and 120 sec), after subjecting to above airstream process, 25 mg samples (corresponding to 250 lg FP, n = 5) were taken from the powder bed. The drug concentration of each of the samples was determined by validated HPLC method as described above. Stability studies
All the DPI formulations (prepared as described above), packed in permeable polystyrene tubes, were placed in the stability chamber (Newtronic, India; Model: QLH-2012) at 40C/75% RH, for 1 month. The in vitro deposition studies of the samples after 1 month storage were performed using MSLI.(28) Statistical analysis
For selected evaluation tests, the mean for surface modified lactose was compared with the unmodified lactose by a one-way analysis of variance (ANOVA) with Dunnett multiple comparison test or the mean of all tested formulations were compared with each other by means of a oneway ANOVA with the Student–t test or two-way ANOVA with the Bonferroni post tests. The statistical significance level ( p) was set at £ 0.05. Results and Discussion Content uniformity
The mixtures produced by blending of FP with different surface modified lactose samples, exhibited good content uniformity (Table 1). The highest variation in content was found when the unmodified lactose was mixed with FP (4.73%), although the variation was still less than 5%. In all the surface modified lactose samples, the variation in content uniformity was within a narrow range of 1.14% to 2.9%. This is indicative of suitability of the mixing method and equipment used in the current small scale of batch size being handled.
In vitro aerosol deposition
In this study, the surface modified lactose was sieved and only the 63–90 lm fraction was used, effect of fines was ignored which has been reported to increase the in vitro performance of DPI formulations.(24,27,29,30) Figure 1 shows the in vitro inhalational index (FPF) of FP with various surface modified lactose formulations obtained by MSLI using the Rotahaler. The FPF was significantly greater in case of surface modified lactose carrier samples than in the FPF of unmodified lactose, indicating that the in vitro inhalation properties of FP were improved. One of the present hypotheses to explain this phenomenon is based on the presence of active sites and the agglomeration of drug and fine excipient.(31) Active sites are interpreted as locations of disturbance on the surface of a crystal where more active molecular groups are presented to the outside. This might be due to simple dislocations in the crystal lattice, or the complete distortion of the molecular order. Such regions might have different depth, but in every case, they present areas of higher surface interaction compared with the surrounding crystal areas. Thus most of drug particles are lost when surface is not modified, leading to lower FPF values. Surface treatment of lactose resulted in an overall reduction of adhesion forces, due to its surface smoothing; and the antistatic property imparted by these force control agents resulted in easier separation of drug particles from the lactose surfaces, and hence a higher FPF. As the drug particles remain captured in the depressions on the surface of carriers after getting emitted from the capsule, it is deposited in stages 1–2 and not transported to stages 3–5, resulting in a low FPF. With surface modified lactose, the amount of roughness and surface area on the lactose particles was lower than that of unmodified lactose. This decreased the number of drug particles remaining in pits and depressions and facilitated drug separation, which being finer in size are carried forward to stages 3–5.(5,32,33) As shown in Figure 1, the FPF values of FP formulations with CRE-Lac, PL-Lac, and GMS-Lac was increased, with increase in coating of the concentration of force control agent up to 0.5%; further increase decreases the FPF values (in case of CRE and PL modified lactose), whereas GMSLac showed an almost similar FPF at 0.5% and 1% concentration. The LN-Lac and PEG-Lac showed decrease in FPF value with increase in concentration. The increase and
Table 1. Per Cent Content Uniformity of FP after Blending with Different Surface Modified Lactose Carriers Coating % of force control agent 0.1 % 0.5 % 1.0 %
UN- Lac
PL-Lac
GMS-Lac
CRE-Lac
LN-Lac
PEG-Lac
MgSt-Lac
101.15 % (*4.73%)
98.63 % (*1.14%) 99.89 % (*2.45%) 96.54 % (*2.05%)
96.70 % (*1.92%) 102.40 % (*1.32%) 99.47 % (*1.78%)
102.40 % (*1.25%) 99.89 % (*1.11%) 103.75 % (*2.54%)
96.70 % (*1.92%) 102.40 % (*1.32%) 99.47 % (*2.70%)
99.47 % (*1.88%) 103.66 % (*1.34%) 101.15 % (*2.90%)
98.66 % (*1.42 %) 99.24 % (*2.12%) 97.94 % (*2.20%)
Data are expressed as mean. * % coefficient of variation (n = 3). CRE Lac, Cremophor RH 40 modified lactose; GMS-Lac, glyceryl monostearate modified lactose; LN-Lac, soya lecithin modified lactose; MgSt-Lac, magnesium stearate modified lactose; PEG-Lac, PEG 6000 modified lactose; PL-Lac, Pluronic F-68 modified lactose; Un-Lac, untreated lactose.
SURFACE MODIFIED LACTOSE PARTICLES FOR DPI
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FIG. 1. FPF values of FP with different surface treated lactose samples. CRE-Lac, Cremophor RH 40 modified lactose; GMS-Lac, glyceryl monostearate modified lactose; LN-Lac, soya lecithin modified lactose; MgSt-Lac, magnesium stearate modified lactose; PEG-Lac, Polyethylene glycol 6000 modified lactose; PL-Lac, Pluronic F-68 modified lactose; UnLac, untreated lactose. **p < 0.01, significant difference compared to Un-Lac and ***p < 0.001 significant difference compared to Un-Lac by two way ANOVA with ‘‘Bonferroni post tests’’.
decrease pattern in value in FPF can be explained by using the active sites and fine agglomerates models.(34,35) With increase in force control agent and decrease in value in FPF can be due to an increased surface contact area, for example, for two flat surfaces in contact. So although it may reduce the areas such as crevices, hollows, and other traps for particles to sit within, and reducing so called surface ‘‘active sites’’, there is also a potential for reduced ease of particle release from the smooth surface.(17) Increase in FPF value was observed with increasing concentration of magnesium stearate as it has a higher affinity to lactose (no electrostatic repulsion).(36) Magnesium stearate when present in higher concentration also reduces the cohesion between the drug–drug particles and thus better dispersion behavior and aerosol performance. The blend containing magnesium stearate showed better FPF values
and low device retention. Similar observation has been reported.(5,24,37–39) Based on these results, the selected concentration for surface covering for GMS-Lac, PL-Lac, CRELac, MgSt-Lac, PEG-Lac, and LN-Lac were 0.5%, 0.5%, 0.5%, 1.0%, 0.1%, and 0.1%, respectively. Flow properties, angle of (y), Carr’s Index
The flow properties of surface modified lactose at aforementioned concentrations of force control agents are reported in Table 2. Carr’s Index and angle of repose values of less than 25 and 35, respectively, are usually taken to indicate good flow characteristics, whereas values beyond 40 and 45, respectively, indicate poor powder flowability.(40) Angle of repose values of all the SML samples (except LN-LAC-lecithin treated sample) have shown a
Table 2. Properties of Surface Treated Lactose Samples Surface modified lactose
Angle of repose () #
Carr’s Index
Specific Surface area (m2/g)
T 50 value (Sec)
GMS-Lac (0.5%) PL-Lac (0.5%) CRE-Lac (0.5%) LN-Lac (0.1%) PEG-Lac (0.1%) MgSt-Lac (1%) UN-Lac
34.60 – 2.4* 38.30 – 0.9* 35.70 – 3.1* 43.80 – 1.8 33.38 – 2.7* 29.7 – 2.9* 47.40 – 2.1
28.5 24.41 30.8 33.5 25.6 21.5 39.6
0.202* 0.187 * 0.205 * 0.211* 0.198* 0.213* 0.244
24.95** 14.29** 38.28** 44.15** 19.70** 11.67** 61.63
CRE Lac, Cremophor RH 40 modified lactose; GMS-Lac, glyceryl monostearate modified lactose; LN-Lac, soya lecithin modified lactose; MgSt-Lac, magnesium stearate; PEG-Lac, Polyethylene glycol 6000 modified lactose; PL-Lac, Pluronic F-68 modified lactose; UnLac, untreated lactose. Figures in parenthesis indicate the % of force control agents used for treatment. # Data are expressed as mean – S.D (n = 3). *p < 0.01, significant difference compared to Un-Lac by Student’s unpaired t-test. T 50 value (Sec) The time point at which 50% of the drug particles separated from the carrier particles; **p < 0.05, significant difference compared to Un-Lac by one way ANOVA with Dunnett multiple comparison test.
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significant decrease; a maximum decrease is evident in Mg stearate treated sample. Similar trend is evident in Carr index values, reflecting the decrease in irregularities on the surface of the carrier. Thus surface treatment of lactose with force control agents can be a useful technique to improve the flow properties of DPI formulations. Differential Scanning Calorimetry (DSC)
It is reported that crystallization of lactose under the influence of mechanical stirring in water–ethanol (50:50%, v/v) introduces disorder within the crystal lattice due to acceleration of mutarotation of a to b lactose, generating amorphous lactose, and the crystals obtained are a mixture of a and b lactose.(41) The DSC thermograms (Fig. 2) of lactose modified with force control agents showed two endothermic transitions which were similar to those of unmodified lactose, suggesting that all the lactose samples after surface treatment existed as a- lactose monohydrate. The first endothermic transition corresponds to the loss of water of crystallization, and the second transition corresponds to the melting of lactose followed by its decomposition. Similar results for untreated lactose was obtained by Ober et al, where the DSC thermogram for lactose microfine shows an endothermic peak at 149C, typical of crystalline a-lactose monohydrate, followed by the characteristic melting endotherm at 209C.(42) X-ray powder diffractometry
The X-ray powder diffractometry patterns of unmodified lactose and modified lactose showed that there is no change in the crystal structure (Fig. 3). Under the experimental conditions, the processing methods have not caused induction of crystal growth, and a-lactose monohydrate was the only stable lactose as observed in DSC study. The changes in the relative intensity of the diffraction lines are due to the geometry of the crystals in the equipment and the removal of fines. Similar XRPD patterns of a-lactose monohydrate were reported by Raut et al.(43)
FIG. 2. DSC thermograms of surface modified lactose samples. CRE-Lac, Cremophor RH 40 modified lactose (0.5%); GMS-Lac, glyceryl monostearate modified lactose (0.5%); LN-Lac, soya lecithin modified lactose (0.1%); MgSt-Lac, magnesium stearate modified lactose (1.0%); PEG-Lac, Polyethylene glycol 6000 modified lactose (0.1%); PL-Lac, Pluronic F-68 modified lactose (0.5%); Un-Lac, untreated lactose.
Specific surface area
The specific surface areas of modified and unmodified lactose are shown in Table 2. It can be observed that all the surface modified lactose samples exhibited significantly lower surface area than untreated lactose ( p < 0.01, Student’s t-test). This may be attributed to decrease in lactose fines and surface irregularities.(20) Pluronic F 68 and PEG modified lactose showed maximum decrease in specific surface area as compared to unmodified lactose. Atomic force microscopy
AFM was employed to evaluate the effect of surface modification on lactose particles. Representative images of treated and unmodified lactose samples are shown in Figure 4. As expected, the morphology of the unmodified lactose was irregular. In order to further elucidate such variation in surface homogeneity, the topography data was processed to produce mean root square roughness (Rrms) value using WSxM (version 4.0) software. All the surface modified lactose samples (with 0.1, 0.5, and 1.0% force control agents) showed a significant decrease (except in case of LNLac) in Rrms values compared to unmodified lactose (UnLac) (Table 3). The Rrms values of lactose modified with GMS-Lac and PL-Lac were decreased, with increase in the concentration up to 0.5%; further increase increases the Rrms values. The lactose treated with CRE-Lac, PEG-Lac and LN-Lac showed increase in Rrms value with increase in concentration. MgSt-Lac showed decrease in Rrms value with increase in concentration. Examination of the topographical data and Rrms values suggested that the surfaces contained areas with pits and asperities that would potentially result in contact area variations with respect to drug particulate adhesion in DPI formulation were decreased in SML. Particle morphology
The ESEM micrographs of the different lactose samples are shown in Figure 5. Clear morphological variations were observed when surfaces of unmodified lactose particles were
SURFACE MODIFIED LACTOSE PARTICLES FOR DPI
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FIG. 3. X-ray powder diffraction patterns of surface modified lactose samples. CRE-Lac, Cremophor RH 40 modified lactose (0.5%); GMS-Lac, glyceryl monostearate modified lactose (0.5%); LN-Lac, soya lecithin modified lactose (0.1%); MgSt-Lac, magnesium stearate modified lactose (1.0%); PEG-Lac, Polyethylene glycol 6000 modified lactose (0.1%); PL-Lac, Pluronic F-68 modified lactose (0.5%); Un-Lac, untreated lactose. compared with surface modified lactose particles. The unmodified lactose particles were rough and many asperities were observed. In the force control agent modified particles, the surface asperities were reduced; gaps and depressions were filled, making the carrier particles smooth. These results are in agreement with Rrms values (Table 3) and AFM topographs (Fig. 4).
Evaluation of adhesion characteristics
The properties of separation of drug particles were investigated by the air depression and mechanical sieve methods represented in Figure 6 and Figure 7. As reported by Flament et al.,(27) sieving by mechanical vibrations is generally well-suited to noncohesive powders. In the case of
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FIG. 4. Atomic force microscopy images of surface modified lactose samples. CRE-Lac, Cremophor RH 40 modified lactose (0.5%); GMSLac, glyceryl monostearate modified lactose (0.5%); LN-Lac, soya lecithin modified lactose (0.1%); MgSt-Lac, magnesium stearate modified lactose (1.0%); PEG-Lac, Polyethylene glycol 6000 modified lactose (0.1%); PL-Lac, Pluronic F-68 modified lactose (0.5%); Un-Lac, untreated lactose.
cohesive powders, it is preferable to envisage sieving by air depression. When the blend was subjected to mechanical vibration for 2 min, the drug adherence was in the order of Un-Lac (63.17%) > LN-Lac (58.56%) > CRE-Lac (56.75%) > GMS-Lac (51.16%) > PEG-Lac (48.93%) > PL-Lac (39.44%) >
MgSt-Lac (36.44%). The percentage of drug retained decreased as the sieving time increased. As drug quantities retained are higher for unmodified lactose than surface modified lactose, it indicates weaker physical interaction between drug particles and surface modified lactose.
Table 3. Root Square Roughness (Rrms) Values of Different Surface Modified Lactose Carriers Conc. of force control agent 0.1 % 0.5 % 1.0 %
UN- Lac
PL-Lac
GMS-Lac
CRE-Lac
LN-Lac
PEG-Lac
MgSt-Lac
231.04 (*12.26%)
94.70 *** (*7.84%) 30.42 *** (*6.09%) 105.52 *** (*8.16%)
113.84 *** (*8.81%) 85.25 *** (*3.12%) 105.88 *** (*8.45%)
74.83 *** (*9.93%) 85.85 *** (*4.25%) 105.33 *** (*7.87%)
185.64 ** (*7.29%) 197.55 (5*.61%) 207.58 (*6.59%)
125.43 *** (*8.25%) 134.94 *** (*12.77%) 145.79 *** (*15.21%)
134.87 *** (*18.99%) 128.25 *** (*13.24%) 119.77 *** (*14.77%)
CRE Lac, Cremophor RH 40 modified lactose; GMS-Lac, glyceryl monostearate modified lactose; LN-Lac, soya lecithin modified lactose; MgSt-Lac, magnesium stearate; PEG-Lac Polyethylene glycol 6000 modified lactose; PL-Lac, Pluronic F-68 modified lactose; UnLac, untreated lactose. Data are expressed as mean and * % coefficient of variation (n = 3) **p < 0.01, significant difference compared to Un-Lac and ***p < 0.001 significant difference compared to Un-Lac by two way ANOVA with ‘‘Bonferroni post tests.’’
SURFACE MODIFIED LACTOSE PARTICLES FOR DPI
9
FIG. 5. ESEM photomicrographs of surface modified lactose samples. CRE-Lac, Cremophor RH 40 modified lactose (0.5%); GMS-Lac, glyceryl monostearate modified lactose (0.5%); LN-Lac, soya lecithin modified lactose (0.1%); MgStLac, magnesium stearate modified lactose (1.0%); PEG-Lac, Polyethylene glycol 6000 modified lactose (0.1%); PL-Lac, Pluronic F-68 modified lactose (0.5%); Un-Lac, untreated lactose.
When blends were submitted to air depression method, FP is rapidly carried away by the airflow. The quantity after 10 sec is an indicator of the quantity of drug that adheres to the lactose. For all the lactose blended formulations, after 10 sec, surface modified lactose showed lower retention, % of FP compared to unmodified lactose. When aspiration time increases, the drug concentration in blend also decreases. After 2 min, the drug adherence was in the order of Un-Lac (40.35%) > LN-Lac (34.8%) > CRE-Lac (33.5%) > GMS-Lac (29.89%) > PEG-Lac (25.21%) > PL-Lac (19.33%) > MgSt-Lac (12.55%). Strong adhesion of the drug to lactose means a difficult separation of drug from carrier particles and hence requiring greater inhalation airflow by the patient. As shown in Figure 8, the logarithmic probability plot showed a linear relationship by air depression method. Such linear relationships were obtained for all samples, and the mean separation time (T50) for each sample was determined using this graph. T50 value is defined as the time point at
which 50% of the drug particles separated from the carrier particles. Table 2 shows the T50 value of all formulations. The T50 values obtained for surface modified lactose samples were significantly shorter than the value obtained for unmodified lactose, indicating that drug separation from the carrier particle was facilitated by surface modification (Fig. 8). The T50 value was in the order of UnLac > LN-Lac > CRE-Lac > GMS-Lac > PEG-Lac > PL-Lac > MgSt-Lac. DPI performance with different devices
The two different DPI devices, Rotahaler and Diskhaler, were compared to evaluate the performance of surface modified lactose formulations of FP. As shown in Figure 9, the FPF values observed with Rotahaler was slightly higher as compared with that of Diskhaler. This may be attributed to differences in construction of the
10
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FIG. 6. Plot of percentage of FP retained against time by mechanical sieve method. CRELac, Cremophor RH 40 modified lactose (0.5%); GMS-Lac, glyceryl monostearate modified lactose (0.5%); LN-Lac, soya lecithin modified lactose (0.1%); MgSt-Lac, magnesium stearate modified lactose (1.0%); PEG-Lac, Polyethylene glycol 6000 modified lactose (0.1%); PL-Lac, Pluronic F-68 modified lactose (0.5%); Un-Lac, untreated lactose. two devices, as the path flow is extremely short in the Diskhaler and drug losses within the device are minimized, allowing higher fraction % of drug emitted. However, with both devices, a marked increased in FPF values was evident for the treated carrier samples, compared to untreated lac-
FIG. 7. Plot of percentage of FP retained against time by air depression method. CRE-Lac, Cremophor RH 40 modified lactose (0.5%); GMS-Lac, glyceryl monostearate modified lactose (0.5%); LN-Lac, soya lecithin modified lactose (0.1%); MgSt-Lac, magnesium stearate modified lactose (1.0%); PEG-Lac, Polyethylene glycol 6000 modified lactose (0.1%); PL-Lac, Pluronic F-68 modified lactose (0.5%); Un-Lac, untreated lactose.
tose. The maximum increase was seen with PL-Lac; the LNLac sample showed only a marginal increase. These observations are in concurrence with the AFM, ESEM, and adhesion studies results, and clearly shows that when modified carriers are used for inhalation delivery of FP they
SURFACE MODIFIED LACTOSE PARTICLES FOR DPI
11
FIG. 8. Logarithmic probability plot of percentage of FP against time by air depression method. CRE-Lac, Cremophor RH 40 modified lactose (0.5%); GMS-Lac, glyceryl monostearate modified lactose (0.5%); LN-Lac, soya lecithin modified lactose (0.1%); MgSt-Lac, magnesium stearate modified lactose (1.0%); PEG-Lac, Polyethylene glycol 6000 modified lactose (0.1%); PL-Lac, Pluronic F-68 modified lactose (0.5%); Un-Lac, untreated lactose.
deliver higher drug, than unmodified carrier, irrespective of the type device used. Stability studies
The effect of moisture on the performance of DPI formulations was evaluated more rapidly by using permeable polystyrene tubes. These permeable tubes allow the formulation to be exposed more to moisture vapors at 40C/ 75% RH than standard materials used for blister packaging of DPI capsule.(28) The FPF value was significantly increased in the unmodified lactose formulations, but not in
the surface modified lactose formulations after storage at 40C/75% RH, in permeable polystyrene (Fig. 10). This could be attributed to a decrease in surface electrostatic properties of FP and lactose due to moisture sorption on particles and surface smoothening during storage.(44) As a result, micronized FP particles were easier to become detached from the surface of carriers during inhalation. Conclusions
Development of an inhalation delivery system is highly complex, requiring multidisciplinary approaches. Among
FIG. 9. Performance of DPI (% FPF), with two different DPI devices Rotahaler and Diskhaler. CRE-Lac, Cremophor RH 40 modified lactose (0.5%); GMS-Lac, glyceryl monostearate modified lactose (0.5%); LN-Lac, soya lecithin modified lactose (0.1%); MgStLac, magnesium stearate modified lactose (1.0%); PEG-Lac, Polyethylene glycol 6000 modified lactose (0.1%); PL-Lac, Pluronic F-68 modified lactose (0.5%); Un-Lac, untreated lactose.
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FIG. 10. FPF after one month stability at 40C/75% RH in polystyrene tubes. CRE-Lac, Cremophor RH 40 modified lactose (0.5%); GMS-Lac, glyceryl monostearate modified lactose (0.5%); LN-Lac, soya lecithin modified lactose (0.1%); MgSt-Lac, magnesium stearate modified lactose (1.0%); PEG-Lac, Polyethylene glycol 6000 modified lactose (0.1%); PL-Lac, Pluronic F-68 modified lactose (0.5%); Un-Lac, untreated lactose.
the various inhalation systems, DPIs are becoming increasingly popular, compared to pressurized meter dose inhalers because of the following advantages: DPIs do not contain propellant and are more stable in environmental conditions. The performance of DPI depends upon the integration of inhaler design, the powder formulation, and patient inspiratory effort. The conventional approach to DPI powder formulation is to blend the micronized drug particle with a larger carrier particle to form interactive or ordered mixtures; a-lactose monohydrate is the most commonly used carrier with reference to physicochemical property, safety, stability profile, and cost. In order to improve the performance of DPI, it is necessary to passivate the carrier surface with force control agents. The present investigation has focused on evaluating various force control agents, namely: Pluronic F-68, Cremophor RH 40, glyceryl monostearate, PEG 6000, magnesium stearate, and soya lecithin on a-lactose monohydrate. The comparative evaluation of treated and untreated lactose carrier samples comprised of physicochemical parameters and aerosolization properties using model drug FP. When surface modification of lactose particles was carried out using force control agents, the amount of surface roughness on the lactose carrier particles reduced, as evidenced by ESEM and AFM studies. Therefore, drug particles entering depressions and remaining there decreased, this facilitated easy separation of drug particles from the carrier particles, which was observed in significant improvement in FPF values. The effect of specific surface area of lactose carrier particles and in vitro inhalation proper aerosolization properties of DPI (FPF) of FP were correlated. Decrease in surface area showed increase in the FPF value. Thus surface modification of lactose carrier particles with force control agents such as Pluronic F-68, Cremophor RH 40, soya lecithin, glyceryl monostearate, and magnesium stearate is an inexpensive and simple technique, compared
to the other particle engineering techniques such as spray drying and supercritical fluid technology. This approach can lead to reducing product development hindrances with regard to content uniformity, drug metering, stability, flowability, less blocking and sticking to filling equipment, and improved inhalational properties of DPI. Acknowledgments
The authors thank Sun Pharmaceuticals Ltd, India, for providing gift sample of fluticasone propionate, Tata Institute for Fundamental Research (TIFR), India for AFM analysis, Cipla Ltd, India, for multistage impinger facility, and the Board of Research in Nuclear Sciences (BRNS) for providing financial assistance (Sanction No. 2004/35/5/ BRNS). Author Disclosure Statement
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. References
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Received on April 2, 2014 in final form, September 18, 2014 Reviewed by: Heidi Mansour Gerhard Pohlmann Address correspondence to: Dr. Mala D. Menon Department of Pharmaceutics, Bombay College of Pharmacy, Kalina, Santacruz (E) Mumbai 400098 Maharashtra India E-mail: [email protected]
Preparation and Evaluation of Surface Modified Lactose Particles for Improved Performance of Fluticasone Propionate Dry Powder Inhaler Deepak J. Singh, PhD,1 Rajesh R. Jain, MPharm,1 P. S. Soni, PhD,2 Samad Abdul, MVSc, PhD,3 Hegde Darshana, PhD,1 Rajiv V. Gaikwad, MVSc, PhD,3 and Mala D. Menon, PhD1
ABSTRACT
Background: Dry powder inhalers (DPI) are generally formulated by mixing micronized drug particles with coarse lactose carrier particles to assist powder handling during the manufacturing and powder aerosol delivery during patient use. Methods: In the present study, surface modified lactose (SML) particles were produced using force control agents, and their in vitro performance on dry powder inhaler (DPI) formulation of Fluticasone propionate was studied. With a view to reduce surface passivation of high surface free energy sites on the most commonly used DPI carrier, a- lactose monohydrate, effects of various force control agents such as Pluronic F-68, Cremophor RH 40, glyceryl monostearate, polyethylene glycol 6000, magnesium stearate, and soya lecithin were studied. Results: DPI formulations prepared with SML showed improved flow properties, and atomic force microscopy (AFM) studies revealed decrease in surface roughness. The DSC and X-ray diffraction patterns of SML showed no change in the crystal structure and thermal behavior under the experimental conditions. The fine particle fraction (FPF) values of lactose modified with Pluronic F-68, Cremophor RH 40, glyceryl monostearate were improved, with increase in concentration up to 0.5%. Soya lecithin and PEG 6000 modified lactose showed decrease in FPF value with increase in concentration. Increase in FPF value was observed with increasing concentration of magnesium stearate. Two different DPI devices, Rotahaler and Diskhaler, were compared to evaluate the performance of SML formulations. FPF value of all SML formulations were higher using both devices as compared to the same formulations prepared using untreated lactose. One month stability of SML formulations at 40C/75% RH, in permeable polystyrene tubes did not reveal any significant changes in FPF values. Conclusion: SML particles can help in reducing product development hindrances and improve inhalational properties of DPI. Key words: dry powder inhaler, Fluticasone propionate, force control agents, surface modified lactose
Waal’s forces. Under normal circumstances, by allowing the particles to dissipate excess electric charges, and under controlled humidity conditions, the van der Waal interactions are the dominant attractive forces, and create what is called a ‘‘Velcro effect’’ between the particles.(1–3) This results in product development hindrance with regard to flow properties, content uniformity, drug metering, stability, and effective deposition in lung.(4–6) To overcome this, respirable drug
Introduction
M
icronized drug particles used in dry powder inhalers have a relatively high surface area to mass ratio and thus exhibit greater cohesiveness and adhesiveness. They tend to stick together and to inhaler surfaces with which they come in contact. Such cohesive interactions arise from a combination of forces: electrostatic, capillary, and van der 1 2 3
Department of Pharmaceutics, Bombay College of Pharmacy, Mumbai, India. Board of Radiation and Isotope Technology and Medical Cyclotron Facility, Parel, Mumbai, India. Department of Medicine, Bombay Veterinary College, Parel, Mumbai, India.
1
2
particles are adhered to surface of larger carrier particles, such as lactose. a-Lactose monohydrate is the most widely used carrier for dry powder inhalers (DPI) and has been recommended by the FDA as a safe excipient of choice for pulmonary delivery formulations.(7–9) In developing such an interactive blend, the interactions between the drug and carrier particles must be balanced, where they are strong enough to form a stable mixture, but sufficiently weak such that they are readily susceptible to dispersion when entrained. In addition, other factors such as the presence of amorphous content, impurity, specific polar/ nonpolar region on the carrier surface can also influence the drug carrier interactions.(10,11) Drug-to-carrier interaction forces are an important aspect to be considered in DPI formulations. The interactions have to be strong enough to guarantee good mixture stability during handling, but weak enough to enable the separation forces during inhalation to detach a substantial fraction of the drug dose from the carrier crystals.(12,13) Aerosolization process from a DPI to occur is divided into two definable stages or processes, namely: fluidization of the powder bed, followed by drug detachment from carrier particles into respirable sizes; both of these stages are influenced by the adhesion/cohesion of the powder.(14) Many attempts have been made to engineer particles and surfaces with low adhesion/cohesion properties, and hence to control the forces between particles, including between micronized drug particles and between drug and excipient carriers.(14,15) Inadequate drug/ carrier separation is one of the main explanations for the low deposition efficiency encountered with DPIs.(16) Surface morphology is believed to affect particle adhesion by increasing or reducing contact area. Thereby, modifying surface morphological properties may be an effective way to alter cohesion/adhesion, thus, influencing aerosol performance.(17–19) The current methods for overcoming such issues include the production of new lactose carriers with controlled shape and roughness and ‘‘filling’’ the potential active sites by increasing the fine-particle content of the drug or excipient on the carrier surface or pacifying the effects of active sites by surface treatment and/or the addition of force-control agents.(20–22) To reduce surface passivation of high surface free energy sites, some studies using force control agents such as leucine,(23) magnesium stearate,(5,24) and polaxamer(25) have been explored. In the present study surface modified lactose (SML) particles were produced using force control agents, and their in vitro performance on DPI formulation of fluticasone propionate was studied. To improve the performance of powder formulations for inhalation, an attempt was made to reduce surface passivation of high surface free energy sites on the commonly used DPI carrier, a-lactose monohydrate, using various force control agents such as Pluronic F-68, Cremophor RH 40, glyceryl monostearate, PEG 6000, magnesium stearate, and soya lecithin. These are common GRAS pharmaceutical excipients with surface active and lubricant properties, and can be expected to reduce the adhesive and cohesive interactions in fine particle mixtures. Also two different popular DPI Devices in India, Rotahaler and Diskhaler, were compared to evaluate the performance of surface modified lactose formulations of FP. Rotahaler is a single unit dose device in which the DPI capsule is loaded by the patient into
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the device, and during inhalation capsule separation, dispersion and aerosolization of the powder takes place via plastic grid. Diskhaler is a multiunit device in which 4–8 doses in foil blisters are arranged around the rim of the disc that the patient inserts into the device. On actuation, each blister is pierced by a thick plastic needle, followed by dispersion of powder via turbulent airflow path and grid.(26) Material and Methods
Fluticasone propionate (FP) (complying to BP specifications) was kindly supplied by Sun Pharmaceutical Pvt ltd. India. a-Lactose monohydrate (Lactohale-inhalation grade) from Burculo Domo Netherlands, soya lecithin from Lucas Meyer, Hamburg, magnesium stearate from Signet, India, Pluronic F-68, Cremophor RH 40, and glyceryl monostearate from BASF, Mumbai, India were obtained as gift samples. PEG 6000 was purchased from S.D. Fine Chemicals, India. All the excipients were of pharmaceutical grade obtained from reliable suppliers. Preparation of surface modified lactose (SML)
Surface modified lactose (SML) was prepared using a process reported by Young et al.(20) with slight modification. Briefly, the inhalation grade a-lactose monohydrate (Lactohale) was sieved to obtain particles in the range of 63– 90 lm. Pluronic F-68 (PL), Cremophor RH 40 (CRE), glyceryl monostearate (GMS), PEG 6000 (PEG), magnesium stearate (MgSt), and soya lecithin (LN) were used as force control agents to modify the surface of lactose. These force control agents (0.1% to 1.0% w/w) were dispersed in a mixture of isopropyl alcohol, acetone, and water (75:15:10). To this dispersion (30 mL), lactose samples (100 g) were mixed and rotated (200 rev/min) and dried under vacuum for 120 min at 50C, by a high-speed Rotavapour (Superfit India Ltd, India). Samples were reprocessed three times with equivalent volumes (30 mL) of wetting solvent and dried. The treated lactose particles were finally sieved to obtain particles in the range of 63–90 lm; the sieved particles were stored in desiccators with silica gel, and used later as carrier for the DPI formulations. Preparation of dry powder inhaler (DPI) formulations
Powder mixtures of 1% w/w FP were prepared by mixing 0.1 g FP and 9.9 g of surface modified lactose carrier particles (63–90 lm) using a vortex mixer (Remi, India) for 5 min. This mixture was passed several times through sieve (80 # size), and 25 mg quantities were packed into disk of the Diskhaler and hard gelatin capsules (size 3) and stored in a desiccator at 25 – 5C in sealed glass vials. Content uniformity. The DPI powder blends were sampled randomly by taking 10 samples from different locations of the mixing vessel. The samples were dissolved in mixture of water: acetonitrile (40:60) and content of FP in each sample was analyzed by a validated reverse phase HPLC method. The chromatographic system consisted of JASCO PU 980 Intelligent Pump, JASCO UV 975, a UV-VIS detector Version 1.50 Build 15 ( Jasco-BorwinTM, Japan) and Rheodyne injector valve bracket fitted with a 20 lL sample loop. HPLC separations were performed on a stainless steel
SURFACE MODIFIED LACTOSE PARTICLES FOR DPI
Technochrom kromacil; C-18 analytical column (250 mm · 4.6 mm) packed with 5 lm diameter particles. Data was processed using Chromatography Software, Hercule 2000 chromatography interface star 800-interface module interface Version 2.0 ( Jasco-BorwinTM). The composition of the mobile phase was a mixture of water:acetonitrile (40:60). The detection of analyte was carried out at the wavelength of 238 nm. The mean drug content and coefficient of variation were determined. Characterization of surface modified lactose samples In vitro aerosol deposition. A Multistage Liquid Impinger (MSLI) (Copley Scientific, UK) with critical flow controller (Model TPK) was used in this study. At a flow rate of 60 L/min, the cut-off diameters of stages 1, 2, 3, 4, and 5 (filter) are 13, 6.8, 3.1, 1.7, and less than 1.7 microns, respectively. In a five-stage MSLI, the FPF is defined as the percentage of the dose recovered from stages 3 to 5 inclusive, representing particles with an aerodynamic diameter of < 6.8 lm at a flow rate of 60 L/min. A total of 25 mg of blend was filled into a gelatin capsule (size 3) and placed in Rotahaler which was attached to the MSLI. Each stage of the MSLI was filled with 20 mL collecting solvent (acetonitrile: water, 60:40). The MSLI was operated at 60 L/min for 5 seconds. Ten capsules were fired into the MSLI and the collecting solvent at each stage was removed for analysis. The throat, capsule and filter were washed with 20 mL collecting solvents. The rinsed solutions were then diluted appropriately to proper volumes and the drug contents were determined by validated HPLC method. In addition to Rotahaler, the optimized formulation was also assessed by Diskhaler. The fine particle fraction (FPF) values of the DPI formulations were calculated (as percentages of delivered dose), and this formed the basis for selecting the concentration of force control agents, which were taken for investigations. The in vitro deposition study using MSLI was conducted in triplicate for each formulation. Flow properties. The surface modified lactose particles were evaluated to assess flow properties like angle of repose (h) and Carr’s Index. Angle of repose was determined by pouring 4 g of the selected treated lactose sample through a funnel on a sheet of paper in the form of heap. The radius (r) and height (h) of the pile was measured and the angle of repose was calculated.
Angle of repose (h) ¼ tan 1 h=r
[Equation 1]
Carr’s Index (CI) of lactose samples was calculated by following equation. CI ¼ (qtap qbulk )=qtap · 100
[Equation 2]
where qbulk is bulk density and qtap -tapped density. Differential scanning calorimetry. DSC experiments were performed using a differential scanning calorimeter (Shimadzu-Thermal Analyzer DT 40, Japan). An accurately measured amount of each of the selected powders (5–10 mg) was loaded in an aluminum pan with a central pin hole under dynamic nitrogen (purity: 99.999%, supplier: Mars
3
Gas Ltd, Mumbai, India) purged at 40 mL/min. An empty aluminum pan was used as reference. Pans were sealed using crimper. The sample was heated from 30–300C at a rate of 10C/min. Measurements were performed in triplicate. X-ray powder diffractometry. The physical state of the lactose after surface modification was assessed by XRPD studies. X-ray powder diffraction patterns of unmodified lactose and surface modified lactose samples were obtained using an X’Pert PRO MPD system with Cu Ka radiation (40 kV, 25 mA) in Bragg-Brentano geometry. The system was equipped with a programmable divergence slit on the incident beam side and X’Celerator detector with antiscatter slit and Ni-filter on the diffracted beam side. 0.04 rad soller slits were used on both sides to limit the axial divergence of the beam. The scanning rate employed was 1/ min over 5–40 diffraction angle (2h) range. Specific surface area. The specific surface areas of the unmodified and modified lactose particles were determined by the Brunauer-Emmett-Teller (BET) adsorption method using a FlowSorb II 2300 (Micromeritics Ltd., USA) instrument determining the quantitative amount of nitrogen adsorption as a single point measurement. Four-g quantities of each sample were degassed at 70C for 2 h under a pressure of 760 Torr in a Flowsorb II 2300 apparatus, using a gas flow composed of a nitrogen/helium mixture 70:30(vol/ vol) (purity for both gases: 99.999%, supplier: Mars Gas Ltd, Mumbai, India). Atomic force microscopy. The AFM measurements were performed in air using a NanoScope Digital Instrument (Santa Barbara, CA) at ambient condition (20–25C/40%– 50% RH). The scans were analyzed with the NanoScope software version 4.22. The mean root mean square roughness value (Rrms) was computed from the AFM height data, from a sample size of 10 lactose particles. Particle morphology. Lactose particles were deposited on small carbon adhesive disk and their structure characterized with an Environmental Scanning Electron Microscope XL-30 ESEM (Philips, France) at 15C, under 3.7Torr pressure and 15-kV voltage. Evaluation of adhesion characteristics
The adhesion characteristics were evaluated by the method reported by Flament et al.(27) Mechanical sieving method. The adhesion forces between drug particles and carrier particles were determined as follows: 5 g of powder blend was placed on a mechanical sieve shaker (Electrolab, India), holding a 63 lm sieve. The assembly with the powder blend was subjected to shakes and shocks, leading to passage of particles with a diameter lower than that of the screen aperture. At periodic intervals of sieving time (5, 10, 20, 30, 60, and 120 sec), 25 mg samples (corresponding to 250 lg FP, n = 5) were taken from the powder bed. The drug concentration in the samples was determined by validated HPLC method as described above.
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Air depression method. The air jet sieve method was used to study the characteristics of separation of the micronized drug from the carrier particles in air steam.(27) Five g of powder blend was kept on 63 lm sieve in a sealed container. Blend was submitted to air flow by a nozzle below the sieve and suspended particles in the air were carried through sieve by aspiration. At periodic intervals of time (5, 10, 20, 30, 60, and 120 sec), after subjecting to above airstream process, 25 mg samples (corresponding to 250 lg FP, n = 5) were taken from the powder bed. The drug concentration of each of the samples was determined by validated HPLC method as described above. Stability studies
All the DPI formulations (prepared as described above), packed in permeable polystyrene tubes, were placed in the stability chamber (Newtronic, India; Model: QLH-2012) at 40C/75% RH, for 1 month. The in vitro deposition studies of the samples after 1 month storage were performed using MSLI.(28) Statistical analysis
For selected evaluation tests, the mean for surface modified lactose was compared with the unmodified lactose by a one-way analysis of variance (ANOVA) with Dunnett multiple comparison test or the mean of all tested formulations were compared with each other by means of a oneway ANOVA with the Student–t test or two-way ANOVA with the Bonferroni post tests. The statistical significance level ( p) was set at £ 0.05. Results and Discussion Content uniformity
The mixtures produced by blending of FP with different surface modified lactose samples, exhibited good content uniformity (Table 1). The highest variation in content was found when the unmodified lactose was mixed with FP (4.73%), although the variation was still less than 5%. In all the surface modified lactose samples, the variation in content uniformity was within a narrow range of 1.14% to 2.9%. This is indicative of suitability of the mixing method and equipment used in the current small scale of batch size being handled.
In vitro aerosol deposition
In this study, the surface modified lactose was sieved and only the 63–90 lm fraction was used, effect of fines was ignored which has been reported to increase the in vitro performance of DPI formulations.(24,27,29,30) Figure 1 shows the in vitro inhalational index (FPF) of FP with various surface modified lactose formulations obtained by MSLI using the Rotahaler. The FPF was significantly greater in case of surface modified lactose carrier samples than in the FPF of unmodified lactose, indicating that the in vitro inhalation properties of FP were improved. One of the present hypotheses to explain this phenomenon is based on the presence of active sites and the agglomeration of drug and fine excipient.(31) Active sites are interpreted as locations of disturbance on the surface of a crystal where more active molecular groups are presented to the outside. This might be due to simple dislocations in the crystal lattice, or the complete distortion of the molecular order. Such regions might have different depth, but in every case, they present areas of higher surface interaction compared with the surrounding crystal areas. Thus most of drug particles are lost when surface is not modified, leading to lower FPF values. Surface treatment of lactose resulted in an overall reduction of adhesion forces, due to its surface smoothing; and the antistatic property imparted by these force control agents resulted in easier separation of drug particles from the lactose surfaces, and hence a higher FPF. As the drug particles remain captured in the depressions on the surface of carriers after getting emitted from the capsule, it is deposited in stages 1–2 and not transported to stages 3–5, resulting in a low FPF. With surface modified lactose, the amount of roughness and surface area on the lactose particles was lower than that of unmodified lactose. This decreased the number of drug particles remaining in pits and depressions and facilitated drug separation, which being finer in size are carried forward to stages 3–5.(5,32,33) As shown in Figure 1, the FPF values of FP formulations with CRE-Lac, PL-Lac, and GMS-Lac was increased, with increase in coating of the concentration of force control agent up to 0.5%; further increase decreases the FPF values (in case of CRE and PL modified lactose), whereas GMSLac showed an almost similar FPF at 0.5% and 1% concentration. The LN-Lac and PEG-Lac showed decrease in FPF value with increase in concentration. The increase and
Table 1. Per Cent Content Uniformity of FP after Blending with Different Surface Modified Lactose Carriers Coating % of force control agent 0.1 % 0.5 % 1.0 %
UN- Lac
PL-Lac
GMS-Lac
CRE-Lac
LN-Lac
PEG-Lac
MgSt-Lac
101.15 % (*4.73%)
98.63 % (*1.14%) 99.89 % (*2.45%) 96.54 % (*2.05%)
96.70 % (*1.92%) 102.40 % (*1.32%) 99.47 % (*1.78%)
102.40 % (*1.25%) 99.89 % (*1.11%) 103.75 % (*2.54%)
96.70 % (*1.92%) 102.40 % (*1.32%) 99.47 % (*2.70%)
99.47 % (*1.88%) 103.66 % (*1.34%) 101.15 % (*2.90%)
98.66 % (*1.42 %) 99.24 % (*2.12%) 97.94 % (*2.20%)
Data are expressed as mean. * % coefficient of variation (n = 3). CRE Lac, Cremophor RH 40 modified lactose; GMS-Lac, glyceryl monostearate modified lactose; LN-Lac, soya lecithin modified lactose; MgSt-Lac, magnesium stearate modified lactose; PEG-Lac, PEG 6000 modified lactose; PL-Lac, Pluronic F-68 modified lactose; Un-Lac, untreated lactose.
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FIG. 1. FPF values of FP with different surface treated lactose samples. CRE-Lac, Cremophor RH 40 modified lactose; GMS-Lac, glyceryl monostearate modified lactose; LN-Lac, soya lecithin modified lactose; MgSt-Lac, magnesium stearate modified lactose; PEG-Lac, Polyethylene glycol 6000 modified lactose; PL-Lac, Pluronic F-68 modified lactose; UnLac, untreated lactose. **p < 0.01, significant difference compared to Un-Lac and ***p < 0.001 significant difference compared to Un-Lac by two way ANOVA with ‘‘Bonferroni post tests’’.
decrease pattern in value in FPF can be explained by using the active sites and fine agglomerates models.(34,35) With increase in force control agent and decrease in value in FPF can be due to an increased surface contact area, for example, for two flat surfaces in contact. So although it may reduce the areas such as crevices, hollows, and other traps for particles to sit within, and reducing so called surface ‘‘active sites’’, there is also a potential for reduced ease of particle release from the smooth surface.(17) Increase in FPF value was observed with increasing concentration of magnesium stearate as it has a higher affinity to lactose (no electrostatic repulsion).(36) Magnesium stearate when present in higher concentration also reduces the cohesion between the drug–drug particles and thus better dispersion behavior and aerosol performance. The blend containing magnesium stearate showed better FPF values
and low device retention. Similar observation has been reported.(5,24,37–39) Based on these results, the selected concentration for surface covering for GMS-Lac, PL-Lac, CRELac, MgSt-Lac, PEG-Lac, and LN-Lac were 0.5%, 0.5%, 0.5%, 1.0%, 0.1%, and 0.1%, respectively. Flow properties, angle of (y), Carr’s Index
The flow properties of surface modified lactose at aforementioned concentrations of force control agents are reported in Table 2. Carr’s Index and angle of repose values of less than 25 and 35, respectively, are usually taken to indicate good flow characteristics, whereas values beyond 40 and 45, respectively, indicate poor powder flowability.(40) Angle of repose values of all the SML samples (except LN-LAC-lecithin treated sample) have shown a
Table 2. Properties of Surface Treated Lactose Samples Surface modified lactose
Angle of repose () #
Carr’s Index
Specific Surface area (m2/g)
T 50 value (Sec)
GMS-Lac (0.5%) PL-Lac (0.5%) CRE-Lac (0.5%) LN-Lac (0.1%) PEG-Lac (0.1%) MgSt-Lac (1%) UN-Lac
34.60 – 2.4* 38.30 – 0.9* 35.70 – 3.1* 43.80 – 1.8 33.38 – 2.7* 29.7 – 2.9* 47.40 – 2.1
28.5 24.41 30.8 33.5 25.6 21.5 39.6
0.202* 0.187 * 0.205 * 0.211* 0.198* 0.213* 0.244
24.95** 14.29** 38.28** 44.15** 19.70** 11.67** 61.63
CRE Lac, Cremophor RH 40 modified lactose; GMS-Lac, glyceryl monostearate modified lactose; LN-Lac, soya lecithin modified lactose; MgSt-Lac, magnesium stearate; PEG-Lac, Polyethylene glycol 6000 modified lactose; PL-Lac, Pluronic F-68 modified lactose; UnLac, untreated lactose. Figures in parenthesis indicate the % of force control agents used for treatment. # Data are expressed as mean – S.D (n = 3). *p < 0.01, significant difference compared to Un-Lac by Student’s unpaired t-test. T 50 value (Sec) The time point at which 50% of the drug particles separated from the carrier particles; **p < 0.05, significant difference compared to Un-Lac by one way ANOVA with Dunnett multiple comparison test.
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significant decrease; a maximum decrease is evident in Mg stearate treated sample. Similar trend is evident in Carr index values, reflecting the decrease in irregularities on the surface of the carrier. Thus surface treatment of lactose with force control agents can be a useful technique to improve the flow properties of DPI formulations. Differential Scanning Calorimetry (DSC)
It is reported that crystallization of lactose under the influence of mechanical stirring in water–ethanol (50:50%, v/v) introduces disorder within the crystal lattice due to acceleration of mutarotation of a to b lactose, generating amorphous lactose, and the crystals obtained are a mixture of a and b lactose.(41) The DSC thermograms (Fig. 2) of lactose modified with force control agents showed two endothermic transitions which were similar to those of unmodified lactose, suggesting that all the lactose samples after surface treatment existed as a- lactose monohydrate. The first endothermic transition corresponds to the loss of water of crystallization, and the second transition corresponds to the melting of lactose followed by its decomposition. Similar results for untreated lactose was obtained by Ober et al, where the DSC thermogram for lactose microfine shows an endothermic peak at 149C, typical of crystalline a-lactose monohydrate, followed by the characteristic melting endotherm at 209C.(42) X-ray powder diffractometry
The X-ray powder diffractometry patterns of unmodified lactose and modified lactose showed that there is no change in the crystal structure (Fig. 3). Under the experimental conditions, the processing methods have not caused induction of crystal growth, and a-lactose monohydrate was the only stable lactose as observed in DSC study. The changes in the relative intensity of the diffraction lines are due to the geometry of the crystals in the equipment and the removal of fines. Similar XRPD patterns of a-lactose monohydrate were reported by Raut et al.(43)
FIG. 2. DSC thermograms of surface modified lactose samples. CRE-Lac, Cremophor RH 40 modified lactose (0.5%); GMS-Lac, glyceryl monostearate modified lactose (0.5%); LN-Lac, soya lecithin modified lactose (0.1%); MgSt-Lac, magnesium stearate modified lactose (1.0%); PEG-Lac, Polyethylene glycol 6000 modified lactose (0.1%); PL-Lac, Pluronic F-68 modified lactose (0.5%); Un-Lac, untreated lactose.
Specific surface area
The specific surface areas of modified and unmodified lactose are shown in Table 2. It can be observed that all the surface modified lactose samples exhibited significantly lower surface area than untreated lactose ( p < 0.01, Student’s t-test). This may be attributed to decrease in lactose fines and surface irregularities.(20) Pluronic F 68 and PEG modified lactose showed maximum decrease in specific surface area as compared to unmodified lactose. Atomic force microscopy
AFM was employed to evaluate the effect of surface modification on lactose particles. Representative images of treated and unmodified lactose samples are shown in Figure 4. As expected, the morphology of the unmodified lactose was irregular. In order to further elucidate such variation in surface homogeneity, the topography data was processed to produce mean root square roughness (Rrms) value using WSxM (version 4.0) software. All the surface modified lactose samples (with 0.1, 0.5, and 1.0% force control agents) showed a significant decrease (except in case of LNLac) in Rrms values compared to unmodified lactose (UnLac) (Table 3). The Rrms values of lactose modified with GMS-Lac and PL-Lac were decreased, with increase in the concentration up to 0.5%; further increase increases the Rrms values. The lactose treated with CRE-Lac, PEG-Lac and LN-Lac showed increase in Rrms value with increase in concentration. MgSt-Lac showed decrease in Rrms value with increase in concentration. Examination of the topographical data and Rrms values suggested that the surfaces contained areas with pits and asperities that would potentially result in contact area variations with respect to drug particulate adhesion in DPI formulation were decreased in SML. Particle morphology
The ESEM micrographs of the different lactose samples are shown in Figure 5. Clear morphological variations were observed when surfaces of unmodified lactose particles were
SURFACE MODIFIED LACTOSE PARTICLES FOR DPI
7
FIG. 3. X-ray powder diffraction patterns of surface modified lactose samples. CRE-Lac, Cremophor RH 40 modified lactose (0.5%); GMS-Lac, glyceryl monostearate modified lactose (0.5%); LN-Lac, soya lecithin modified lactose (0.1%); MgSt-Lac, magnesium stearate modified lactose (1.0%); PEG-Lac, Polyethylene glycol 6000 modified lactose (0.1%); PL-Lac, Pluronic F-68 modified lactose (0.5%); Un-Lac, untreated lactose. compared with surface modified lactose particles. The unmodified lactose particles were rough and many asperities were observed. In the force control agent modified particles, the surface asperities were reduced; gaps and depressions were filled, making the carrier particles smooth. These results are in agreement with Rrms values (Table 3) and AFM topographs (Fig. 4).
Evaluation of adhesion characteristics
The properties of separation of drug particles were investigated by the air depression and mechanical sieve methods represented in Figure 6 and Figure 7. As reported by Flament et al.,(27) sieving by mechanical vibrations is generally well-suited to noncohesive powders. In the case of
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FIG. 4. Atomic force microscopy images of surface modified lactose samples. CRE-Lac, Cremophor RH 40 modified lactose (0.5%); GMSLac, glyceryl monostearate modified lactose (0.5%); LN-Lac, soya lecithin modified lactose (0.1%); MgSt-Lac, magnesium stearate modified lactose (1.0%); PEG-Lac, Polyethylene glycol 6000 modified lactose (0.1%); PL-Lac, Pluronic F-68 modified lactose (0.5%); Un-Lac, untreated lactose.
cohesive powders, it is preferable to envisage sieving by air depression. When the blend was subjected to mechanical vibration for 2 min, the drug adherence was in the order of Un-Lac (63.17%) > LN-Lac (58.56%) > CRE-Lac (56.75%) > GMS-Lac (51.16%) > PEG-Lac (48.93%) > PL-Lac (39.44%) >
MgSt-Lac (36.44%). The percentage of drug retained decreased as the sieving time increased. As drug quantities retained are higher for unmodified lactose than surface modified lactose, it indicates weaker physical interaction between drug particles and surface modified lactose.
Table 3. Root Square Roughness (Rrms) Values of Different Surface Modified Lactose Carriers Conc. of force control agent 0.1 % 0.5 % 1.0 %
UN- Lac
PL-Lac
GMS-Lac
CRE-Lac
LN-Lac
PEG-Lac
MgSt-Lac
231.04 (*12.26%)
94.70 *** (*7.84%) 30.42 *** (*6.09%) 105.52 *** (*8.16%)
113.84 *** (*8.81%) 85.25 *** (*3.12%) 105.88 *** (*8.45%)
74.83 *** (*9.93%) 85.85 *** (*4.25%) 105.33 *** (*7.87%)
185.64 ** (*7.29%) 197.55 (5*.61%) 207.58 (*6.59%)
125.43 *** (*8.25%) 134.94 *** (*12.77%) 145.79 *** (*15.21%)
134.87 *** (*18.99%) 128.25 *** (*13.24%) 119.77 *** (*14.77%)
CRE Lac, Cremophor RH 40 modified lactose; GMS-Lac, glyceryl monostearate modified lactose; LN-Lac, soya lecithin modified lactose; MgSt-Lac, magnesium stearate; PEG-Lac Polyethylene glycol 6000 modified lactose; PL-Lac, Pluronic F-68 modified lactose; UnLac, untreated lactose. Data are expressed as mean and * % coefficient of variation (n = 3) **p < 0.01, significant difference compared to Un-Lac and ***p < 0.001 significant difference compared to Un-Lac by two way ANOVA with ‘‘Bonferroni post tests.’’
SURFACE MODIFIED LACTOSE PARTICLES FOR DPI
9
FIG. 5. ESEM photomicrographs of surface modified lactose samples. CRE-Lac, Cremophor RH 40 modified lactose (0.5%); GMS-Lac, glyceryl monostearate modified lactose (0.5%); LN-Lac, soya lecithin modified lactose (0.1%); MgStLac, magnesium stearate modified lactose (1.0%); PEG-Lac, Polyethylene glycol 6000 modified lactose (0.1%); PL-Lac, Pluronic F-68 modified lactose (0.5%); Un-Lac, untreated lactose.
When blends were submitted to air depression method, FP is rapidly carried away by the airflow. The quantity after 10 sec is an indicator of the quantity of drug that adheres to the lactose. For all the lactose blended formulations, after 10 sec, surface modified lactose showed lower retention, % of FP compared to unmodified lactose. When aspiration time increases, the drug concentration in blend also decreases. After 2 min, the drug adherence was in the order of Un-Lac (40.35%) > LN-Lac (34.8%) > CRE-Lac (33.5%) > GMS-Lac (29.89%) > PEG-Lac (25.21%) > PL-Lac (19.33%) > MgSt-Lac (12.55%). Strong adhesion of the drug to lactose means a difficult separation of drug from carrier particles and hence requiring greater inhalation airflow by the patient. As shown in Figure 8, the logarithmic probability plot showed a linear relationship by air depression method. Such linear relationships were obtained for all samples, and the mean separation time (T50) for each sample was determined using this graph. T50 value is defined as the time point at
which 50% of the drug particles separated from the carrier particles. Table 2 shows the T50 value of all formulations. The T50 values obtained for surface modified lactose samples were significantly shorter than the value obtained for unmodified lactose, indicating that drug separation from the carrier particle was facilitated by surface modification (Fig. 8). The T50 value was in the order of UnLac > LN-Lac > CRE-Lac > GMS-Lac > PEG-Lac > PL-Lac > MgSt-Lac. DPI performance with different devices
The two different DPI devices, Rotahaler and Diskhaler, were compared to evaluate the performance of surface modified lactose formulations of FP. As shown in Figure 9, the FPF values observed with Rotahaler was slightly higher as compared with that of Diskhaler. This may be attributed to differences in construction of the
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FIG. 6. Plot of percentage of FP retained against time by mechanical sieve method. CRELac, Cremophor RH 40 modified lactose (0.5%); GMS-Lac, glyceryl monostearate modified lactose (0.5%); LN-Lac, soya lecithin modified lactose (0.1%); MgSt-Lac, magnesium stearate modified lactose (1.0%); PEG-Lac, Polyethylene glycol 6000 modified lactose (0.1%); PL-Lac, Pluronic F-68 modified lactose (0.5%); Un-Lac, untreated lactose. two devices, as the path flow is extremely short in the Diskhaler and drug losses within the device are minimized, allowing higher fraction % of drug emitted. However, with both devices, a marked increased in FPF values was evident for the treated carrier samples, compared to untreated lac-
FIG. 7. Plot of percentage of FP retained against time by air depression method. CRE-Lac, Cremophor RH 40 modified lactose (0.5%); GMS-Lac, glyceryl monostearate modified lactose (0.5%); LN-Lac, soya lecithin modified lactose (0.1%); MgSt-Lac, magnesium stearate modified lactose (1.0%); PEG-Lac, Polyethylene glycol 6000 modified lactose (0.1%); PL-Lac, Pluronic F-68 modified lactose (0.5%); Un-Lac, untreated lactose.
tose. The maximum increase was seen with PL-Lac; the LNLac sample showed only a marginal increase. These observations are in concurrence with the AFM, ESEM, and adhesion studies results, and clearly shows that when modified carriers are used for inhalation delivery of FP they
SURFACE MODIFIED LACTOSE PARTICLES FOR DPI
11
FIG. 8. Logarithmic probability plot of percentage of FP against time by air depression method. CRE-Lac, Cremophor RH 40 modified lactose (0.5%); GMS-Lac, glyceryl monostearate modified lactose (0.5%); LN-Lac, soya lecithin modified lactose (0.1%); MgSt-Lac, magnesium stearate modified lactose (1.0%); PEG-Lac, Polyethylene glycol 6000 modified lactose (0.1%); PL-Lac, Pluronic F-68 modified lactose (0.5%); Un-Lac, untreated lactose.
deliver higher drug, than unmodified carrier, irrespective of the type device used. Stability studies
The effect of moisture on the performance of DPI formulations was evaluated more rapidly by using permeable polystyrene tubes. These permeable tubes allow the formulation to be exposed more to moisture vapors at 40C/ 75% RH than standard materials used for blister packaging of DPI capsule.(28) The FPF value was significantly increased in the unmodified lactose formulations, but not in
the surface modified lactose formulations after storage at 40C/75% RH, in permeable polystyrene (Fig. 10). This could be attributed to a decrease in surface electrostatic properties of FP and lactose due to moisture sorption on particles and surface smoothening during storage.(44) As a result, micronized FP particles were easier to become detached from the surface of carriers during inhalation. Conclusions
Development of an inhalation delivery system is highly complex, requiring multidisciplinary approaches. Among
FIG. 9. Performance of DPI (% FPF), with two different DPI devices Rotahaler and Diskhaler. CRE-Lac, Cremophor RH 40 modified lactose (0.5%); GMS-Lac, glyceryl monostearate modified lactose (0.5%); LN-Lac, soya lecithin modified lactose (0.1%); MgStLac, magnesium stearate modified lactose (1.0%); PEG-Lac, Polyethylene glycol 6000 modified lactose (0.1%); PL-Lac, Pluronic F-68 modified lactose (0.5%); Un-Lac, untreated lactose.
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FIG. 10. FPF after one month stability at 40C/75% RH in polystyrene tubes. CRE-Lac, Cremophor RH 40 modified lactose (0.5%); GMS-Lac, glyceryl monostearate modified lactose (0.5%); LN-Lac, soya lecithin modified lactose (0.1%); MgSt-Lac, magnesium stearate modified lactose (1.0%); PEG-Lac, Polyethylene glycol 6000 modified lactose (0.1%); PL-Lac, Pluronic F-68 modified lactose (0.5%); Un-Lac, untreated lactose.
the various inhalation systems, DPIs are becoming increasingly popular, compared to pressurized meter dose inhalers because of the following advantages: DPIs do not contain propellant and are more stable in environmental conditions. The performance of DPI depends upon the integration of inhaler design, the powder formulation, and patient inspiratory effort. The conventional approach to DPI powder formulation is to blend the micronized drug particle with a larger carrier particle to form interactive or ordered mixtures; a-lactose monohydrate is the most commonly used carrier with reference to physicochemical property, safety, stability profile, and cost. In order to improve the performance of DPI, it is necessary to passivate the carrier surface with force control agents. The present investigation has focused on evaluating various force control agents, namely: Pluronic F-68, Cremophor RH 40, glyceryl monostearate, PEG 6000, magnesium stearate, and soya lecithin on a-lactose monohydrate. The comparative evaluation of treated and untreated lactose carrier samples comprised of physicochemical parameters and aerosolization properties using model drug FP. When surface modification of lactose particles was carried out using force control agents, the amount of surface roughness on the lactose carrier particles reduced, as evidenced by ESEM and AFM studies. Therefore, drug particles entering depressions and remaining there decreased, this facilitated easy separation of drug particles from the carrier particles, which was observed in significant improvement in FPF values. The effect of specific surface area of lactose carrier particles and in vitro inhalation proper aerosolization properties of DPI (FPF) of FP were correlated. Decrease in surface area showed increase in the FPF value. Thus surface modification of lactose carrier particles with force control agents such as Pluronic F-68, Cremophor RH 40, soya lecithin, glyceryl monostearate, and magnesium stearate is an inexpensive and simple technique, compared
to the other particle engineering techniques such as spray drying and supercritical fluid technology. This approach can lead to reducing product development hindrances with regard to content uniformity, drug metering, stability, flowability, less blocking and sticking to filling equipment, and improved inhalational properties of DPI. Acknowledgments
The authors thank Sun Pharmaceuticals Ltd, India, for providing gift sample of fluticasone propionate, Tata Institute for Fundamental Research (TIFR), India for AFM analysis, Cipla Ltd, India, for multistage impinger facility, and the Board of Research in Nuclear Sciences (BRNS) for providing financial assistance (Sanction No. 2004/35/5/ BRNS). Author Disclosure Statement
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. References
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SINGH ET AL.
Received on April 2, 2014 in final form, September 18, 2014 Reviewed by: Heidi Mansour Gerhard Pohlmann Address correspondence to: Dr. Mala D. Menon Department of Pharmaceutics, Bombay College of Pharmacy, Kalina, Santacruz (E) Mumbai 400098 Maharashtra India E-mail: [email protected]
