Download Introduction

127
THE EFFECTS OF CAPSULE FILL WEIGHT AND DRUG/CARRIER
BLEND RATIO ON THE AEROSOLIZATION OF A MODEL
DRUG FROM A SPINHALER
Moawia M. Al-Tabakha1* and Adi I. Arida2
‫يهد هذاددلعذع إلدددذا ددتذثيع ددوذنددلمعبذع ددالكذع لإ ددلذةددلذع ر فددا وذن فد وذع إاددتيذةساين ددع ذ ي نمعا ددعت ع ذث ف د بعكذ‬
‫ذندددلذ سدددوذةساين دددع ذ‬. ™‫ع لفددد عذ إادددتيذ لدددال لذ سأتاددددذيسدددتذ ثع ذيلسعدددوذع ددد هذاددد ذ ثع ذع ددد هذ ع فددد هعسب‬
‫ي نمعا عت ع ذث ف بعكذع ل جذي ذطبيقذع ج ئذع ل تشبذاعذع فتذال الذ حتثيذع لت ذع لإ لذ سأصدالذيسدتذ سدعوذ‬
‫ذاسغدلذط دقذ إلسعدوذع د هذةدلذ هدتلذ‬104‫ذذذذن‬26‫ععذعألنلعكذ‬
‫ذنط قذع صلعلذع إتاسلذ س جتيبذبت‬.4:22‫ذنذ‬1:25‫ب ف وذ‬
‫ذنلذناصعفذع لفأاقذع لفد عذحفدتذناليدعذع أ ع دتلذبت فد وذ سأجدللذع شدردذنع صدفتلذ‬.‫عالينطتعذ ي ذع شال ل‬
‫ذنل د ذ‬%23.1‫ذا دتذ‬%14.9‫ذنق ذعينفدعذ د ذع أ ع دتلذع قعادوذع لأفدابوذاد ذع دالكذع لإ دلذةدلذع ر فدا وذاد ذ‬.‫ع أبعييو‬
‫ذقدددذعح ددتوذةساين ددع ذ ي نمعا ددعت ع ذ‬. ‫ذاسغددل‬26‫ذ(بت ف د وذ سددالكذ‬4:22‫ذا ددتذ‬1:25‫ي د اتذعينفإد ذ ف د وذع سددعوذا د ذ‬
‫ذنق ذقدذع اطبذع أب لذع هداعيلذ ا دعوذع ر سدوذ‬.‫ نذليتث ذع ف وذةلذع سعو‬/‫ث ف بعكذةلذعألثع ذاعذليتث ذع الكذع لإ لذن‬
‫ذاسغدلذن هدلعذ‬26‫ذاتيربناع ب ذنل ذي ذليتث ذ فد وذع سدعوذ سدالكذع لإ دتذ‬3.27‫ذا تذ‬3.59‫ن ر ذ عسذبشردذنعضحذ(ا ذ‬
‫ ذ‬.‫ع ف تذةإكذليتث ذع الكذع لإ لذةلذع ر فا وذ نذ ف وذع إاتيذ سأتادذيأف ذا ذ ثع ذيلسعوذع ه‬
‫ذ‬
‫ذ‬
The purpose of this work was to examine the effect of capsule fill weight and drug/carrier blend
ratio of fluorescein isothiocyanate (FITC)-Dextran used as a model drug on the aerosolization
performance from Spinhaler. Micronised FITC-Dextran was tumbled with modified -lactose‫ذ‬
monohydrate in the ratio of 1:25 and 4:22. Factorial design experiments were carried out to test‫ذ‬
capsule fill weights of 26 and 104 mg for aerosolization using Andersen cascade impactor (ACI).
Powders were characterised in terms of particle size distribution, morphology and thermal
properties. Fine particle fraction based on loaded dose (FPF Total) was increased significantly from
14.9 to 23.1% when the blend ratio was increased from 1:25 to 4:22 (fill weight of 26 mg). The
Device retention of FIT-Dextran was reduced as the fill weight and/or blend ratio increased. Mass
median aerodynamic diameter (MMAD) of FITC-Dextran decreased slightly but significantly
(from 3.59 to 3.27µm) with the increase in blend ratio for the fill weight 26 mg. Therefore the
increase in the capsule fill weight and/or drug: carrier blend ratio improves the aerosolization
performance. The effect of blend ratio was however greater compared to fill weight.
Keywords: FITC-Dextran, blend ratio, fill weight, dry powder aerosol, Spinhaler ; Andersen
cascade impactor.
1
Department of Pharmaceutics, Faculty of Pharmacy and Health
Sciences, Ajman University of Science and Technology Network,
P.O. Box 2202, Al-Fujairah, UAE. 2 Faculty of Pharmacy,
Philadelphia University, P.O. Box 1, Post code 19392, Jordan.
*
To whom correspondence should be addressed.
E-mail: [email protected]
Saudi Pharmaceutical Journal, Vol. 15, No.2, April 2007
128
AL-TABAKHA & ARIDA
Introduction
Respiratory drug delivery, which includes both
pulmonary and nasal routes, may offer certain
advantages over other drug delivery systems. The
respiratory tract is void of gastric acid and has a
reduced level of degrading enzymes, which are
mainly intracellular, compared to that of the
gastrointestinal tract (1, 2). For systemic drugs
absorption is facilitated by a large surface area (50
m2) and an extensive pulmonary-capillary network
(3). When considering drugs administered for local
action within the lungs, the oral administration may
be limited by unacceptable toxicity to the liver for
example (4); hence topical administration to the lung
can be a solution. One of the advantages of the
pulmonary route is the rapid and predictable onset of
action when considering local effects. Peptides and
proteins that have poor oral bioavailability due to
inefficient transport across the gastrointestinal
epithelium or high levels of first-pass hepatic
clearance can well be delivered through pulmonary
route. Many macromolecular drugs such as
polypeptides and proteins have been developed
because of the application of recombinant DNA
technology. Recently this has increased attention to
the use of inhalation route for delivery of inhaled
proteins (5). The therapeutic and economic requirements of this route demand the high efficiency and
reproducibility of the delivery system. FITC-Dextran
of M. Wt. 4,400 Daltons was used as a model to
represent a macromolecular, water-soluble group of
drugs, even though it lacks the secondary, tertiary, or
quaternary structures of proteins; since it belongs to
carbohydrate class and not proteins. Many drugs
used in inhalation therapy are water-soluble and
hygroscopic (6) which make FITC-Dextran a
suitable choice.
Three types of device are recognised for drug
delivery to the lungs: pressurized pack metered-dose
inhalers (pMDIs), nebulizers and dry-powder inhalers (DPIs) (7). Of these systems, DPIs are receiving
a resurgence of interest (8). The low resistance unit
dose Spinhaler (0.051 cmH2O1/2/ (L/min)) (9) was
the first DPI to be introduced to market by Fisons,
which later became part of Rhône-Poulenc Rorer and
now Rhône-Poulenc Rorer is part of Sanofi-Aventis.
The minimum airflow required to expel the powder
into the inhaled air from this device was found to be
35 L/min (10). The emission from this device was
found to be dependant on the particle size with the
Saudi Pharmaceutical Journal, Vol. 15, No. 2, April 2007
highest emission occurring for lactose size range
(70-100 m) while fine particles < 10 m
intensively coated the internal wall of the hard
gelatin capsule (11). French et al. (12) reported that
the coarse carrier (PEG 8000) emitted from Spinhaler exceeded that of the active drug by 20-30%.
Lucas et al. (13) considered that the preferential
retention of a drug protein in the device when
aerosolized from a blend with coarse lactose was due
to electrostatic and density effects. Podczeck (14)
showed that the adhesion force of drug particles to
the capsule walls can be high resulting in the loss of
drug in the device and varies depending on the
additives used with the capsule. Although Spinhaler
is known to have poor delivery characteristics (15),
it was used in this work because it allows easier
optimisation of powder formulations as the operation
simply relies on loading size 2 capsules containing
the prepared formulations. Modifying the performance of dry powder formulations by changing the
order in which FPL, sieved lactose and the active
drug was previously investigated (16, 17). Such
studies revealed that FPL significantly improved the
dispensability of the emitted powder. This effect was
attributed to a reduction in the electrostatic charge of
the particles, formation of drug-FPL multiplets and
the reduction of the adhesion force between drug
particles and coarse lactose by FPL occupying the
strongest binding sites. The highest stepimprovement in the aerosol performance was found
at FPL level of 5% (13). On the other hand, there is a
lack of published data regarding the effect of
increasing blend ratio of a drug to a carrier and
hence the percentage of drug particles in the mixture.
This may be due to the fact that drugs intended for
inhalation in dry powder aerosols are formulated
with pre-determined dose. Increasing the amount of
the model drug in the capsule loaded formulations
may act in similar way to that of FPL. Therefore
such study was conducted and accompanied by a
parallel study where the capsule content of FITCDextran was varied by using different fill weights to
provide an explanation of the formulation performance.
Materials and Methods
-Lactose monohydrate (batch no. 750707) was
obtained from Borculo Whey Products, UK. FITCDextran mol wt 4,400 Daltons (lot no. 77H0362) and
sorbitan trioleate (Span 85, lot no. 23H0642) were
THE EFFECTS OF CAPSULE FILL
purchased from Sigma, UK. Chloroform (batch no.
9896217388) was obtained from Fisher, UK. Gelatin
capsules of size 2 (Farillon Limited, UK) was used
with Spinhaler from Fisons.
The coarse carrier lactose (75-106 m) was
prepared, using a mechanical tap sifter (Pascall
Engineering, England), from -lactose monohydrate
in order to remove particles of other sizes particularly the fine particles. The sieving was carried out
as described in the Pharmacopeial Forum (18) using
two sieves, one with an aperture of 75 μm and the
other of 106 μm (laboratory test sieves, Endecotts
Ltd, England). For this purpose 25 g of the lactose
was loaded to the top sieve (106µm) and sieved for
30 minutes. Micronised lactose to be added to the
coarse lactose as FPL and micronised FITC-Dextran
were pulverised separately using a fluid jet mill
(Gem-T Air-Impact Mill, Glen Creston Ltd., UK) at
the differential pressure set (70-100 psig) as
recommended by the mill company. Before milling,
each powder was ground using a mortar and pestle to
reduce any large particles and to aid in achieving a
normal particle size distribution.
Fluorimetric Analysis of FITC-Dextran:
Fluorescence measurements were obtained using
the LS-5 luminescence spectrometer (Perkin Elmer,
UK). To produce a standard calibration curve, the
fluorescence from three sets of concentrations of
FITC-Dextran solution (0.00-0.42 g/ml) in phosphate buffer medium (pH 8.00  0.05) was made. The
temperature of the cuvette in the jacketed slot was
maintained at 25 C by circulating water. The
scanned excitation wavelength (ex) and emission
wavelength (em) by the LS-5 for the solution
containing FITC-Dextran were found at 492 and 516
nm respectively. From the equation of the calibration
curve, the amount of FITC-Dextran in any sample
was calculated.
Preparation of the powder blends:
The carrier system was first prepared by
tumbling on a roller (speed of 90 rpm) FPL (5%)
with sieved lactose (75-106 m) for one hour.
Powder blends of FITC-Dextran and the prepared
carrier in the ratio of 1:25 and 4:22 were then
similarly prepared by accurately weighing the
fractions of powders which were transferred to a
small glass vial. The contents of the vial were
tumbled on a roller for 1 hr at a speed of 90 rpm.
Loading the capsules with the required weight was
Saudi Pharmaceutical Journal, Vol. 15, No. 2, April 2007
129
made manually using the back of the 25 ml
volumetric flask cap to mount the capsule body and
microspatula to transfer the formulation.
In the European Pharmacopoeia (19), test B is
applied to the uniformity of pre-dispensed dose of
powders for inhalation. The homogeneity of the
mixtures was evaluated by analysing FITC-Dextran
in ten random samples from each blend (lactose did
not interfere with the fluorescence measurements).
The coefficient of variation (% C.V.) was then
calculated for each blend to express the degree of
homogeneity. As two different fill weights were
used in the current study, the smaller weight 26 mg
was the scale of scrutiny.
Particle Size Distribution and Morphology:
Micronised FITC-Dextran, FPL, the sieved
lactose (75-106 m) and the modified sieved lactose
containing the 5% w/w of FPL were measured for
particle size using Malvern system 2600 (Malvern
Instruments Ltd., UK.) which employs laser
diffraction method. Size analysis of suspended
particles was carried out in liquid made of
chloroform plus 0.1% w/v sorbitan trioleate as a
wetting agent and using an appropriate lens. Particle
size was expressed in terms of volume diameters of
the median (VMD) and the 10 and 90% fractiles of
the size distributions. Additionally, the volume of
the particles below 10 m was calculated. Independent particle size model was used and the
obscuration was adjusted between 0.11 and 0.19.
The suspended particles were measured at least in
triplicate.
Deposition Profile of FITC-Dextran Using an
Andersen Cascade Impactor (ACI):
The storage and testing of the formulation
products were undertaken in controlled temperature
and humidity laboratory of 18 C and 35-40 % R.H.
respectively. This is to avoid hygroscopic growth of
particles (20). ACI was used to assess depositions
from the different formulations emitted from a
Spinhaler at the flow rate of 60 L/min for 4 sec. It
consists of 8 impaction plates and a filter stage,
starting from stage 0, then 1, 2, 3, 4, 5, 6, 7 and a
filter stage, the latter was fitted with glass microfibre
filter paper. The effective cut-off diameters of these
stages at 60 L/min are: 6.18, 3.98, 3.23, 2.27, 1.44,
0.76, 0.48 and 0.27 m (21). A pre-separator was
fitted on top of the impactor to prevent particle
bouncing and re-entrainment errors and to reduce
130
overloading of the Andersen stages used (22). The
filling of the capsules (size 2) was made just before
aerosolization. The capsule to be tested was
introduced to the Spinhaler. The latter was fitted
into a moulded rubber mouthpiece attached to the
throat piece of the pre-separator. After ensuring that
the assembly is vertical and airtight, the flow rate
was adjusted at 60 L/min and the pump was then
switched off. The capsule was then pierced by the
Spinhaler and the pump was switched on for the
period of 4s to release the dose from the capsule.
The masses of FITC-Dextran deposited on the
various sites of the assembly were then washed with
phosphate buffer solution (pH 8.00  0.05) and
quantified fluorimetrically. This experiment was
repeated five times for each blend ratio and fill
weight. The deposition profile of FITC-Dextran after
aerosolization was expressed in terms of percentage
to allow a comparison between the prepared
formulations containing micronised FITC-Dextran
and lactose in the ratio of 1:25 and 4:22 (fill weight
of 26 and 104 mg). The data collected from five
separate aerosolization experiments were compared
using ANOVA (p<0.05, n=5) for each blend and fill
weight, the differing groups being identified using
the least significant difference test. The calculated
aerosol parameters to assess the formulation
performance were the device retention which is
calculated by subtracting the emitted FITC-Dextran
from the loaded, and the fine particle fraction (FPF)
that is assumed to have a predictive value for the
amount of drug that will reach the lungs in vivo (23)
and is calculated as cumulative percentage under
size of stage two (< 3.98 m) based on loaded and
emitted dose. The first is an index of formulation
efficiency denoted as FPFTotal, while the second
(FPFEmitted) is an index to the extent of emitted dose
dispersion but ignores any dose metering or device
deposition. The mass median aerodynamic diameter
(MMAD) is the most common parameter employed
to characterise an airborne particle. The mass
distribution of FITC-Dextran on the various stages
of the impactor was converted to a cumulative
percentage under size. The probit values of the
cumulative were plotted as the ordinate versus the
log effective cut-off diameters as the abscissa. From
a straight line on points close to the cumulative
percentage of 50% (probit = 5), that is from 20 to
80% (from probit 4.16 to probit 5.84), the MMAD
was calculated.
Saudi Pharmaceutical Journal, Vol. 15, No. 2, April 2007
AL-TABAKHA & ARIDA
Experimental Design:
In addition to the ANOVA analysis, factorial
design was applied which serves as a test for the
influence of certain factors on one or several
responses and if any interaction occur (24, 25). The
experiment shows two factors (i.e. drug to carrier
ratio (factor A) and fill weight (factor B)) on two
levels (i.e. low when the blend ratio is 1:25 or when
the fill weight is 26 mg and are given the negative
sign - or high when the blend ratio is 4:22 or when
the fill weight is 104 mg and are given the positive
sign +). This results in a 22-factorial design. The
experiments as shown in table 1 are listed in
standard order as (1), a, b and ab, where (1) denotes
the experiment when all levels are at their lowest
while ab denotes the experiment when the factors A
and B are at their highest. The magnitude of any
factor can be calculated by taking the mean when the
factor is at highest and subtracting from it the mean
when the factor is at lowest.
Results
Powders Characterisation:
The volume percentage of particles < 10 m is
considered important for drug delivery to the lung.
Micronised FITC-Dextran revealed that the volume
median diameter (VMD) was 5.30 m with 81.3% of
the particles volume below 10 m. The VMD of
micronised lactose was found to be 5.62 m with all
particles below 20.70 m. Micronised lactose
particles were rounded and have smooth surfaces in
comparison to the micronised FITC-Dextran when
examined by an electron microscope. Sieved lactose
fraction (75-106 m) had VMD of 116.39 m which
lies outside the designated size fraction. Sieving of
lactose to remove all fine particles was not
completely successful as there were 0.8 % of the
particle volumes below 10.0 m as measured by
Malvern. The addition of FPL to the coarse lactose
fraction (75-106 m) resulted in lowering the VMD
to 112.13 m and an increase in the fraction <10.0
m to 5.1%. Examination of this powder by an
electron microscope showed the presence of FPL
freely dispersed in the powder.
Content Uniformity:
The blends tested were found to be homogenous
and to pass the uniformity of pre-dispensed dose in
accordance to European Pharmacopoeia (19) as the
THE EFFECTS OF CAPSULE FILL
131
coefficient of variation was < 2.9% (n= 10) for all
blends.
100%
Experiment
(1)
a
b
ab
Factor
A (ratio)
+
+
Factor B
(fill weight)
+
+
Interaction
of A and B
+
+
% FITC-Dextran
80%
Table 1: Factorial design of two factors with two
levels experiment (22).
60%
40%
20%
0%
1:25, 26
4:22, 26
1:25, 104
4:22, 104
Formulation
FPFT otal
Table 2.: FITC-Dextran deposition (mean  (SD))
after aerosolization using two blend ratios and two
fill weights (n=5).
Pre-separator
Device
Figure 1. The effect of varying blend ratio and/or
fill weight on the dispersion of FITC-Dextran
formulation.
Formulations (1:25, 26) (4:22, 26) (1:25, 104) (4:22, 104)
Aerosol
parameters
Device (%)
FPFTotal (%)
FPFEmitted(%)
MMAD (µm)
59.0
(2.4)
14.9
(1.0)
36.2
(1.2)
3.59
(0.09)
49.7 (1.2) 40.0 (1.9) 35.9 (2.9)
23.1 (0.7) 22.3 (0.8) 27.8 (1.1)
46.0 (1.6) 37.2 (1.0) 43.4 (0.6)
3.27 (0.07) 3.73 (0.04) 3.53 (0.04)
Abbreviations: The formulations are represented by
the (blend ratio, fill weight). SD: Standard deviation
Table 3: The effect of the blend ratio and the fill
weight and their interaction on the percentage of
FITC-Dextran retained by the device, fine particle
fraction (FPFTotal and FPFEmitted) and mass median
aerodynamic diameter (MMAD).
Place of effect
Factor A Factor B Interaction
(ratio) (fill weight) of A and B
Factor magnitude on - 6.7
-16.4
2.6
device retention (%)
Factor magnitude on
6.9
6.1
-1.4
FPFTotal (%)
Factor magnitude on
8.0
-0.8
-1.8
FPFEmitted (%)
Factor magnitude on -0.26
0.20
0.06
MMAD (m)
Saudi Pharmaceutical Journal, Vol. 15, No. 2, April 2007
Deposition Profile of FITC-Dextran:
The deposition profile of FITC-Dextran after
aerosolization is given in table 2 and figure 1. The
results indicate that the presence of higher ratios of
FITC-Dextran to lactose improves the emission of
FITC-Dextran (p< 0.00007) for the fill weight 26 mg
and (p< 0.03) for the fill weight 104 mg. Similarly,
increasing the capsule fill weight and hence the
amount of FITC-Dextran resulted in increased
emission (p< 8* 10-7) for the blend ratio 1:25 and
(p<0.00001) for the blend ratio 4:22. Therefore the
presence of larger amounts of FITC-Dextran in the
capsule is beneficial to the emission.
When using high blend ratio (4:22) with the fill
weight of 26 mg in comparison with similar FITCDextran capsule content using blend ratio of 1:25
and the fill weight of 104 mg, the effect of FITCDextran fine particles on the bulk properties of the
aerosolized formulation is obvious. The emitted dose
of FITC-Dextran for the first (50.3%) is significantly
lower than the second (60.0%), (p<0.00002)
probably because of flowability issues. This is
because fine particles enhance the van der Waals
cohesive forces which operate between neighbouring
particles (26). On the other hand, such difference did
not improve performance when considering FPFTotal,
while when considering FPFEmitted and MMAD, it is
the freely dispersed FITC-Dextran (hence the higher
blend ratio) that significantly improved the
performance of the aerosolized powder.
132
Additional information was obtained by applying
the principles of factorial design to the experiments
as shown in table 3. The experiments show two
factors (i.e. drug to carrier ratio (factor A) and fill
weight (factor B)) on two levels. The fill weight was
shown to be more effective in reducing the
percentage of FITC-Dextran retained by the device
compared to the blend ratio (16.4% to 6.7%) as a
result of higher percentage of fines present in the
latter formulation. Although both factors acted
synergistically (indicated by the greater FITCDextran emission when both factors were used at
their maximum compared to any single factor), there
was some degree of interaction that reduces device
emptying (2.6%).
Although the fill weight was more important to
percentage emission of FITC-Dextran compared to
blend ratio, this was not reflected in the results of
FPFTotal (i.e. both factors showed a similar effect (6.1
and 6.9% respectively). On the other hand, the
increase in the FITC-Dextran emission by increasing
the blend ratio (6.7%) resulted in similar corresponding increase in the FPFTotal (6.9%). Both factors
(blend ratio and fill weight) acted synergistically, but
there was small negative interaction (1.4%) on the
FPFTotal.
When examining FPFEmitted, it was clear that
blend ratio is the factor to consider in order to
achieve improvement. The fill weight had a small
and negative effect on the FPFEmitted (0.8%).
Although the factors acted antagonistically, the
effect of blend ratio was apparent compared to the
negative interaction (8.0 to -1.8% respectively).
The results of MMAD indicate similar conclusions to that of FPFEmitted, but the reduction of
MMAD by increasing the blend ratio was as signifycant as the opposing increase achieved by increasing
the fill weight. The interaction was small (0.06 m)
compared to any individual effect.
It was possible to decrease the retained dose of
FITC-Dextran in the device to nearly half (from
59.0% to 35.9%) by modifying the formulation with
a ratio of 1:25 and fill weight of 26 mg to a ratio of
4:25 and fill weight of 104 mg. The increases of
FPFTotal from 14.9% to 27.8% and FPFEmitted from
36.2% to 43.4% without significantly affecting the
MMAD were also achieved. The deaggregation
pattern of the emitted dose was better when higher
ratios of FITC-Dextran to lactose were used as
indicated from the results of fine particle fraction
(FPFEmitted) and the MMAD.
Saudi Pharmaceutical Journal, Vol. 15, No. 2, April 2007
AL-TABAKHA & ARIDA
Discussion
Powders Characterisation:
The measured VMD of sieved lactose fraction
(75-106 m) by Malvern showed a value larger than
the designated fraction because the measured
particles were not spherical (27). Fine particles were
not completely removed by sieving, because such
particles adhere sufficiently tenaciously to the coarse
particles not to be displaced during sieving (28). The
presence of the freely dispersed FPL upon mixing
with sieved lactose indicates the quick saturation of
the binding sites on the coarse lactose particle by
FPL. A similar observation with lactose fraction (6390 m) even at a lower level of added FPL ( 1.5%)
was noted by other workers (29).
The larger proportion of fine particles freely
dispersed in the powder formulation with blend
ratios of 1:25 and 4:25 are expected to be largely of
micronised FITC-Dextran because the coarse
particles are already saturated by the FPL and since
FITC-Dextran can only adhere to the coarse particle
directly by replacing FPL (redistribution of particles)
or indirectly by building up particle aggregates. As
such, it is expected that the formulation performance
would be attributed to these freely dispersed particles.
Deposition Profile of FITC-Dextran:
The increased emission of FITC-Dextran whether by increasing fill weight and/or increasing blend
ratio indicates that a fraction of FITC-Dextran is
adsorbed on the inner walls of the capsule and the
device. When the walls are coated with adsorbed
particles, the percentage retention of the remaining
FITC-Dextran by the device would be expected to
decrease allowing an increase in emission. The
intensive coating of the inner wall of a capsule by
fine lactose (< 10 m) was previously reported (11).
Such effect can be attributed to a variety of particle
surface interactions. Particle size, density, electrostatic charge and moisture content of FITC-Dextran
can influence the device retention. Because of FITCDextran hygroscopicity and because a capsule
inherently contains 12-15% water, liquid bridging
may form resulting in such loss to the device. As
FITC-Dextran was micronised by jet milling, which
processes powder by attrition and impaction, the
presence of particle charge would not be surprising
and this can contribute to device losses.
THE EFFECTS OF CAPSULE FILL
The interaction between increased fill weight and
increased blend ratio (i.e. 2.6%) is opposite to the
action of increasing the blend ratio or the fill weight.
This is nearly half the magnitude of the blend ratio’s
effect, while it is negligible when compared to the
fill weight effect. Therefore more attention should be
given to the fill weight when higher emission is
required. The interaction indicates that the volume
occupied by the powder in the capsule may affect
emission.
As the increase in the FPFTotal for increased fill
weight or blend ratio (6.1 and 6.9% respectively) are
similar, it indicates that there is a corresponding
increase in the FITC-Dextran deposition in the preseparator and on the upper stages of the Andersen
impactor resulting from modifying the fill weight
which increases emission. This can be attributed to
the effect of the fill weight on modifying the plates
of the Andersen impactor. The more particles
deposited on the upper stages can prevent the
succeeding smaller particles from penetrating to the
lower stages of the ACI. This was demonstrated by
Graham et al. (30) and Nasr and Allgire (31). The
latter recommended the use of least number of doses
and/or fill weight in one experiment. Therefore a
factor can be introduced by the Andersen impactor
for high fill weight.
The small negative effect of increasing the fill
weight (0.8%) on the FPFEmitted, is probably because
of the same reason explained before, as the large fill
weights would modify the fractionation of the
aerosolized powders by Andersen impactor. and
therefore can be used to counteract any negative
affect from the fill weight that might actually be due
to Andersen sampling effect.
When considering the results of both FPFEmitted
and MMAD, combination of blend ratio with the fill
weight can counteract the negative effect of the
latter, while both were important to increasing
device emission and FPFTotal. Hence it is important
to optimise both factors when preparing formulations for inhalation.
Conclusion
The results suggest that increasing the fill weight
and/or drug: carrier blend ratio enhances the
aerosolization of a model drug FITC-Dextran. The
results are explained on the basis of physical
interactions of micronised FITC-Dextran with
themselves, FPL, sieved lactose and capsule and
Saudi Pharmaceutical Journal, Vol. 15, No. 2, April 2007
133
device walls. When greater numbers of micronised
FITC-Dextran particles are available in the studied
limits, the emission and dispersion improved, when
flow is also considered. The results highlight the
need to examine different types of permissible fine
particles as performance modifiers for the aerosolized formulations. The interaction of FITC-Dextran
particles with the capsule and device walls needs
further investigation.
References
1. Gonda I. Systemic delivery of drugs to humans via inhalation.
J Aerosol Med. 2006; 19(1):47-53.
2. Tirumalasetty PP and Eley JG. Permeability enhancing effects
of the alkylglycoside, octylglucoside, on insulin permeation
across epithelial membrane in vitro. J Pharm Pharmaceut
Sci.; 2006; 9(1):32-39.
3. Auricchio A, O’Connor E, Weiner D, Gao G-P, Hildinger M,
Wang L, Calcedo R, and Wilson JM. Noninvasive gene
transfer to the lung for systemic delivery of therapeutic
proteins. J Clin Invest. 2002; 110(4): 499-504.
4. Brooks AD, Tong W, Benedetti F, Kaneda Y, Miller V,
Warrell RP Jr. Inhaled aerosolization of all-trans-retinoic acid
for targeted pulmonary delivery. Cancer Chemother
Pharmacol. 2000; 46(4):313-8.
5. Kumar TR, Soppimath K and Nachaegari SK. Novel delivery
technologies for protein and peptide therapeutics. Curr Pharm
Biotechnol. 20067; (4):261-76.
6. Hickey AJ, Gonda I, Irwin WJ and Fildes FJT. Effect of
hydrophobic coating on the behaviour of a hygroscopic
aerosol powder in an environment of controlled temperature
and relative humidity. J. Pharm. Sci. 1990; 79(11): 10091014.
7. Rau JL. Practical problems with aerosol therapy in COPD.
Respir Care. 2006; 51(2):158-72.
8. Chan HK. Dry powder aerosol delivery systems: current and
future research directions. J Aerosol Med. 2006; 19(1):21-7.
9. Clark AR and Hollingworth AM. The relationship between
powder inhaler resistance and peak inspiratory conditions in
healthy volunteers – Implications for in vitro testing. J.
Aerosol Med. 1993; 6(2): 99-110.
10. Morén F. Aerosol dosage forms and formulations. In: Morén
F, Dolovich MB, Newhouse MT and Newman SP, eds.
Aerosols in Medicine: Principles, Diagnosis and Therapy:
Elsevier, London, 1993: 321-350.
11. Bell JH, Hartley, PS and Cox JSG. Dry powder aerosols I: A
new powder inhalation device. J. Pharm. Sci. 1971; 60(10):
1559-1563.
12. French DL, Edwards, DA and Niven, RW. The influence of
formulation on emission, deaggregation and deposition of dry
powders for inhalation. J. Aerosol Sci. 1996; 27(5): 769-783.
13. Lucas P, Anderson K and Staniforth JN. Protein deposition
from dry powder inhalers: Fine particle multiplets as
performance modifiers. Pharm. Res. 1998; 15(4): 562-569.
14. Podczeck F. Evaluation of the adhesion properties of
salbutamol sulphate to inhaler materials. Pharm. Res. 1998;
15(5): 806-808.
15. Tobyn M, Staniforth JN, Morton D, Harmer Q and Newton
ME. Active and intelligent inhaler device development. Int J
Pharm. 2004; 277(1-2):31-7.
134
16. Zeng XM, Martin GP, Marriott C, Pritchard J., Lactose as a
carrier in dry powder formulations: the influence of surface
characteristics on drug delivery. J Pharm Sci., 2001;
90(9):1424-34.
17. Shah SP and Misra A. Liposomal amphotericin B dry powder
inhaler: effect of fines on in vitro performance. Pharmazie.
200459(10):812-3,.
18. US Pharmacopeia 24-NF 18. Chapter <786>, "Particle-Size
Distribution Estimation by Analytical Sieving". U.S.
Pharmacopeial Convention, Rockville, MD, 2000: 1965–
1967.
19. European Pharmacopoeia. Uniformity of content of singledose preparation. Volume 1, 5th edition, Council of Europe,
67075 Strasbourg Cedex, France, 2004: 234.
20. Mitchell JP, Nagel MW, Wiersema KJ, Doyle CC, Migounov
VA. The delivery of chlorofluorocarbon-propelled versus
hydrofluoroalkane-propelled beclomethasone dipropionate
aerosol to the mechanically ventilated patient: a laboratory
study. Respir. Care. 2003; 48(11): 1025-32.
21. Van Oort M. and Truman K. What is a respirable dose?.
Journal of Aerosol Medicine. 1998; 11(Supplement 1): 89-95.
22. Andersen operating manual, Graseby Andersen, GA, 1985.
23. Lim JG, Shah B, Rohatagi S, Bell A. Development of a dry
powder inhaler, the Ultrahaler, containing triamcinolone
acetonide using in vitro-in vivo relationships. Am J Ther.
2006; 13(1):32-42.
24. Armstrong NA and James KC. Understanding Experimental
Saudi Pharmaceutical Journal, Vol. 15, No. 2, April 2007
AL-TABAKHA & ARIDA
Design and Interpretation in Pharmaceutics. Ellis Horwood Ltd.,
England, 1990.
25. Snavely WK, Subramaniam B, Rajewski RA and Defelippis
MR. Micronization of insulin from halogenated alcohol
solution using supercritical carbon dioxide as an antisolvent. J
Pharm Sci. 2002; 91(9):2026-39.
26. Begat P, Morton DA, Staniforth JN and Price R. The
cohesive-adhesive balances in dry powder inhaler
formulations II: influence on fine particle delivery
characteristics. Pharm Res. 2004; 21(10):1826-33.
27. Diffraction reference, Windows Sizer Reference Manual,
Malvern Instruments Ltd., Worcs, Manual number MAN
0073, Issue 1.1, 1993.
28. Twitchell A. Mixing. In: Aulton ME, eds. Pharmaceutics, The
Science of Dosage form Design. 2nd edition, Churchill
Livingtone, London, 2002: 181-196.
29. Zeng XM, Martin GP, Tee S-K and Marriott C. The role of
fine particle lactose on the dispersion and deaggregation of
salbutamol sulphate in an air stream in vitro. Int. J. Pharm.
1998; 176: 99-110.
30. Graham SJ, Lawrence RC, Ormsby ED and Pike RK. Particle
size distribution of single and multiple sprays of salbutamol
metered-dose inhalers (MDIs). Pharm. Res. 1995: 12(9):
1380-1384.
31. Nasr MM and Allgire JF. Loading effect on particle size
measurements by inertial sampling of albuterol metered dose
inhalers. Pharm. Res. 1995; 12(11): 1677-1681.