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Chemical Industry & Chemical Engineering Quarterly
Chem. Ind. Chem. Eng. Q. 21 (3) 457−464 (2015)
JIAJIA DAI BENFANG H. RUAN YING ZHU XIANRUI LIANG FENG SU WEIKE SU Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China SCIENTIFIC PAPER UDC 616-085:615:54:66 DOI 10.2298/CICEQ140609001D
CI&CEQ
PREPARATION OF NANOSIZED FLUTICASONE PROPIONATE NASAL SPRAY WITH IMPROVED STABILITY AND UNIFORMITY Article Highlights • We prepare nanosized fluticasone propionate nasal spray by high pressure homogenization • The influence of three factors during high pressure homogenization process is calculated by ANOVA • The finished nasal sprays offer a more uniform drug content compared to marketed formulation Abstract
Transmucosal nasal delivery has been recognized as up-and-coming option for delivery of therapeutic compounds. However, the short residence time of the formulation within the nasal cavity coupled with its low permeability is regarded as the barrier to good bioavailability. To overcome those limitations, we developed a new formulation – nanosized fluticasone propionate (FP) nasal spray. High pressure homogenization (HPH) was employed to achieve effective particle size reduction. Latin square experimental design (LSED) was implemented for high pressure homogenization process. With optimized process conditions, the resulting particles were less than 250 nm in size. The aging effect in FP nanosuspensions after 30-day refrigerated storage was not considerable. However, for long-term storage, a combination of homogenization and lyophilization (HL) was required to acquire stable FP nanocystals. The crystallinity of FP was examined by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD), and no alternation was observed before or after homogenization and lyophilization process. The finished nasal spray offered more uniform drug content compared to marketed formulation, which ensure the consistency and reproducibility of dose delivery. The study confirmed the effectiveness of homogenization, the usefulness of Latin square design and the feasibility of nano nasal spray. Keywords: fluticasone propionate; nano nasal spray; high pressure homogenization; uniformity.
Due to highly vascularized epithelial layer and relatively large surface area for drug absorption provided by nasal mucosa, nasal drug delivery with
Correspondence: W. Su, Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China. E-mail:
[email protected] Paper received: 9 June, 2014 Paper revised: 30 November, 2014 Paper accepted: 8 January, 2015
easily performed drug application is considered as an attractive approach. It also circumvents gastrointestinal degradation and hepatic first-pass metabolism [1]. However, rapid mucociliary clearance and low permeability of the nasal mucosa to certain drugs were shown to counteract these advantages [2]. Meanwhile, nasal drug delivery usually requires only a small dosage of a drug, so it is technically challenging to ensure the consistency and reproducibility of a drug, which is delivered to nasal sites of action. The issue of uniformity of a drug in suspension could be solved through nanosuspension. Compared
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to microparticles [3], nanoparticles have special advantages. The small particle size allows more precise delivery of certain amounts of the drug, increases the drug particles' total surface area to enhance the drug saturation solubility and results in much better diffusion efficiency at the site of absorption [4]. Also, nanoparticles can adhere better to the cell membrane [5], which leads to prolonged residence time. Nanosized nasal spray formulation might be better than microsized formulation, because it increases drug residence time, facilitates rapid absorption via distal penetration [6], and enhances pharmacokinetic benefits with a safety profile. To prepare nanosized particles, various methods have been developed, such as nanoprecipitation [7], media milling [8], HPH [9], spray drying [10] or a combination of these strategies [11]. Among these, HPH has been recognized as a promising approach, is applicable to most drugs and can be performed under aseptic condition with low risk of contamination. Latin square design has a long pedigree in experimental science. It is arranged as a main effect model via a particular residual sum of squares, postulating the estimation of error, leaving an evaluation of the principal effect unaffected by the nuisance effects [12]. What’s more, it allows experiments with a relatively small number of runs, and it can be replicated if more runs are available. Compared to randomized arrangement and randomized block, it has been proved to have the smallest experimental error [13]. So far, nanosized FP has been formulated for aerosol delivery, dry powder inhaler and topical therapy of skin diseases [14-16], but the nanosized FP nasal spray formulation and its physical properties have not been applied. Here, we investigated the development of nanosized FP nasal spray formulation for rhinitis therapy. EXPERIMENTAL
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available solvents and reagents were used without further purification. High pressure homogenization (HPH) Size reduction of fluticasone propionate was obtained by an AH-PILOT nano-homogenizer (ATS Engineering Inc., Canada). The drug loading was 1 mg FP per 90 mL Tween 80 solution. Pre-suspensions were mixed using a Eurostar 20 high speed digital stirrer (IKA®, Germany) at 5000 rpm for 5 min and immediately transferred to the AH-Pilot nanohomogenizer. All samples were homogenized under the conditions given in Tables 1 and 2. Latin square experimental design (LSED) A 4×4 LSED was introduced to estimate the influences of three factors in the HPH process: homogenization pressure, number of cycles and surfactant (Tween 80) concentration. The levels of these factors (Table 1) were based on previous studies [17]. Surfactant concentrations for intended optimization were then changed on the basis of polydispersity index (PdI) and indicated in Table 2. ANOVA (shown in Table 3) was performed on the Z-average size of resulting particle to identify the significant factors affecting particle breakdown at 95% confident level using IBM SPSS 19 software (IBM SPSS, Chicago, IL, USA). Stability of FP nanosuspensions The stability assessment of FP nanosuspensions was carried out by Laser diffraction. The FP nanosuspensions after homogenization were immediately kept in a glass container wrapped in tinfoil for 30 days at 4 °C. Samples were examined at premeditated time intervals, day-0, day-7 and day-30. Before examination, the suspensions were mixed using a Eurostar 20 high speed digital overhead Stirrers at 500 rpm for 3 min to obtain uniform samples for laser diffraction. The mixing process has no effect on the particle size.
Materials
Laser diffraction
FP (purity 99%) and dextrose were kindly supplied by Junye Pharmaceutical Co., Ltd. (Taizhou, Zhejiang, China). Tween 80 was purchased from Chaoneng Shiye Co., Ltd. (Zhaoqing, Guangdong), Phenethyl alcohol from Guangfu Fine Chemical Plant (Tianjin, China), Benzalkonium Chloride from Kehongda Co., Ltd. (Chengdu, China), Avecel® RC-591 from Youpuhui Pharmaceuticals Co., Ltd. (Shenzhen, China, produced by Asahi Kasei Co., Ltd., Japan). Purified water was prepared by a Nano-purification system obtained from Thermo, USA. All commercially
A Zetasizer Nano ZS90 (Malvern Instruments, Malvern, UK) was employed to examine the particle size of FP nanocrystals. The refractive index was 1.550 and the imaginary refractive index was 0.001.
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Lyophilization A lab scale freeze dryer FD-1-50 (Boyikang, Beijing, China) was employed to get lyophilized powder. The lyophilization temperature was set at –50 °C, degree of vacuum was below 25 Pa and lyophilization time was 48 h. In the homogenization and lyophil-
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zation process, FP nanosuspensions were frozen at –85 °C in the ultra-low temperature freezer (MDF-192, Sanyo, Japan). The lyophilized temperature was set at –50 °C, degree of vacuum was below 25 Pa and lyophilization time was 48 h. Lyophilized samples were stored in a vacuum desiccator over silica gel and protected from light at room temperature. Differential scanning calorimetry (DSC) Thermal analysis was carried out on a Mettler Q100 apparatus (TA Corporation, USA) equipped with a differential scanning calorimeter. About 4 mg sample was weighed and placed in an aluminum pan with lid and crimp sealed. At a heating rate of 10 °C/min, the samples were heated from 50 to 300 °C under a 10 mL/min stream of nitrogen purge. Powder X-ray diffraction (PXRD) The X-ray diffraction patterns were performed on an X’Pert PRO diffractometer with an X’Celerator (PANalytical Corporation, Holland). Samples were analyzed at a voltage of 40 kV, a current of 40 mA, and a scanning rate of 0.2 °/min-1 over a 2θ range of 5-45°. Preparation of nano nasal sprays Nano nasal sprays of FP lyophilized naocrystals were prepared by Eurostar 20 high speed digital and the final dose was 50 μg FP per 100 mg nasal spray according to a previous study [18]. Nano nasal sprays were packed as 120 sprays per bottle in a 25 mL bottle, equipped with standard 100-μL Classic Line spray pumps (Aptar Pharma, Philadeiphia, PA, USA). And they were preserved in tight, light-resistant containers at room temperature. Optical microscopy The size and shape of pre-milled and microsized FP particles were analyzed by optical microscopy on Leica DM 500 (Leica Microsystems, Germany) at magnification of 10×10. Viscosity measurements Viscosity of nanosuspension was measured by DV-II-Pro programmable viscometer (Brookfield Engineering, USA) connected with a temperature controlled circulation bath (2000 series, LabWorks, USA). Samples were analyzed at a shear rate of 5.0 rpm, a temperature of 25±0.1 °C. Osmolality measurements Osmolality by depression of freeze point was detected on an Osmette A automatic osmometer (Precision Systems Inc, USA).
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Droplet size distribution (DSD) Droplet size distribution, carried out in standard 100-μL Classic Line spray pumps, was measured by a Malvern Spraytec (Malvern Instruments, Malvern, UK) laser diffraction particle size system and actuated by a MightRunt Actuation Station (InnovaSystems, Inc. New Jersey, USA). Actuation force was set at 4 kg and min travel distance at 2.5 mm. The distance of the nozzle from the laser was 50 mm. Delivered dose uniformity (DDU) The samples for delivered dose uniformity test were prepared as following: the first two actuations (1 dose) and the last two actuations (119 and 120) of a nano nasal spray were collected in a 25 mL flask, 20 mL of diluent (acetonitrile and 0.001 M hydrochloric acid, 60:40, V/V) was added, and shaken well for 10 min to disperse the suspension. The suspension was then diluted with the diluent to volume, and mixed thoroughly. The flask was allowed to stand until the excipients had settled. The clear supernatant was then injected. The samples were detected by an HPLC system (Alliance HPLC e2695, Waters Corporation, USA) equipped with a Spherisorb ODS1 reversed-phase column (250 mm×4.6 mm, 5 µm). A mobile phase of methanol, acetonitrile, and buffer with 1.2 g/L of monobasic ammonium phosphate, a pH of 3.5 adjusted with phosphoric acid, (50:15:35) was used at a flow rate of 1.5 mL/min and a column temperature of 40 °C. The UV detector was set at 239 nm to analyze the column effluent. RESULTS AND DISCUSSION Latin square experimental design (LSED) In the homogenization process, levels of three factors (homogenization pressure, number of cycles and surfactant (Tween 80) concentration) were first conducted to the conditions shown in Table 1. After homogenization, the Z-average of FP particle sizes were significantly reduced, ranging from 60 to 450 nm. Values of PdI (Table 1) were mostly around 1, meaning that the homogenized samples under these conditions were very polydisperse and may contain large particles/aggregates/dust. However, PdI of samples with 0.5% Tween concentration were different, whose values were no more than 0.18. It was speculated that the high levels of Tween 80 concentration contributed to aggregation of nanoparticles; meanwhile heterogeneity of the pre-suspensions impacted the existence of large particles.
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Chem. Ind. Chem. Eng. Q. 21 (3) 457−464 (2015)
Table 1. 4-level, 3-factor latin square experiment designed to attain initial values. SD: standard deviation; Z-ave: Z-average size, as a mean value of the hydrodynamic diameter of the particle Exp. ID
Factor
PdIa±SD
Z-ave±SD, nm
Number of cycle
Pressure, bar
Tween 80 content, %
1
2
400
0.5
0.01±0.00
207±5
2
4
400
1
1.00±0.00
404±37
3
6
400
1.5
1.00±0.00
284±39
4
8
400
2
1.00±0.00
421±47
5
2
500
1
1.00±0.00
330± 40
6
4
500
1.5
1.00±0.00
265±14
7
6
500
2
0.32±0.03
122±17
8
8
500
0.5
0.15±0.01
68±5
9
2
600
1.5
1.00±0.00
209±33
10
4
600
2
1.00±0.00
204±42
11
6
600
0.5
0.18±0.02
103±1
12
8
600
1
0.84±0.05
139±23
13
2
700
2
1.00±0.00
264±37
14
4
700
0.5
0.12±0.02
91±4
15
6
700
1
0.57± 0.04
118±33
16
8
700
1.5
1.00±0.00
290±43
a
Polydispersity index, as a measure of the width of the particle size distribution. Values greater than 0.700 indicate that the sample has a very broad size
distribution, values no more than 0.350 are acceptable. PdI = the square of the standard deviation / mean diameter
Thereby, levels of Tween 80 (%) were adjusted to 0.125, 0.25, 0.375 and 0.5, as shown in Table 2, and all the pre-suspensions were first homogenized at low pressure (200 bar) for 4 cycles. The Z-average sizes were further declined ranged from 40 to 138 nm. PdI were 0.22 and less, indicating very narrow size distributions of all samples. Because the three factors were independent and their scales were interval, one-way analysis of variance (ANOVA) was used to offer insight into the relationship between homogenization pressure, number of cycles, Tween 80 (%) and Z-average means. Sig. (Signification) values of three factors less than 0.05 were considered to be statistically significant. The ANOVA results, given in Table 3, revealed that the number of cycles factor was dominant in affecting the final particle sizes. As a result of the aforementioned optimization, no significant influence of Tween 80 (%) on Z-ave. was observed, suggesting that levels of Tween 80 (%) in Table 3 were all suitable for HPH. Stability of FP nanosuspensions The impact of aging effect on FP nanosuspensions is shown in Table 2. All suspensions stored after 7 days yielded particles with Z-average size between 40 to 134 nm, which was consistent with Z-average size of day-0. PdI of samples with refrigerated storage for 7 days did not vary from that of freshly prepared samples. Size particles of Day-30
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samples maintained blew 250 nm for 30 days. It manifested that the presence of Tween 80 (0.125, 0.25, 0.375 and 0.5 mass%) did not contribute to crystal growth. On the contrary, Tween 80, as a stabilizer, can hinder the aging effect of FP particles. After stored for 30 days, PdI of all suspensions were 0.20 and less. It denoted that crystal growth produced no apparent effect on size distributions, which were still very narrow. Hence, the Ostwald ripening [19] was not a noticeable issue for day-7 and day-30 refrigerated storage samples. Crystal form determined by DSC and PXRD HPH needs to be conducted in suspension, but the presence of solvent (e.g., water) during homogenization could cause stability issues, such as Ostwald ripening and agglomeration through physical interactions, and/or chemically hydrolysis [20]. To prevent those adverse events, the nanosized samples were lyophilized after homogenization. In lyophilization process, moisture content is reduced to a level that does not support biological growth or chemical reactions. Therefore, drugs that are thermolabile and/or unstable in aqueous media could be lyophilized and stored as a solid form [21]. However, the whole process may take several hours to a few days to achieve. The solid-state structure of powder, such as polymorphism, change of crystallinity and the level of crystal imperfections, can affect the clinical perfor-
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Chem. Ind. Chem. Eng. Q. 21 (3) 457−464 (2015)
Table 2. 4-level, 3-factor latin square experiment designed to attain optimized values, demonstrated PdI values were within limits; stability results of day-7 and day-30 FP nanosuspensions, showed samples exerted great stability in 30 days Exp. ID
PdI (value±SD)
Factor Number of cycle Pressure, bar
Z-ave (value±SD, nm)
Tween 80 content, %
Day-0
Day-7
Day-30
Day-0
Day-7
Day-30
17
2
400
0.125
0.10±0.04
0.17±0.06
0.20±0.01
137±3
134±9
128±2
18
4
400
0.25
0.12±0.01
0.17±0.04
0.09±0.02
99±9
99±1
250±4
19
6
400
0.375
0.13±0.02
0.10±0.02
0.18±0.00
76±7
77±0
83±3
20
8
400
0.5
0.10±0.05
0.10±0.03
0.06±0.01
74± 9
71±0
184±4
21
2
500
0.25
0.07±0.03
0.03±0.00
0.09±0.02
105±5
104±3
178±5
22
4
500
0.375
0.19±0.01
0.22±0.02
0.09±0.02
58±4
57±8
106±2
23
6
500
0.5
0.02±0.00
0.13±0.00
0.10±0.04
62±2
63±1
64±4
24
8
500
0.125
0.10±0.04
0.16±0.02
0.16±0.02
61±1
62±3
109±5
25
2
600
0.375
0.04±0.01
0.19±0.05
0.03±0.00
130±7
131±8
103±9
26
4
600
0.5
0.13±0.00
0.11±0.04
0.07±0.00
63±9
64±7
103±4
27
6
600
0.125
0.10±0.02
0.10±0.02
0.16±0.04
71±6
73±2
105± 5
28
8
600
0.25
0.15±0.01
0.18±0.02
0.20±0.01
40±1
40±2
36±1
29
2
700
0.5
0.22±0.04
0.05±0.02
0.10±0.02
122±2
123±4
157± 8
30
4
700
0.125
0.07±0.03
0.12±0.03
0.16±0.04
57±8
58± 5
65±1
31
6
700
0.25
0.12±0.00
0.11±0.02
0.18±0.01
51±7
49±7
54±2
32
8
700
0.375
0.18±0.02
0.17±0.03
0.14±0.01
44±4
44±5
46±2
The characteristic PXRD patterns for the four samples of were displayed in Figure 1b. FP was crystalline as confirmed by presence of principal peaks at 10.07, 14.79, 15.87, 21.10 and 24.65° [23]. The main peaks disclosed that the stable crystal FP form I was existed in both pre-homogenized and nanocrystals [24]. The result agreed well with the DSC thermograms FP and demonstrated no discernable alteration in the crystal form post the homogenization process. The results demonstrated that the obtained FP nanocrystals by homogenization and lyophilization were physically stable.
mance [22]. DSC and PXRD were carried out to evaluate the crystal form after homogenization and lyophilization. DSC thermograms of pre-homogenized and FP nanocrystals were shown in Figure 1a. The melting point of pre-homogenized FP was from 281 to 284 °C, suggesting the crystalline nature of the drug. The endothermic peaks of all FP nanocrystals resembled that of pre-homogenized FP, which mean that the combined effect of cavitation, shear and turbulence produced by HPH had no big impact on FP nanocrystals. The crystallinity FP form after homogenization and lyophilization showed no alteration. The very slight shift of the melting points can be explained by the presence of Tween 80 with a very low concentration.
Characterization of nasal sprays To evaluate the effect of FP particle size (particle sizes of pre-homogenize and microsized FP
Table 3. ANOVA of Table 3 from Latin experimental design Source Corrected model
Sum of squares 13414.888
a
Dfb
Mean square
9
c
Fd
Sig.
e
1490.543
10.783
0.005
Intercept
97489.134
1
97489.134
705.249
0.000
Number of cycle
11523.476
3
3841.159
27.787
0.001
Pressure, bar
1770.287
3
590.096
4.269
0.062
Tween 80 content, %
121.124
3
40.375
.292
0.830
Error
829.402
6
138.234
-
-
Total
111733.424
16
-
-
-
Corrected total
14244.290
15
-
-
-
a
b
The sum of squares column gives the sum of squares for each of the estimates of variance; the degrees of freedom for each estimate of variance; ceach mean square is calculated by dividing the sum of square by its degrees of freedom, e.g., Mean square(Number of cycle) = Sum of squares(Number of cycle) / d e / df(Number of cycle); the F ratio, calculated as F(Number of cycle) = Mean square(Number of cycle) / Mean square(Pressure); significance: also known as p-value, gives the significance of the F ratio
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were shown in Figure 2), we further measured various physical properties of 6 different nasal sprays, including the commercial sample “Flixonase®”. As depicted in Table 4, pH, viscosity, osmolarity values, and droplet size distribution (DSD) had no remarkable differences among nanosized FP nasal sprays, prehomogenized nasal spray, microsized nasal spray and marketed formulation. Delivered dose uniformity (DDU) value was an essential criterion for therapeutic usage, acceptable USP criteria of which should be within 85-115%. Nanosized (44-137 nm) formulation and Flixonase® met DDU criteria, but neither the prehomogenized nor the microsized (10-200 μm) formulation. What is more, the marketed formulation Flixonase® and the nanosized formulations prepared using our HL procedure, showed remarkably large difference in the DDU test. Nanosized formulation provided better uniformity than the marketed formulation Flixonase® and was stable enough for therapeutic usage.
Chem. Ind. Chem. Eng. Q. 21 (3) 457−464 (2015)
CONCLUSIONS The HPH technique was proven to be a practical method for efficient particle size reduction. Particle size of HPH processed nanosuspensions remained the same in 30 days and no precipitation was observed; the stability may be due to the presence of Tween 80. Except for size reduction and homogeneous distribution, no crystallinity transformation of FP crystal before or after HPH process was observed. The finished nano nasal spray demonstrated comparable product performance to the marketed formulation in the terms of pH, viscosity, osmolarity and DSD. In addition, nanosized nasal spray showed better performance in DDU test. Taken together, nanosized nasal spray could be a promising formulation for rhinitis therapy with industrial applicability.
Figure 1. a) Differential scanning calorimetry thermograms and b) X-ray diffractograms: 1) pre-homogenized FP, 2) FP nanocrystals after lyophilization of Exp.17, 3) FP nanocrystals after lyophilization of Exp.18 and 4) FP nanocrystals after lyophilization of Exp.32, indicating there was no crystallinity transformation of FP nanocrystals.
Figure 2. Optical microscopy image of: a) pre-homogenize and b) microsized FP.
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Table 4. Physical properties of nasal sprays, indicating that FP particle size affected DDU performance of nasal spray while other properties had relation to ingredients Exp. ID
Nasal spray
a,b
pH
Viscosity, cps
Osmolarity, mOsm
DDU c
DSDd,e, μm Dv10
Dv50
Dv90
33
Flixonase
®
6.4
118
312
90±3%
29.5
76.4
166.9
34
20-200 μm
6.3
120
298
57±28%
29.7
80.0
179.1
35
10-20 μm
6.3
116
303
90±7%
25.8
50.4
103.3
36
137 nm
6.4
112
308
99±3%
27.1
64.0
151.1
37
99 nm
6.4
120
306
96±2%
26.1
57.9
129.7
38
44 nm
6.5
120
314
102±3%
26.2
57.8
131.3
a
b
All the measurements in the table have been replicated 3 times; particle size of FP used to prepare nasal sprays or trade name of nasal spray; cdelivered d dose uniformity, acceptance criteria of DDU data should be within 100±15%; droplet size distribution, a cumulative size distribution parameter, here based e on volume, e.g., Dv10 is the particle size below which 10% of the spray lies; span values of DSD data were between 1.54-1.94, meaning that no big deviations of the distribution width of all nasal sprays were detected
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J. DAI et al.: PREPARATION OF NANOSIZED FLUTICASONE PROPIONATE…
JIAJIA DAI BENFANG H. RUAN YING ZHU XIANRUI LIANG FENG SU WEIKE SU Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China NAUČNI RAD
Chem. Ind. Chem. Eng. Q. 21 (3) 457−464 (2015)
PRIPREMA NANO-STRUKTURIRANOG FLUTIKAZON-PROPIONAT NAZALNOG SPREJA SA POBOLJŠANOM STABILNOŠĆU I UNIFORMNOŠĆU Transmukozna nazalna primena terapeutskih jedinjenja je sve češće u upotrebi. Međutim, kratko vreme zadržavanja pomenutih formulacija unutar nosne šupljine uz njegovu nisku permeabilnost se smatra glavnom barijerom kad je u pitanju dobra bioraspoloživost. Da bi se prevazišla ova ograničenja, razvijena je nova formulacija - sprej za nos na bazi flutikazon-propionata (FP) u obliku nanočestica. Korišćena je homogenizacija pod visokim pritiskom (HPH) u cilju efikasnog smanjenja veličine čestica. Za optimizaciju procesa homogenizacije je korišćen eksperimentalni plan tipa latinskog kvadrata. Sa optimalnim uslovima procesa, nastale su čestice veličine manje od 250 nm. Efekat starenja FP nanosuspenzija posle 30 dana stajanja u frižideru je bio beznačajan. Međutim, pri dugoročnom skladištenju, potrebno je kombinovati homogenizaciju i liofilizaciju da bi se dobili stabilni FP nanokristali. Kristalnost FP je analiziran diferencijalnom skenirajućom kalorimetrijom i X-difrakcijom iz praha, i nije uočena nikakava alternacija pre i posle homogenizacije i liofilizacije. Gotov sprej za nos daje ravnomerniji sadržaj leka u odnosu na tržišnu formulaciju, što obezbeđuje doslednost i reproduktivnost prilikom davanja doze. Studija je potvrdila efikasnost homogenizacije, korisnost latinskog kvadrata i praktičnost nano spreja za nos. Ključne reči: flutikazon-propionat; nano-nazalni sprej; homogenizacija pod visokim pritiskom; ravnomernost.
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