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Chimeral agglomerates of microparticles for the administration of caffeine nasal powders
J. DRUG DEL. SCI. TECH., 14 (6) 449-454 2004
Chimeral agglomerates of microparticles for the administration of caffeine nasal powders P. Russo*, F. Buttini, F. Sonvico, R. Bettini, G. Massimo, C. Sacchetti, P. Colombo, P. Santi University of Parma, Department of Pharmacy, Via delle Scienze, 43100 Parma, Italy *Correspondence: [email protected] The manufacturing and performance of caffeine powders having a form of chimeral agglomerates designed for nasal insufflation are described in this paper. Agglomerates containing caffeine were prepared in a rotating cylindrical container by tumbling primary microparticles prepared by spray drying drug and excipient solutions. Production yield, agglomerate morphology and size, insufflation performance and caffeine dissolution rate were the determined characteristics. Agglomerate formation and behavior during insufflation were favorably influenced by the presence of lecithin in the microparticle formulation. Insufflation through three different devices showed that the agglomerate structure enabled the complete emission of the dose. The agglomerates were broken into fragments of a size appropriate for nasal deposition. Finally, the agglomeration process did not reduce the dissolution rate of caffeine. Key words: Nasal powders – Caffeine – Spray drying – Chimeral agglomerates – Insufflators.
Additionally, they have to be promptly disaggregated by water in the primary microparticles and dissolved. The agglomerates are defined «chimeral» since their size is non-permanent, being reduced during insufflation. In a previous study [26], we prepared caffeine spray dried micronized powders intended for nasal delivery in the prevention of neurodegenerative disorders [27]. The use of excipients such as mannitol, hydroxypropylmethylcellulose (HPMC) and polyethylenglycol (PEG) allowed to modulate the size and shape of the spray-dried caffeine microparticles. These microparticles could be used for chimeral agglomerate preparation. Then, the manufacturing and behaviour of agglomerates for nasal delivery remained to be explored. The aim of this work was to study the manufacturing and the technological performance of caffeine powders in form of chimeral agglomerates for nasal insufflations. The goal was to have as final formulation a free flowing powder, deliverable by insufflations and promptly dissolving in water. Primary microparticles of caffeine were prepared by spray drying solutions of caffeine and excipients. Tumbling the primary microparticles in a rotating cylindrical container allowed for the preparation of agglomerates that were collected by sieving. The influence of caffeine powder composition on agglomerate properties was examined. The agglomerates were studied as for micromeritics, insufflations performance with different devices and caffeine dissolution rate.
Conventionally, the nose is a drug administration site for the treatment of local diseases such as rhinitis. However, nasal administration has been exploited for systemic drug delivery, especially when rapid onset of action is required [1-6]. This route could be appropriate for drugs used in crisis treatments, such as pain, migraine, insomnia or anxiety. In addition, centrally acting drugs, on account of the nose/brain pathway, might face a direct uptake when deposited on the olfactory mucosa [7, 8]. Liquid preparations are the most common nasal dosage forms. However, they present several drawbacks, such as: preservative use that could impair mucociliary function [9], reduced chemical stability of dissolved drug and short residence time of formulation in the nasal cavity. Dry powders are less frequently used in nasal drug delivery [10-16]. The dry state of dosage form could improve stability and prolong the contact time with the nasal mucosa in case of the bioadhesive formulations [17-21]. In general, the nasal powder particles have to be small enough for insufflation delivery and prompt drug dissolution. However, small particles are problematic to handle during dosage form manufacturing, particularly for loading and metering of powders into the administration device. Therefore, a nasal powder should be at the same time fine enough for delivery and coarse enough for flowing and packing during metering. This technological problem could be solved by particle agglomeration, a process in which the powder size is increased by the preparation of spheroidal soft clusters of microparticles. Agglomerated powders (soft pellets) have been used in pulmonary powder delivery where they have to be completely disaggregated in the aerosol, with particles lower than 5 µm in order to be respirable [22-24]. No applications of agglomerates have been described in nasal dosage forms. The rationale for the use of spheroidal agglomerates of microparticles for nasal powder administration is that these soft structures, during emission from nasal insufflators, are broken into fragments with a larger size than the primary microparticles. The fragments must be within non-respirable size range (diameter greater than 10 µm for nasal deposition [25]).
I. MATERIALS AND METHODS
Caffeine USP was supplied from Merk, Darmstadt, Germany; mannitol Ph. Eur. was a gift from Lisapharma, Erba, CO, Italy; hydroxypropylmethylcellulose (Methocel E3 Premium EP) was purchased from Colorcon Limited, Orpington, United Kingdom; polyethylenglycol (PEG 6000) was obtained from Hoechst AG, Strasbourg, France; lecithin (Lipoid S45) was supplied by Lipoid AG, Cham, Switzerland. All solvents were of analytical grade. The Puvlizer, Miat and Monopowder nasal insufflators were kindly provided by Teijin Ltd., Tokyo, Japan, Miat SpA 449
J. DRUG DEL. SCI. TECH., 14 (6) 449-454 2004
Chimeral agglomerates of microparticles for the administration of caffeine nasal powders P. Russo, F. Buttini, F. Sonvico, R. Bettini, G. Massimo, C. Sacchetti, P. Colombo, P. Santi
Milan, Italy, and Valois Dispray, Mezzovico, Switzerland, respectively.
glass following weight and size determination. The glass was then placed on a mobile platform under the measuring head of a calibrated load cell (514 QD, DS Europe, Milan, Italy). The elevation of the platform, at a rate of 0.2 mm/min, caused the compression of the agglomerate against the measuring head. The force-time curve was recorded by means of an adequate software program (Chart v 3.5 AdInstruments Ltd., Oxfordshire, United Kingdom). The force under which the agglomerate fractured was recorded. From the crushing force, F (N), the tensile strength, σ (N/m2), was calculated by the Equation 2 [29]:
1. Primary microparticle preparation
Micronized primary particles were prepared by spray drying caffeine and excipient solutions in accordance with a previous work [26]. Briefly, solutions were prepared by dissolving caffeine and mannitol under stirring, with or without PEG 6000 and HPMC. The solutions containing lecithin were prepared by adding, under stirring, a solution of lecithin in ethanol (0.5 g in 40 ml) to the aqueous solution of caffeine and excipients (solid content 10 g in 350 ml). The solution was spray dried using a Buchi Mini Spray Dryer B-191 (Buchi Laboratoriums-Tecnik, Flawil, Switzerland) in the following experimental conditions: inlet temperature 130°C; outlet temperature 45-50°C; feed rate 6.5 ml/min; nozzle diameter 1.0 mm; drying air flow 600 l/h.
σ = 2.8F/πd2 where d is the agglomerate diameter.
Eq. 2
5. Agglomerate delivery from insufflation devices
The amount of dose emitted by insufflation of nasal powders or agglomerates was measured and pictures of the delivery sequence were taken. Three different devices, i.e. Puvlizer, Miat and Monopowder, were employed (Figure 1). Puvlizer and Miat are equipped with a squeezable rubber bulb for air insufflation, and Monopowder with a piston pump. The air stream produces the emission of the dose contained in the device reservoir. Twenty milligrams of agglomerates was loaded into the reservoir of each device. Quantitative delivery of agglomerates from the insufflators was determined by weighing the insufflator before and after each actuation. The air flow produced by the three devices was measured by means of a flowmeter (Thermal Mass Flowmeter TSI Model 3063, TSI Incorporated, Shoreview, MN, United States) connected to a computer. The plumes produced by the insufflation of the agglomerates from the nasal devices were recorded by a video camera (Panasonic F 15, Matsushita Electric Industrial Co. Ltd., Osaka, Japan).
2. Chimeral agglomerate manufacturing
Chimeral agglomerates were prepared by rolling 5 g of microparticle powders into a Bakelite cylindrical ointment jar (Ø 5.0 cm, 4.4 cm length), rotating at 30 rpm for 30 min on the cylinder axis tilted at 90°. Agglomerates between 106 and 850 µm were collected by sieving. The agglomerations were performed at temperature and humidity conditions ranging between 22-24°C and 60-70% RH, respectively.
3. Microparticle and agglomerate micromeritics
The size distribution of the spray-dried microparticles was checked using laser light diffraction apparatus (series 2600 Malvern Instruments Ltd., Spring Lane South Malvern, Worcestershire, United Kingdom) by suspending caffeine microparticles in ethyl acetate. The morphology of the spray-dried microparticles agglomerates of caffeine was assessed by means of an optical stereomicroscope (magnification 40x) (Citoval 2, aus Jena, Jena, Germany) connected to a video camera (JVC, Tokyo, Japan). Agglomerate size distribution was measured using Ø10 cm sieves (Endecotts Limited, London, United Kingdom) with nominal apertures of 850, 600, 425, 300, 212, 150 and 106 µm. A sample of 5 g of agglomerates was placed on top of the sieve stack which was vibrated for 10 min (amplitude 3) in a vibratory laboratory sieve shaker (Analysette 3 Fritz model, Fritsch GmbH, Idar-Oberstein, Germany). The particle size distribution of agglomerates after ejection from Monopowder Valois was also determined by performing twenty insufflations directly on the sieve stack under the measurement conditions described above. Bulk and tapped densities were measured according to the European Pharmacopoeia 4, whereas Carrʼs Index (CI) was calculated by the Equation 1 [28]:
6. Chimeral agglomerate dissolution
Twenty milligrams of caffeine agglomerates was suspended under magnetic stirring in a beaker containing 100 ml of dis-
Eq. 1 CI = [(Dt - Db)/Dt] · 100 where Dt is the tapped density and Db is the bulk density.
4. Chimeral agglomerate tensile strength
Figure 1 - Three different nasal insufflators, from right to left: Puvlizer, Miat device and Monopowder Valois.
A single agglomerate was placed on a microscope cover 450
Chimeral agglomerates of microparticles for the administration of caffeine nasal powders P. Russo, F. Buttini, F. Sonvico, R. Bettini, G. Massimo, C. Sacchetti, P. Colombo, P. Santi
tilled water at 37°C. The solution was filtered and circulated in a flow-through cell of UV-Vis spectrophotometer (Jasco V530, Jasco Inc., Easton, United States) for caffeine content determination at 276 nm.
J. DRUG DEL. SCI. TECH., 14 (6) 449-454 2004
Table I also reports the yield of the agglomeration process. Not all spray-dried powders could be agglomerated. Finally, the inclusion of lecithin in the spray-dried powders resulted as being decisive for agglomeration, as shown by the high yields obtained with powders # 5, 7 and 8. We verified that the spray dried primary particles and the corresponding agglomerates did not affect the dissolution rate of caffeine. It was not the purpose of this test to mimic the dissolution in the nose, but simply to assess that the spray drying and agglomeration did not reduce significantly the dissolution rate of caffeine crystals. In fact, nasal powders have to dissolve quickly in the small volume of water lining the mucosa [30]. The dissolution of the spray-dried powders was practically instantaneous: in one minute the caffeine content of primary particles and corresponding agglomerates was completely dissolved without a significant difference from caffeine crystal dissolution (data not shown).
III. RESULTS AND DISCUSSION 1. Manufacturing of primary microparticles and agglomerates
The first step of the chimeral powder manufacturing was the preparation of primary microparticles to be agglomerated in soft structures. We have shown in a previous work [26] that the spray drying of caffeine/mannitol (70/30) solution produced acicular caffeine particles. By introducing into this formulation hydroxypropylmethylcellulose (HPMC) and polyethylenglycol (PEG 6000), alone or in combination, the size and shape of spray-dried microparticles were substantially changed. Adding also lecithin to these compositions, a new series of primary microparticle powders was prepared with the intent to verify the adjuvant effect on spray-dried microparticulate powders and relative agglomerates (Table I). As already observed before [26], the presence of mannitol allowed for the preparation of spray-dried particles of caffeine in acceptable yield, considering the small scale of the production; the presence of PEG 6000 reduced the spray drying yield, due to excessive particles sticking on the spray drier chamber and the addition of HPMC in part counteracted this PEG effect. The introduction into the formulation of lecithin was very favorable for spray drying yield, except in the case of the combination with PEG. In principle, all these microparticle powders could be insufflated into the nose, but their flow and packing were poor for the nasal product preparation. Soft spheroidal agglomerates, due to their improved packing and flow properties, could substantially favour powder metering and filling of insufflators, without affecting the insufflation performance. The prepared caffeine spray-dried microparticles showed differing agglomeration after rotation in the Bakelite container. In fact, it was observed that microparticles agglomerated in soft structures in differing yields according to their composition. The aptitude of spray-dried powders to agglomerate was evaluated by measuring the obtained amount of agglomerates having a size between 106 and 850 µm in ratio to the amount of tumbled microparticles.
2. Micromeritics, morphology and strength of chimeral agglomerates
The packing and flow properties of the powders and agglomerates containing lecithin are presented in Table II. The comparison between the values exhibited by the powders and respective agglomerates illustrates the evident advantage of agglomeration for the flowability and packing of micronized powders. The agglomerates were free flowing and exhibited a strongly improved Carrʼs Index in comparison with the respective microparticulate powders. The morphology of the agglomerates, studied by optical microscopy, was dependent on the formula composition. For example, powder # 2 differed from powder # 7 on account of the absence of lecithin, and likewise powder # 4 differed from powder # 8. These powders without lecithin (powders # 2 and 4) produced rougher and less compact agglomerates. Concerning the two formulations containing lecithin, the agglomerates without PEG 6000 (powder # 7) were smoother than those from powder # 8. In general, when lecithin was not present in the formulation, more powdery agglomerates were obtained, as formulations # 2 and 4 illustrate in Figure 2. The agglomerates were tested for crushing strength. Figure 3 shows optical microscopy pictures of agglomerate # 5, before and after crushing: the spheroidal agglomerate broke
Table I - Composition of the spray-dried microparticles and agglomerates and yields of the processes. Standard deviation into brackets. Code
Composition Caffeine
Mannitol
Yield
HPMC
PEG 6000
Lecithin
Microparticles
Agglomerates
Microparticle mean diameter (µm) and Span
#1
70
30
-
-
-
58
**
29.9 (1.45)
#2
68.6
29.4
2
-
-
75
31*
5.00 (0.94)
#3
66.5
28.5
-
5
-
1.3
***
37.6 (1.32)
#4
65.1
27.9
2
5
-
53
26*
5.04 (1.02)
#5
66.5
28.5
-
-
5
60 (1.2)
86.3 (1.0)
5.29 (1.07)
#6
63
27
-
5
5
6.9
***
4.27 (1.27)
#7
65.1
27.9
2
-
5
66 (2.0)
88 (4.2)
12.3 (1.39)
#8
61.6
26.4
2
5
5
47.6 (5.5)
80 (6.3)
4.78 (1.08)
*These powers were difficult to agglomerate due to the excessive electrostaticity and adhesion to the container wall. **This powder could not be agglomerated in a Bakelite container. ***These powders were not agglomerated due to the low amount of particles obtained by spray drying. 451
J. DRUG DEL. SCI. TECH., 14 (6) 449-454 2004
Chimeral agglomerates of microparticles for the administration of caffeine nasal powders P. Russo, F. Buttini, F. Sonvico, R. Bettini, G. Massimo, C. Sacchetti, P. Colombo, P. Santi
Table II - Bulk and tapped density and Carr’s Index of microparticulate powders and agglomerates # 5, 7 and 8 (mean values and standard deviations; n = 3). Code
Microparticulate powders
Agglomerates
Bulk density (g/ml)
Tapped density (g/ml)
Carr's Index (%)
Bulk density (g/ml)
Tapped density (g/ml)
Carr's Index (%)
#5
0.24 (0.001)
0.28 (0.002)
15.0
0.26 (0.006)
0.28 (0.003)
8.6
#7
0.23 (0.004)
0.28 (0.003)
16.5
0.27 (0.006)
0.30 (0.002)
8.4
#8
0.23 (0.001)
0.31 (0.001)
24.8
0.25 (0.001)
0.28 (0.002)
10.5
Figure 3 - Optical microscopy pictures of agglomerate # 5 before (a) and after (b) the crushing test.
3. Powder and agglomerate insufflations
The nasal drug product consists of the combination of the powder formulation and the device for its delivery. The Puvlizer device is a nasal powder insufflator consisting of a squeezable rubber bulb connected to a nasal adaptor. A hard gelatin capsule containing pre-metered powder or agglomerate is inserted in the nasal adaptor and perforated with a needle. The air stream produced by squeezing the rubber bulb then provides the emission of the dose contained in the capsule. The size of the rubber bulb determines the peak flow rate and time course of the air stream produced and, consequently, the amount of powder emitted. The Puvlizer insufflators were designed with a small rubber bulb and, therefore, the complete delivery of the capsule content requires several actuations (normally eight). In principle, this is not considered a disadvantage since, by alternate insufflation into both nostrils, powder can be deposited in the whole nasal cavity. Figure 4 shows the percentage of dose emitted from the Puvlizer nasal insufflators plotted against the number of device actuations. There was a great difference between powders and agglomerates in delivered doses. Contrarily to the corresponding powders, the ejection of agglomerates was already fast and quantitative after six actuations. A possible explanation is that the agglomeration process reduced particle adhesion to the capsule or the device. Powder delivery was tested also with the two other devices, which should be able to emit the entire dose loaded in a single actuation. Similarly to Puvlizer, the Miat nasal powder insufflator contains a hard gelatin capsule and presents a squeezable rubber bulb connected to the nasal adaptor. For this device, the bigger rubber bulb provides an air stream able to emit the entire powder content of the capsule in a single actuation. The Monopowder Valois exhibits a different ejection mechanism. Here, a piston pump and a plastic cylindrical reservoir replace the squeezable bulb and the gelatin capsule, respectively. A firmly inserted plastic sphere seals the reservoir containing the pre-metered powder. The air pressure raised by the piston pump actuation provokes the reservoir opening and hence, the sudden emission of the powder. Table IV presents the results of dose emission from the
Figure 2 - Optical microscopy pictures of agglomerates obtained from powders # 2 (a), # 7 (b), # 4 (c) and # 8 (d).
into fragments in tension along the axis of crushing force application. Among the agglomerates without lecithin, the tensile strength was measurable only with formulation # 2, in which there was no PEG 6000. In contrast, when lecithin was present in the formulation, the tensile strength values increased indicating a superior mechanical resistance of the agglomerates (Table III). These agglomerates could be handled in metering operation without affecting their structure. It is not possible at the moment to indicate a reference value of the optimal tensile strength, since the value depends on the insufflation device, on the filling operations and, in case of multi-dose devices, also on the metering manoeuvres. In any case, the values obtained with the formulations # 5, 7 and 8 were considered appropriate for the insufflation, metering and other manipulations performed in this work. Hence, lecithin resulted in a very useful adjuvant for the manufacturing of these types of agglomerates, considering that high yield and acceptable mechanical strength were obtained. It is likely that its effect was due to binding improvement between the microparticles. Table III - Agglomerate tensile strength (mean values and standard deviations; n = 8). Chimeral agglomerate
Tensile strength*103 (N/m2)
Caffeine, mannitol, HPMC (# 2) Caffeine, mannitol, lecithin (# 5) Caffeine, mannitol, HPMC, lecithin (# 7) Caffeine, mannitol, HPMC, PEG 6000, lecithin (# 8)
4.11 (1.71) 79.2 (16.3) 32.5 (14.2) 51.8 (21.7) 452
Chimeral agglomerates of microparticles for the administration of caffeine nasal powders P. Russo, F. Buttini, F. Sonvico, R. Bettini, G. Massimo, C. Sacchetti, P. Colombo, P. Santi
J. DRUG DEL. SCI. TECH., 14 (6) 449-454 2004
100
Dose emitted (%)
80 60
40 20
Figure 5 - Delivery plumes of agglomerate # 5 from Puvlizer at 0.28 s (a), from Miat device at 0.20 s (b), and from Monopowder Valois at 0.08 s (c).
0 0
2
4
6
8
10
12
Actuation number
Table V - Peak flow rate and amount of air emitted of Puvlizer, Miat and Monopowder Valois devices (mean values and standard deviations; n = 5).
Figure 4 - Percent of dose emitted from Puvlizer insufflator versus number of actuations (formulation # 5 circle; formulation # 8 square; powder open symbol; agglomerates full symbols).
Puvlizer Miat device Monopowder
Table IV - Percentage of dose emitted from Miat and Monopowder Valois devices in one actuation (mean values and standard deviations; n = 3). Formulation
Miat device Agglomerate
Microparticles
Agglomerate
#5
12.1 (2.3)
95.6 (1.0)
98.6 (0.5)
99.1 (0.3)
#7
36.5 (12.8)
92.4 (8.5)
96.6 (2.7)
96.9 (3.1)
#8
93.0 (6.7)
96.9 (4.0)
98.2 (0.1)
98.9 (0.3)
Air emitted (ml)
4.93 (0.58) 28.07 (1.68) 16.62 (1.58)
6.52 (0.87) 48.00 (1.63) 4.50 (0.23)
The peak flow rate of Monopowder Valois was lower than the value exhibited by the Miat device and the volume of air emitted was the smallest, but the Valois device was more efficient in extracting the powder from the reservoir (see Table IV). In fact, the design of the Valois device enabled an efficient flow of a sudden and intense air stream through the powder reservoir. In contrast, in the Miat device, we observed a large dispersion of the air insufflated: not all the air flowed into the gelatine capsule, but a part was dispersed in the conducting channel of the nasal adaptor where the capsule is lodged. The opposite happened with the Valois device where, despite the low amount of air displaced, the air stream was forced to pass through the powder dosed in the reservoir. Finally, the effect of insufflation on agglomerate breaking was studied by measuring the particle size distribution before and after emission. In particular, the particle size distribution of agglomerates # 5, 7 and 8 was investigated before and after ejection from the Valois nasal insufflator. The results are shown in Figure 6. The figure shows a significant reduction in the size of agglomerates after insufflation with the Valois device, but the size of agglomerate fragments was larger than that of original microparticles. The agglomerates have been broken in fragments depending on their mechanical resistance (see Table III). Among the agglomerates containing lecithin, formulation # 5 was significantly harder than agglomerate # 7 (p < 0.01). The agglomerate # 5 broke into fragments of microparticles with a mean diameter lower than 250 µm, while the agglomerate # 7 broke into fragments with a mean diameter lower than 128 µm, reflecting the respective mechanical resistance.
Valois Monopowder
Microparticles
Peak flow rate (l/min)
one-shot devices. The data refer to powders and agglomerates with compositions # 5, 7 and 8. In general, the powders and the agglomerates introduced in the reservoir of the Valois device were completely emitted in one shot. The same was not observed with the Miat device, in particular when the non-agglomerated powder # 5 and 7 were used for insufflations. The delivery plumes of agglomerates from the Miat, Puvlizer and Valois nasal insufflators were recorded (Figure 5). The pictures show the powder clouds during the first actuation of the device (Puvlizer) or the single actuation for Miat and Valois. The pictures were taken while the fully developed phase of the plume was still in contact with the actuator tip. The aspect of the plumes depended on the device used. In the case of Puvlizer, the cloud was low, and several spots corresponding to large fragments were clearly visible. The cloud emitted from the Miat device was elongated with smaller agglomerate fragments visible. The cloud emitted from the insufflator Valois was high, large and fluffy; in this case, a few small fragments were visible in a plume having a less regular shape. The velocity of powder emission from the devices also differed greatly. We expected that high powder velocity during ejection would prompt the particles to impact on the nasal mucosa. The puff was emitted in approximately 0.28 s with the Puvlizer insufflator and 0.20 s with the Miat device. The Valois device produced a puff delivered in 0.08 s. The results obtained were justified by the peak flow rate and volume of air emitted by the three insufflators (Table V): the Miat device exhibited the highest peak flow rate, whereas the Puvlizer presented the lowest. This was due to the large size of the rubber bulb of the Miat insufflator.
* * * The results obtained allow us to conclude that chimeral agglomerates of spray-dried microparticles intended for nasal powder administration improves the flow and packing of micronized powders and are more efficiently delivered than 453
Cumulative undersize (%)
J. DRUG DEL. SCI. TECH., 14 (6) 449-454 2004
Chimeral agglomerates of microparticles for the administration of caffeine nasal powders P. Russo, F. Buttini, F. Sonvico, R. Bettini, G. Massimo, C. Sacchetti, P. Colombo, P. Santi
100
12.
80
13.
60
14. 40
15. 20
16. 0 <53
64 90.5 128 181 256 362.5 512.5 725 >850
Mean diameter (µm)
17.
Figure 6 - Effect of insufflation on particle size distribution of agglomerates # 5 (▲, Δ) # 7 (●, ❍) and # 8 (■, ❐) (full symbols before delivery; empty symbols after delivery).
18. 19.
microparticle powders using differing insufflation devices. The chimeral size allowed the complete emission of agglomerated powder in fragments larger than primary microparticles, having non-respirable size suitable for nasal deposition. The agglomerates did not affect drug dissolution since the weak structure of this dosage form was immediately disintegrated by water uptake. Caffeine carried by the agglomerates promptly dissolved in water. Among the several adjuvants used to manufacture the agglomerate, lecithin resulted very efficient in terms of yield, strength and morphology of agglomerate structures. It could be deduced that the presence of lecithin in the primary particles improves the cohesion between the microparticles that leads to the formation of the agglomerates.
20. 21.
22. 23. 24.
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powder. - Br. J. Clin. Pharmacol., 47, 619-24, 1999. CALLENS C., REMON J.P. - Evaluation of starch-maltodextrinCarbopol 974 P mixtures for the nasal delivery of insulin in rabbits. - J. Control. Release., 66, 215-20, 2000. KIVISAARI E., BAKER R.C., PRICE M.J. - Comparison of once daily fluticasone propionate aqueous nasal spray with once daily budesonide reservoir powder device in patients with perennial rhinitis. - Clin. Exp. Allergy., 31, 855-63, 2001. ISHIKAWA F., KATSURA M., TAMAI I., TSUJI A. - Improved nasal bioavailability of elcatonin by insoluble powder formulation. - Int. J. Pharm., 224, 105-114, 2001. GARCIA-ARIETA A., TORRADO-SANTIAGO S., GOJA L., TORRADO J.J. - Spray-dried powders as nasal absorption enhancers of cyanocobalamin. - Biol. Pharm. Bull., 24, 1411-6, 2001. TESHIMA D., YAMAUCHI A., MAKINO K., KATAOKA Y., ARITA Y., NAWATA H., OISHI R. - Nasal glucagone delivery using microcrystalline cellulose in healthy volunteers. - Int. J. Pharm., 233, 61-6, 2002. UGKOWE M.I., VERBEKE N., KINGET R. - The biopharmaceutical aspects of nasal mucoadhesive drug delivery. - J. Pharm. Pharmacol., 53, 3-21, 2001. DONDETI P., ZIA H., NEEDHAM T.E. - Bioadhesive and formulation parameters affecting nasal absorption. - Int. J. Pharm., 127, 115-133, 1996. CALLENS C., CEULEMANS J., LUDWIG A., FOREMAN P., REMON J.P. - Rheological study on mucoadhesive of some nasal powder formulations. - Eur. J. Pharm. Biopharm., 55, 323-8, 2003 CALLENS C., PRINGELS E., REMON J.P. - Influence of multiple nasal administrations of bioadhesive powders on the insulin bioavailability. - Int. J. Pharm., 250, 415-422, 2003. UGKOWE M.I., EXAUD S., VAN DEN MOOTER G., VERBEKE N., KINGET R. - Biovailability of apomorphine following intranasal administration of mucoadhesive drug delivery sistems in rabbits. Eur. J. Pharm. Sci., 9, 213-9, 1999. BELL J.H. - Composition for treating airway disease. - US Patent 4,161,516, 1979. WETTERLIN K. - Turbuhaler: a new powder inhaler for administration of drugs to the airways. - Pharm. Res., 5, 506, 1988. YANG T.T., KENYON D. - Use of an agglomerate formulation in a new multidose dry powder inhaler. - In: Respiratory Drug Delivery VII, Dalby R.N., Byron P.R., Farr S.J., Peart J. Eds, Serentec Press, 2000, pp. 503-505. ILLUM L., JORGENSEN H., BISGAARD H., KROGSGAARD O., ROSSING N. - Bioadhesive microspheres as a potential nasal drug delivery system. - Int. J. Pharm., 39, 189, 1987. SACCHETTI C., ARTUSI M., SANTI P., COLOMBO P. - Caffeine microparticles for nasal administration obtained by spray drying. - Int. J. Pharm., 242, 335, 2002. CHEN J.F., XU K., PETZER J.P., STAAL R., XU Y.H., BEILSTEIN M., SONSALLA P.K., CASTAGNOLI K., CASTAGNOLI N.Jr., SCHWARZSCHILD M.A. - Neuroprotection by caffeine and A2A adenosine receptors inactivation in a model of Parkinson’s disease. - J. Neurosci., 21, 10, RC143, 2001. CARR. R.L. - Evaluating flow properties of solids. -Chem Eng. 72, 163-168, 1965. HIRAMATSU Y., OKA Y. - Determination of the tensile strength of rock by a compression test of an irregular test piece. - Int. J. Rock Mech. Min. Sci., 3, 89, 1966. BEHL C.R., PIMPLASKAR H.K., SILENO A.P., DEMEIRELES J., ROMEO V.D. - Effects of physicochemical properties and other factors on systemic nasal drug delivery. - Adv. Drug Del. Rev., 29, 89, 1998.
ACKNOWLEDGEMENTS The authors would like to acknowledge the support of COFIN 2002, Lisapharma SpA, Erba, and Fidia Farmaceutici SpA, Abano Terme.
MANUSCRIPT Received 9 April 2004, accepted for publication 2 September 2004. 454
Chimeral agglomerates of microparticles for the administration of caffeine nasal powders P. Russo*, F. Buttini, F. Sonvico, R. Bettini, G. Massimo, C. Sacchetti, P. Colombo, P. Santi University of Parma, Department of Pharmacy, Via delle Scienze, 43100 Parma, Italy *Correspondence: [email protected] The manufacturing and performance of caffeine powders having a form of chimeral agglomerates designed for nasal insufflation are described in this paper. Agglomerates containing caffeine were prepared in a rotating cylindrical container by tumbling primary microparticles prepared by spray drying drug and excipient solutions. Production yield, agglomerate morphology and size, insufflation performance and caffeine dissolution rate were the determined characteristics. Agglomerate formation and behavior during insufflation were favorably influenced by the presence of lecithin in the microparticle formulation. Insufflation through three different devices showed that the agglomerate structure enabled the complete emission of the dose. The agglomerates were broken into fragments of a size appropriate for nasal deposition. Finally, the agglomeration process did not reduce the dissolution rate of caffeine. Key words: Nasal powders – Caffeine – Spray drying – Chimeral agglomerates – Insufflators.
Additionally, they have to be promptly disaggregated by water in the primary microparticles and dissolved. The agglomerates are defined «chimeral» since their size is non-permanent, being reduced during insufflation. In a previous study [26], we prepared caffeine spray dried micronized powders intended for nasal delivery in the prevention of neurodegenerative disorders [27]. The use of excipients such as mannitol, hydroxypropylmethylcellulose (HPMC) and polyethylenglycol (PEG) allowed to modulate the size and shape of the spray-dried caffeine microparticles. These microparticles could be used for chimeral agglomerate preparation. Then, the manufacturing and behaviour of agglomerates for nasal delivery remained to be explored. The aim of this work was to study the manufacturing and the technological performance of caffeine powders in form of chimeral agglomerates for nasal insufflations. The goal was to have as final formulation a free flowing powder, deliverable by insufflations and promptly dissolving in water. Primary microparticles of caffeine were prepared by spray drying solutions of caffeine and excipients. Tumbling the primary microparticles in a rotating cylindrical container allowed for the preparation of agglomerates that were collected by sieving. The influence of caffeine powder composition on agglomerate properties was examined. The agglomerates were studied as for micromeritics, insufflations performance with different devices and caffeine dissolution rate.
Conventionally, the nose is a drug administration site for the treatment of local diseases such as rhinitis. However, nasal administration has been exploited for systemic drug delivery, especially when rapid onset of action is required [1-6]. This route could be appropriate for drugs used in crisis treatments, such as pain, migraine, insomnia or anxiety. In addition, centrally acting drugs, on account of the nose/brain pathway, might face a direct uptake when deposited on the olfactory mucosa [7, 8]. Liquid preparations are the most common nasal dosage forms. However, they present several drawbacks, such as: preservative use that could impair mucociliary function [9], reduced chemical stability of dissolved drug and short residence time of formulation in the nasal cavity. Dry powders are less frequently used in nasal drug delivery [10-16]. The dry state of dosage form could improve stability and prolong the contact time with the nasal mucosa in case of the bioadhesive formulations [17-21]. In general, the nasal powder particles have to be small enough for insufflation delivery and prompt drug dissolution. However, small particles are problematic to handle during dosage form manufacturing, particularly for loading and metering of powders into the administration device. Therefore, a nasal powder should be at the same time fine enough for delivery and coarse enough for flowing and packing during metering. This technological problem could be solved by particle agglomeration, a process in which the powder size is increased by the preparation of spheroidal soft clusters of microparticles. Agglomerated powders (soft pellets) have been used in pulmonary powder delivery where they have to be completely disaggregated in the aerosol, with particles lower than 5 µm in order to be respirable [22-24]. No applications of agglomerates have been described in nasal dosage forms. The rationale for the use of spheroidal agglomerates of microparticles for nasal powder administration is that these soft structures, during emission from nasal insufflators, are broken into fragments with a larger size than the primary microparticles. The fragments must be within non-respirable size range (diameter greater than 10 µm for nasal deposition [25]).
I. MATERIALS AND METHODS
Caffeine USP was supplied from Merk, Darmstadt, Germany; mannitol Ph. Eur. was a gift from Lisapharma, Erba, CO, Italy; hydroxypropylmethylcellulose (Methocel E3 Premium EP) was purchased from Colorcon Limited, Orpington, United Kingdom; polyethylenglycol (PEG 6000) was obtained from Hoechst AG, Strasbourg, France; lecithin (Lipoid S45) was supplied by Lipoid AG, Cham, Switzerland. All solvents were of analytical grade. The Puvlizer, Miat and Monopowder nasal insufflators were kindly provided by Teijin Ltd., Tokyo, Japan, Miat SpA 449
J. DRUG DEL. SCI. TECH., 14 (6) 449-454 2004
Chimeral agglomerates of microparticles for the administration of caffeine nasal powders P. Russo, F. Buttini, F. Sonvico, R. Bettini, G. Massimo, C. Sacchetti, P. Colombo, P. Santi
Milan, Italy, and Valois Dispray, Mezzovico, Switzerland, respectively.
glass following weight and size determination. The glass was then placed on a mobile platform under the measuring head of a calibrated load cell (514 QD, DS Europe, Milan, Italy). The elevation of the platform, at a rate of 0.2 mm/min, caused the compression of the agglomerate against the measuring head. The force-time curve was recorded by means of an adequate software program (Chart v 3.5 AdInstruments Ltd., Oxfordshire, United Kingdom). The force under which the agglomerate fractured was recorded. From the crushing force, F (N), the tensile strength, σ (N/m2), was calculated by the Equation 2 [29]:
1. Primary microparticle preparation
Micronized primary particles were prepared by spray drying caffeine and excipient solutions in accordance with a previous work [26]. Briefly, solutions were prepared by dissolving caffeine and mannitol under stirring, with or without PEG 6000 and HPMC. The solutions containing lecithin were prepared by adding, under stirring, a solution of lecithin in ethanol (0.5 g in 40 ml) to the aqueous solution of caffeine and excipients (solid content 10 g in 350 ml). The solution was spray dried using a Buchi Mini Spray Dryer B-191 (Buchi Laboratoriums-Tecnik, Flawil, Switzerland) in the following experimental conditions: inlet temperature 130°C; outlet temperature 45-50°C; feed rate 6.5 ml/min; nozzle diameter 1.0 mm; drying air flow 600 l/h.
σ = 2.8F/πd2 where d is the agglomerate diameter.
Eq. 2
5. Agglomerate delivery from insufflation devices
The amount of dose emitted by insufflation of nasal powders or agglomerates was measured and pictures of the delivery sequence were taken. Three different devices, i.e. Puvlizer, Miat and Monopowder, were employed (Figure 1). Puvlizer and Miat are equipped with a squeezable rubber bulb for air insufflation, and Monopowder with a piston pump. The air stream produces the emission of the dose contained in the device reservoir. Twenty milligrams of agglomerates was loaded into the reservoir of each device. Quantitative delivery of agglomerates from the insufflators was determined by weighing the insufflator before and after each actuation. The air flow produced by the three devices was measured by means of a flowmeter (Thermal Mass Flowmeter TSI Model 3063, TSI Incorporated, Shoreview, MN, United States) connected to a computer. The plumes produced by the insufflation of the agglomerates from the nasal devices were recorded by a video camera (Panasonic F 15, Matsushita Electric Industrial Co. Ltd., Osaka, Japan).
2. Chimeral agglomerate manufacturing
Chimeral agglomerates were prepared by rolling 5 g of microparticle powders into a Bakelite cylindrical ointment jar (Ø 5.0 cm, 4.4 cm length), rotating at 30 rpm for 30 min on the cylinder axis tilted at 90°. Agglomerates between 106 and 850 µm were collected by sieving. The agglomerations were performed at temperature and humidity conditions ranging between 22-24°C and 60-70% RH, respectively.
3. Microparticle and agglomerate micromeritics
The size distribution of the spray-dried microparticles was checked using laser light diffraction apparatus (series 2600 Malvern Instruments Ltd., Spring Lane South Malvern, Worcestershire, United Kingdom) by suspending caffeine microparticles in ethyl acetate. The morphology of the spray-dried microparticles agglomerates of caffeine was assessed by means of an optical stereomicroscope (magnification 40x) (Citoval 2, aus Jena, Jena, Germany) connected to a video camera (JVC, Tokyo, Japan). Agglomerate size distribution was measured using Ø10 cm sieves (Endecotts Limited, London, United Kingdom) with nominal apertures of 850, 600, 425, 300, 212, 150 and 106 µm. A sample of 5 g of agglomerates was placed on top of the sieve stack which was vibrated for 10 min (amplitude 3) in a vibratory laboratory sieve shaker (Analysette 3 Fritz model, Fritsch GmbH, Idar-Oberstein, Germany). The particle size distribution of agglomerates after ejection from Monopowder Valois was also determined by performing twenty insufflations directly on the sieve stack under the measurement conditions described above. Bulk and tapped densities were measured according to the European Pharmacopoeia 4, whereas Carrʼs Index (CI) was calculated by the Equation 1 [28]:
6. Chimeral agglomerate dissolution
Twenty milligrams of caffeine agglomerates was suspended under magnetic stirring in a beaker containing 100 ml of dis-
Eq. 1 CI = [(Dt - Db)/Dt] · 100 where Dt is the tapped density and Db is the bulk density.
4. Chimeral agglomerate tensile strength
Figure 1 - Three different nasal insufflators, from right to left: Puvlizer, Miat device and Monopowder Valois.
A single agglomerate was placed on a microscope cover 450
Chimeral agglomerates of microparticles for the administration of caffeine nasal powders P. Russo, F. Buttini, F. Sonvico, R. Bettini, G. Massimo, C. Sacchetti, P. Colombo, P. Santi
tilled water at 37°C. The solution was filtered and circulated in a flow-through cell of UV-Vis spectrophotometer (Jasco V530, Jasco Inc., Easton, United States) for caffeine content determination at 276 nm.
J. DRUG DEL. SCI. TECH., 14 (6) 449-454 2004
Table I also reports the yield of the agglomeration process. Not all spray-dried powders could be agglomerated. Finally, the inclusion of lecithin in the spray-dried powders resulted as being decisive for agglomeration, as shown by the high yields obtained with powders # 5, 7 and 8. We verified that the spray dried primary particles and the corresponding agglomerates did not affect the dissolution rate of caffeine. It was not the purpose of this test to mimic the dissolution in the nose, but simply to assess that the spray drying and agglomeration did not reduce significantly the dissolution rate of caffeine crystals. In fact, nasal powders have to dissolve quickly in the small volume of water lining the mucosa [30]. The dissolution of the spray-dried powders was practically instantaneous: in one minute the caffeine content of primary particles and corresponding agglomerates was completely dissolved without a significant difference from caffeine crystal dissolution (data not shown).
III. RESULTS AND DISCUSSION 1. Manufacturing of primary microparticles and agglomerates
The first step of the chimeral powder manufacturing was the preparation of primary microparticles to be agglomerated in soft structures. We have shown in a previous work [26] that the spray drying of caffeine/mannitol (70/30) solution produced acicular caffeine particles. By introducing into this formulation hydroxypropylmethylcellulose (HPMC) and polyethylenglycol (PEG 6000), alone or in combination, the size and shape of spray-dried microparticles were substantially changed. Adding also lecithin to these compositions, a new series of primary microparticle powders was prepared with the intent to verify the adjuvant effect on spray-dried microparticulate powders and relative agglomerates (Table I). As already observed before [26], the presence of mannitol allowed for the preparation of spray-dried particles of caffeine in acceptable yield, considering the small scale of the production; the presence of PEG 6000 reduced the spray drying yield, due to excessive particles sticking on the spray drier chamber and the addition of HPMC in part counteracted this PEG effect. The introduction into the formulation of lecithin was very favorable for spray drying yield, except in the case of the combination with PEG. In principle, all these microparticle powders could be insufflated into the nose, but their flow and packing were poor for the nasal product preparation. Soft spheroidal agglomerates, due to their improved packing and flow properties, could substantially favour powder metering and filling of insufflators, without affecting the insufflation performance. The prepared caffeine spray-dried microparticles showed differing agglomeration after rotation in the Bakelite container. In fact, it was observed that microparticles agglomerated in soft structures in differing yields according to their composition. The aptitude of spray-dried powders to agglomerate was evaluated by measuring the obtained amount of agglomerates having a size between 106 and 850 µm in ratio to the amount of tumbled microparticles.
2. Micromeritics, morphology and strength of chimeral agglomerates
The packing and flow properties of the powders and agglomerates containing lecithin are presented in Table II. The comparison between the values exhibited by the powders and respective agglomerates illustrates the evident advantage of agglomeration for the flowability and packing of micronized powders. The agglomerates were free flowing and exhibited a strongly improved Carrʼs Index in comparison with the respective microparticulate powders. The morphology of the agglomerates, studied by optical microscopy, was dependent on the formula composition. For example, powder # 2 differed from powder # 7 on account of the absence of lecithin, and likewise powder # 4 differed from powder # 8. These powders without lecithin (powders # 2 and 4) produced rougher and less compact agglomerates. Concerning the two formulations containing lecithin, the agglomerates without PEG 6000 (powder # 7) were smoother than those from powder # 8. In general, when lecithin was not present in the formulation, more powdery agglomerates were obtained, as formulations # 2 and 4 illustrate in Figure 2. The agglomerates were tested for crushing strength. Figure 3 shows optical microscopy pictures of agglomerate # 5, before and after crushing: the spheroidal agglomerate broke
Table I - Composition of the spray-dried microparticles and agglomerates and yields of the processes. Standard deviation into brackets. Code
Composition Caffeine
Mannitol
Yield
HPMC
PEG 6000
Lecithin
Microparticles
Agglomerates
Microparticle mean diameter (µm) and Span
#1
70
30
-
-
-
58
**
29.9 (1.45)
#2
68.6
29.4
2
-
-
75
31*
5.00 (0.94)
#3
66.5
28.5
-
5
-
1.3
***
37.6 (1.32)
#4
65.1
27.9
2
5
-
53
26*
5.04 (1.02)
#5
66.5
28.5
-
-
5
60 (1.2)
86.3 (1.0)
5.29 (1.07)
#6
63
27
-
5
5
6.9
***
4.27 (1.27)
#7
65.1
27.9
2
-
5
66 (2.0)
88 (4.2)
12.3 (1.39)
#8
61.6
26.4
2
5
5
47.6 (5.5)
80 (6.3)
4.78 (1.08)
*These powers were difficult to agglomerate due to the excessive electrostaticity and adhesion to the container wall. **This powder could not be agglomerated in a Bakelite container. ***These powders were not agglomerated due to the low amount of particles obtained by spray drying. 451
J. DRUG DEL. SCI. TECH., 14 (6) 449-454 2004
Chimeral agglomerates of microparticles for the administration of caffeine nasal powders P. Russo, F. Buttini, F. Sonvico, R. Bettini, G. Massimo, C. Sacchetti, P. Colombo, P. Santi
Table II - Bulk and tapped density and Carr’s Index of microparticulate powders and agglomerates # 5, 7 and 8 (mean values and standard deviations; n = 3). Code
Microparticulate powders
Agglomerates
Bulk density (g/ml)
Tapped density (g/ml)
Carr's Index (%)
Bulk density (g/ml)
Tapped density (g/ml)
Carr's Index (%)
#5
0.24 (0.001)
0.28 (0.002)
15.0
0.26 (0.006)
0.28 (0.003)
8.6
#7
0.23 (0.004)
0.28 (0.003)
16.5
0.27 (0.006)
0.30 (0.002)
8.4
#8
0.23 (0.001)
0.31 (0.001)
24.8
0.25 (0.001)
0.28 (0.002)
10.5
Figure 3 - Optical microscopy pictures of agglomerate # 5 before (a) and after (b) the crushing test.
3. Powder and agglomerate insufflations
The nasal drug product consists of the combination of the powder formulation and the device for its delivery. The Puvlizer device is a nasal powder insufflator consisting of a squeezable rubber bulb connected to a nasal adaptor. A hard gelatin capsule containing pre-metered powder or agglomerate is inserted in the nasal adaptor and perforated with a needle. The air stream produced by squeezing the rubber bulb then provides the emission of the dose contained in the capsule. The size of the rubber bulb determines the peak flow rate and time course of the air stream produced and, consequently, the amount of powder emitted. The Puvlizer insufflators were designed with a small rubber bulb and, therefore, the complete delivery of the capsule content requires several actuations (normally eight). In principle, this is not considered a disadvantage since, by alternate insufflation into both nostrils, powder can be deposited in the whole nasal cavity. Figure 4 shows the percentage of dose emitted from the Puvlizer nasal insufflators plotted against the number of device actuations. There was a great difference between powders and agglomerates in delivered doses. Contrarily to the corresponding powders, the ejection of agglomerates was already fast and quantitative after six actuations. A possible explanation is that the agglomeration process reduced particle adhesion to the capsule or the device. Powder delivery was tested also with the two other devices, which should be able to emit the entire dose loaded in a single actuation. Similarly to Puvlizer, the Miat nasal powder insufflator contains a hard gelatin capsule and presents a squeezable rubber bulb connected to the nasal adaptor. For this device, the bigger rubber bulb provides an air stream able to emit the entire powder content of the capsule in a single actuation. The Monopowder Valois exhibits a different ejection mechanism. Here, a piston pump and a plastic cylindrical reservoir replace the squeezable bulb and the gelatin capsule, respectively. A firmly inserted plastic sphere seals the reservoir containing the pre-metered powder. The air pressure raised by the piston pump actuation provokes the reservoir opening and hence, the sudden emission of the powder. Table IV presents the results of dose emission from the
Figure 2 - Optical microscopy pictures of agglomerates obtained from powders # 2 (a), # 7 (b), # 4 (c) and # 8 (d).
into fragments in tension along the axis of crushing force application. Among the agglomerates without lecithin, the tensile strength was measurable only with formulation # 2, in which there was no PEG 6000. In contrast, when lecithin was present in the formulation, the tensile strength values increased indicating a superior mechanical resistance of the agglomerates (Table III). These agglomerates could be handled in metering operation without affecting their structure. It is not possible at the moment to indicate a reference value of the optimal tensile strength, since the value depends on the insufflation device, on the filling operations and, in case of multi-dose devices, also on the metering manoeuvres. In any case, the values obtained with the formulations # 5, 7 and 8 were considered appropriate for the insufflation, metering and other manipulations performed in this work. Hence, lecithin resulted in a very useful adjuvant for the manufacturing of these types of agglomerates, considering that high yield and acceptable mechanical strength were obtained. It is likely that its effect was due to binding improvement between the microparticles. Table III - Agglomerate tensile strength (mean values and standard deviations; n = 8). Chimeral agglomerate
Tensile strength*103 (N/m2)
Caffeine, mannitol, HPMC (# 2) Caffeine, mannitol, lecithin (# 5) Caffeine, mannitol, HPMC, lecithin (# 7) Caffeine, mannitol, HPMC, PEG 6000, lecithin (# 8)
4.11 (1.71) 79.2 (16.3) 32.5 (14.2) 51.8 (21.7) 452
Chimeral agglomerates of microparticles for the administration of caffeine nasal powders P. Russo, F. Buttini, F. Sonvico, R. Bettini, G. Massimo, C. Sacchetti, P. Colombo, P. Santi
J. DRUG DEL. SCI. TECH., 14 (6) 449-454 2004
100
Dose emitted (%)
80 60
40 20
Figure 5 - Delivery plumes of agglomerate # 5 from Puvlizer at 0.28 s (a), from Miat device at 0.20 s (b), and from Monopowder Valois at 0.08 s (c).
0 0
2
4
6
8
10
12
Actuation number
Table V - Peak flow rate and amount of air emitted of Puvlizer, Miat and Monopowder Valois devices (mean values and standard deviations; n = 5).
Figure 4 - Percent of dose emitted from Puvlizer insufflator versus number of actuations (formulation # 5 circle; formulation # 8 square; powder open symbol; agglomerates full symbols).
Puvlizer Miat device Monopowder
Table IV - Percentage of dose emitted from Miat and Monopowder Valois devices in one actuation (mean values and standard deviations; n = 3). Formulation
Miat device Agglomerate
Microparticles
Agglomerate
#5
12.1 (2.3)
95.6 (1.0)
98.6 (0.5)
99.1 (0.3)
#7
36.5 (12.8)
92.4 (8.5)
96.6 (2.7)
96.9 (3.1)
#8
93.0 (6.7)
96.9 (4.0)
98.2 (0.1)
98.9 (0.3)
Air emitted (ml)
4.93 (0.58) 28.07 (1.68) 16.62 (1.58)
6.52 (0.87) 48.00 (1.63) 4.50 (0.23)
The peak flow rate of Monopowder Valois was lower than the value exhibited by the Miat device and the volume of air emitted was the smallest, but the Valois device was more efficient in extracting the powder from the reservoir (see Table IV). In fact, the design of the Valois device enabled an efficient flow of a sudden and intense air stream through the powder reservoir. In contrast, in the Miat device, we observed a large dispersion of the air insufflated: not all the air flowed into the gelatine capsule, but a part was dispersed in the conducting channel of the nasal adaptor where the capsule is lodged. The opposite happened with the Valois device where, despite the low amount of air displaced, the air stream was forced to pass through the powder dosed in the reservoir. Finally, the effect of insufflation on agglomerate breaking was studied by measuring the particle size distribution before and after emission. In particular, the particle size distribution of agglomerates # 5, 7 and 8 was investigated before and after ejection from the Valois nasal insufflator. The results are shown in Figure 6. The figure shows a significant reduction in the size of agglomerates after insufflation with the Valois device, but the size of agglomerate fragments was larger than that of original microparticles. The agglomerates have been broken in fragments depending on their mechanical resistance (see Table III). Among the agglomerates containing lecithin, formulation # 5 was significantly harder than agglomerate # 7 (p < 0.01). The agglomerate # 5 broke into fragments of microparticles with a mean diameter lower than 250 µm, while the agglomerate # 7 broke into fragments with a mean diameter lower than 128 µm, reflecting the respective mechanical resistance.
Valois Monopowder
Microparticles
Peak flow rate (l/min)
one-shot devices. The data refer to powders and agglomerates with compositions # 5, 7 and 8. In general, the powders and the agglomerates introduced in the reservoir of the Valois device were completely emitted in one shot. The same was not observed with the Miat device, in particular when the non-agglomerated powder # 5 and 7 were used for insufflations. The delivery plumes of agglomerates from the Miat, Puvlizer and Valois nasal insufflators were recorded (Figure 5). The pictures show the powder clouds during the first actuation of the device (Puvlizer) or the single actuation for Miat and Valois. The pictures were taken while the fully developed phase of the plume was still in contact with the actuator tip. The aspect of the plumes depended on the device used. In the case of Puvlizer, the cloud was low, and several spots corresponding to large fragments were clearly visible. The cloud emitted from the Miat device was elongated with smaller agglomerate fragments visible. The cloud emitted from the insufflator Valois was high, large and fluffy; in this case, a few small fragments were visible in a plume having a less regular shape. The velocity of powder emission from the devices also differed greatly. We expected that high powder velocity during ejection would prompt the particles to impact on the nasal mucosa. The puff was emitted in approximately 0.28 s with the Puvlizer insufflator and 0.20 s with the Miat device. The Valois device produced a puff delivered in 0.08 s. The results obtained were justified by the peak flow rate and volume of air emitted by the three insufflators (Table V): the Miat device exhibited the highest peak flow rate, whereas the Puvlizer presented the lowest. This was due to the large size of the rubber bulb of the Miat insufflator.
* * * The results obtained allow us to conclude that chimeral agglomerates of spray-dried microparticles intended for nasal powder administration improves the flow and packing of micronized powders and are more efficiently delivered than 453
Cumulative undersize (%)
J. DRUG DEL. SCI. TECH., 14 (6) 449-454 2004
Chimeral agglomerates of microparticles for the administration of caffeine nasal powders P. Russo, F. Buttini, F. Sonvico, R. Bettini, G. Massimo, C. Sacchetti, P. Colombo, P. Santi
100
12.
80
13.
60
14. 40
15. 20
16. 0 <53
64 90.5 128 181 256 362.5 512.5 725 >850
Mean diameter (µm)
17.
Figure 6 - Effect of insufflation on particle size distribution of agglomerates # 5 (▲, Δ) # 7 (●, ❍) and # 8 (■, ❐) (full symbols before delivery; empty symbols after delivery).
18. 19.
microparticle powders using differing insufflation devices. The chimeral size allowed the complete emission of agglomerated powder in fragments larger than primary microparticles, having non-respirable size suitable for nasal deposition. The agglomerates did not affect drug dissolution since the weak structure of this dosage form was immediately disintegrated by water uptake. Caffeine carried by the agglomerates promptly dissolved in water. Among the several adjuvants used to manufacture the agglomerate, lecithin resulted very efficient in terms of yield, strength and morphology of agglomerate structures. It could be deduced that the presence of lecithin in the primary particles improves the cohesion between the microparticles that leads to the formation of the agglomerates.
20. 21.
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ACKNOWLEDGEMENTS The authors would like to acknowledge the support of COFIN 2002, Lisapharma SpA, Erba, and Fidia Farmaceutici SpA, Abano Terme.
MANUSCRIPT Received 9 April 2004, accepted for publication 2 September 2004. 454