Cospray Dried Antibiotics for Dry Powder Lung Delivery

Cospray Dried Antibiotics for Dry Powder Lung Delivery HANDOKO ADI,1 PAUL M. YOUNG,1 HAK-KIM CHAN,1 PETER STEWART,2 HELEN AGUS,3 DANIELA TRAINI1 1

Advanced Drug Delivery Group, Faculty of Pharmacy (A15), University of Sydney, Sydney, NSW 2006, Australia

2

Department of Pharmaceutics, Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia 3 Molecular and Microbial Biosciences, Faculty of Science (G08), Biochemistry Building University of Sydney, Sydney, NSW 2006, Australia

Received 26 May 2007; revised 16 July 2007; accepted 2 October 2007 Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21239

ABSTRACT: The aim of this study was to assess the potential of delivering a combination antibiotic therapy, containing doxycycline and ciprofloxacin (both hydrochloride) as a dry powder (DPI) formulation for inhalation. Single and combination antibiotics were produced by spray drying. Particle size distributions were characterized by laser diffraction and imaging conducted by scanning electron microscopy. Solid-state characterisation of the antibiotics was carried out using differential scanning calorimetry, dynamic vapour sorption, X-ray powder diffraction, and differential scanning calorimetry. Using the Aerolizer1 device, the aerosol performance was measured using multistage liquid impinger and analysed using high performance liquid chromatography (R2 ¼ 1.0, CV ¼ 0.4–1.0%). Furthermore, a disk diffusion test was performed for the assessment of the in vitro antimicrobial activity of the raw and spray dried antibiotics against bacteria. Results showed that cospray drying of the ciprofloxacin and doxycycline produced an antibiotic formulation (in a 1:1 ratio) suitable for inhalation that showed to be physically more stable then the analogous single spray dried antibiotic. The cospray dried powder has improved dispersion over the less stable single spray dried ciprofloxacin. The spray dried antibiotics were observed to have similar antimicrobial activity to the original antibiotics for Staphylococcus aureus, Pseudomonas aeruginosa and Streptococcus pyrogenes, suggesting the spray drying process does not affect the anti-bacterial activity of the drug. Cospray dried antibiotics from a DPI is thus feasible and can potentially be an attractive delivery alternative to the more conventional systemic delivery route. ß 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:3356–3366, 2008

Keywords: dry powder inhaler; DPI; antibiotics; doxycycline hydrochloride; ciprofloxacin hydrochloride; cospray drying

INTRODUCTION Delivery of antibiotics via the pulmonary tract to treat respiratory infection, such as pneumonia,

Correspondence to: Daniela Traini (Telephone: þ61-2-93512356; Fax: þ61-2-93514391; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 97, 3356–3366 (2008) ß 2007 Wiley-Liss, Inc. and the American Pharmacists Association

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is advantageous over more conventional routes, since the lungs are directly targeted. Using targeted delivery, the therapeutic dose may be lower, leading to a decrease in potential drug resistance build-up and reduction in side effects, often associated with high oral doses. Currently antibiotic inhalation therapy is limited to small volume nebulisers,1 which are cumbersome, expensive and require routine maintenance.2 These systems have, in general, low efficiency

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and poor delivery reproducibility.3,4 At present, only a handful of antibiotic molecules have been investigated using the inhalation route. These include amikacin,5 carbenicillin,6 gentamicin,6,7 colistin,8 colistin sulfomethate8,9 and tobramycin,10,11 the only antibiotic solution for inhalation approved by the Food and Drug Administration. In general these systems have been studied using conventional nebuliser systems, however, recently some interest has focussed on using dry powder delivery systems. Dry powder inhalation (DPI) formulations incorporate a powder containing the drug as micron sized particles (aerodynamic diameter less than <5 mm), which, upon inhalation is aerosolised from a device to deposit in the lower respiratory tract. Dry powder systems have many advantages over liquid nebuliser systems. For example, DPI based formulations are in the solid state and therefore less susceptible to chemical degradation. Furthermore, the devices are generally less expensive, require little maintenance and can be manufactured in a disposable form. Examples of DPI antibiotic studies include the use of gentamicin,12,13 colistin sulphate,14,15 colistin sulfomethate16 and tobramycin sulphate.17 These studies mostly focused on the clinical relevance of the dose regiment chosen in comparison with nebulisers. In general, they have shown that sputum (or plasma) concentrations and lung depositions of the drug may be comparable to those achieved with nebulisation. Interestingly, these studies focussed on relatively high doses (30– 180 mg) of inhaled powder and in general had issues with the efficiency of the powder formulation aerosolisation.13,15,18–20 The authors recognize that if very high doses of antibiotics are required this cannot be administered with current available formulations and/or delivery systems for inhalation unless extreme dose regiments are accepted13 or devices having greater delivery efficiency are manufactured.21 More recent studies, however, have demonstrated more acceptable doses of DPI powders could be used (for example 25 mg of colistine sulphate and colistine sulphomethate) to provide therapeutic outcomes.14,15,18–20 To increase the therapeutic effect, the combination of a mixture of antibiotics may be utilised. Recent studies have shown that using a combination of two antibiotic therapies, a synergistic effect superior to the simple additive activity of each of the antibiotics may be observed.22,23 Conversely, it is logical to conclude that using combination formulations, a smaller dose would be probably DOI 10.1002/jps

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sufficient to achieve the same therapeutic outcome. Utilizing this synergistic approach in DPI formulation, the two antibiotic molecules, should ideally reach the target bacterial cells simultaneously. One method of achieving this goal would be to coprocess the materials using spray drying or a similar technique. To our knowledge, no combined dry powder antibiotic inhalation product exists on the market to date. Thus a new method that can decrease the burden of treatment and offer patients more independence is highly desirable. The novel approach presented in this research project was to assess the suitability of two combination antibiotics, doxycycline and ciprofloxacin, in dry powder formulation after spray drying alone, or combined, from aqueous solution. Ciprofloxacin and doxycycline were chosen as model antibiotics since they are broad-spectrum antibiotics that are active against most gramnegative bacteria and gram-positive cocci. The spray dried formulations were tested in terms of physical characteristics, physical stability, antimicrobial activity and in vitro aerosolisation efficiency.

MATERIALS AND METHODS Materials Ciprofloxacin and doxycycline (both hydrochlorides) were chosen as model antibiotics and used as supplied (MP, Biomedical Australasia Pty Limited, Seven Hills, NSW, Australia). Water was purified by reverse osmosis (MilliQ, Millipore, France). All solvents were obtained from Biolab (Clayton, Victoria, Australia) and were of analytical grade. The model bacteria used in this study were Staphylococcus aureus, Pseudomonas aeruginosa and Streptococcus pyogenes (all strains were obtained from the University of Sydney, Sydney, NSW, Australia). Sheep blood agar (Oxoid, Heidelberg West, NSW, Australia) was used as the culture media for the antibacteric activity test.

Cospray Dried Antibiotics Single antibiotic and combination powders (ratio 1:1) were obtained by spray drying using a Buchi B-191 spray dryer (Flawil, Postfach, Switzerland). The antibiotic was dissolved in MilliQ water and feed solution spray dried at the following JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 8, AUGUST 2008

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conditions: feed rate of 4 mL min1, aspiration rate of 47.6 m3 h1, inlet and outlet measured temperatures of 110 and 598C, respectively, atomising pressure of 800 kPa and feed concentration of 50 mg mL1.

Scanning Electron Microscopy The morphology of each antibiotic drug powder was investigated using a JOEL JSM 6000F SEM (JEOL, Japan) at 5 kV. All samples were mounted on adhesive black carbon tabs, (premounted on aluminium stubs), and sputter-coated with platinum (Sputter coater S150B, Edwards High Vacuum, Sussex, UK) at 40 nm thickness prior to analysis.

Particle Size Distribution Particle size distributions of the spray dried single and cospray dried antibiotics were determined by laser scattering using a Scirocco cell and Scirocco 2000 dry powder feeder (Mastersizer 2000, Malvern, UK). Approximately 3 mg of spray dried doxycicline, ciprofloxacin and cospray dried antibiotics was dispersed in air using 4 bar pressure. All samples were measured with refractive index of 1.52. Each sample was analysed in triplicate.

Dynamic Vapour Sorption Dynamic vapour sorption (DVS) was used to investigate the relative moisture sorption of all the spray dried powders. Samples (ca. 8 mg) were added to glass sample pans, which were placed in the sample chamber of a commercially available DVS (DVS-1, Surface Measurement Systems Ltd., London, UK). Each sample was dried at 0% RH before being exposed to 10% RH increments for two 0–90% RH (258C). Equilibrium moisture content at each increment was determined by a dm/dt of 0.002% min1.

Differential Scanning Calorimetry The thermal response of each of the powders was analysed using a differential scanning calorimeter (DSC, TA Instruments, Rydalmere, NSW, Australia). Samples (3–5 mg) were crimp-sealed in DSC sample pans and thermal properties analysed at a 108C min1 temperature ramp between 40 and 4008C. Exothermal and endothermic peak temperatures, onset temperature and heat of enthalpy (DH) for each peak were determined using TA Instrument Universal Analysis software V.3.4C (TA Instruments).

Evaluation of In Vitro Aerosolisation Efficiency The aerosolisation efficiency of both the single spray dried drugs and the cospray dried antibiotic formulation were investigated using the multistage liquid impinger (MSLI) (Copley Scientific, Nottingham, UK). The methodology followed that of European Pharmacopoeia (Apparatus A, European Pharmacopoeia, Chapter 2.9.18). The flow through the MSLI apparatus was controlled using a GAST rotary vein pump and solenoid valve timer (Copley Scientific). Flow rate was tested prior to operation using a calibrated flow meter (TSI, Shoreview, MN). The collection stages of the MSLI were filled with 20 mL of MilliQ water. A size 3 hard gelatine capsule (Capsugel, Sydney, Australia) was filled with 20  0.2 mg of spray dried powder and placed into the dosage chamber of the Aerolizer1 (Novartis, Surrey, UK).24–26 The Aerolizer was inserted into a custom-made mouthpiece adapter, which was connected to the MSLI via a United State Pharmacopoeia (USP) throat. The device was tested for 4 s at 60 L min1. Temperature and humidity throughout the testing was 258C and 45% RH. After actuation, the device, capsule, throat, all sample stages and filter were washed into separate volumetric flasks using water. Appropriate sample dilutions were made prior to testing by high performance liquid chromatography (HPLC). Each sample was tested in triplicate.

X-Ray Powder Diffraction The crystal structure of both the single and cospray dried antibiotics were characterised using X-ray powder diffraction (D5000, Siemans, Karlsruhe, Germany). Settings were as follows; 5–408 2u, step size 0.048 2u, step time 1 s, temperature 258C. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 8, AUGUST 2008

Quantitative Analysis of Antibiotic Concentrations by HPLC Quantification of ciprofloxacin and doxycyline in vitro deposition samples were analysed using HPLC. The HPLC system consisted of a Waters 717þ autosampler, 600 pump, 486 detector, DOI 10.1002/jps

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600 controller with Millennium V.32 software (all Waters Ltd., Sydney, Australia) and Phenosphere-NEXT C-18 column, 5 mm, 150  4.60 mm (Phenomenex, Lane Cove, NSW, Australia). Standards and samples were prepared in MillQ water. Mobile phase consisted of a mixture of acetonitrile and 0.1 M sodium dihydrogen phosphate (30:70, v/v), adjusted to pH 3.35 with phosphoric acid. Settings were as follows: detection wavelength 350 nm; flow rate 1.5 mL min1; injection volume 50 mL. Linearity was obtained between 1.0 and 20 mg mL1 (R2 ¼ 0.999) with a retention time of 1.8 and 3.3 min for ciprofloxacin and doxycycline, respectively.

Assessment of the Antimicrobial Activity of the Dry Powder Formulations In order to quantitatively assess the in vitro antimicrobial activity of the original and the spray dried antibiotics (single and combined) against bacteria, a disk diffusion test was performed. The method was based on the standard National Committee for Clinical Laboratory methodology27 for the testing of the susceptibility of S. aureus, P. aeruginosa and Streptococcus pyrogenes against antimicrobial agents. Briefly, bacteria were swabbed uniformly onto the surface of a sheep blood agar plate. To allow assessment of the antibiotics activity prior to and postspray drying, standard aqueous solutions were prepared containing individual antibiotic solutions of original and spray dried antibiotics, mixtures of the original and a solution of the cospray dried formulation. Concentrations were prepared such that an individual experimental disk contained a total dose of 20 mg (10 mg of each antibiotic in order to get 1:1 ratio in the combination formulation). Solutions were impregnated on separate 12 mm diameter filter disks, which were placed on the surface of the agar plate and the antibiotic(s) allowed to diffuse into the adjacent medium. After overnight incubation at 358C in aerobic conditions, the diameters of the zones of inhibition of bacterial growth were measured.

Statistical Analysis Data were subjected to analysis of variance (ANOVA, Minitab 12.1, Minitab Ltd., Coventry, UK). Significant difference between formulations were analysed using Fishers Pairwise post hoc DOI 10.1002/jps

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multiple comparisons where p values p < 0.05 indicated significant differences.

RESULTS AND DISCUSSION In order to understand the aerosol properties of the combination formulation the study was divided into two primary sections: (1) physical characterisation of formulation and (2) in vitro characterisation of the antibiotics formulation.

Physical Characterisation of Formulation Scanning electron micrographs of the single ciprofloxacin, doxycycline and cospray dried samples are shown in Figure 1A–C, respectively. In general, the spray dried particulates had a spherical geometry and exhibited a corrugated surface that was consistent with rapid particle drying, cavity formation and particle collapse.28 Since all the powders were prepared under the same drying conditions, and had similar aqueous solubility (30–50 mg mL1) and similar molecular weights (MW 385.8–480.6) the final particle size distributions between samples were comparable (Fig. 2) and exhibited a similar bi-modal distribution, which fell within the size range for respiratory delivery. In general, median volume diameters of 4.0  0.1 mm, 3.4  0.1 mm and 3.7  0.1 mm were observed for ciprofloxacin, doxycycline, and the cospray dried antibiotic powder, respectively (n ¼ 3). The X-ray powder diffraction patterns of the initial antibiotic powders, spray dried and cospray dried antibiotic powders are shown in Figure 3. The sharp peaks, present in the XRPD diffraction patterns for ciprofloxacin and doxycycline antibiotic raw starting materials suggest a crystalline state, with a high degree of order. In general, the diffraction peaks were in good correlation with those reported previously.29,30 As expected, a 1:1 ratio physical mixture of the two starting materials produced a similar diffraction pattern, with peaks corresponding to both crystalline powders. In comparison, the XRPD data for the spray dried powders indicated a single broad diffuse peak characteristic of a material with no longrange order. The influence of the heat flow on the thermal properties of the original, single and cospray dried ciprofloxacin and doxycycline are shown in the Figure 4. The DSC thermogram of the original JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 8, AUGUST 2008

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Figure 2. Particle size distribution of single and cospray dried antibiotics measured using laser diffraction with dry dispersion system.

Figure 1. Scanning electron microscopy of antibiotics. (A) Spray dried ciprofloxacin, (B) spray dried doxycycline and (C) cospray dried ciprofloxacin and doxycycline.

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crystalline ciprofloxacin was in good agreement with previously published data29 (to the authors knowledge, no DSC trace has been reported for doxycycline hydrochloride). For the original crystalline ciprofloxacin, the endothermic peak at 1648C may be attributed to de-hydration, while the endothermic peak at 3338C was attributed to melting. The broad peak at 3528C was characteristic of ciprofloxacin decomposition. Similar results were observed for the spray dried ciprofloxacin, however a series of exothermic peaks at 53 and 888C suggested a phase transition of the amorphous ciprofloxacin and recrystallisation (Fig. 4A). The DSC thermograms of original doxycycline showed a complex transition and endothermic peak at 1778C, most likely attributed to a melt followed by an exothermic peak at 2248C, corresponding to a crystallisation (Fig. 4B). In comparison, the spray dried doxycycline showed a broader endothermic peak at 1538C, most likely due to a glass transition followed by an exothermic peak of crystallisation at 2218C. When both ciprofloxacin and doxycycline were combined as a physical mixture or as a cospray dried powder, analysis of the thermograms indicated similar thermal transitions indicative of each component (Fig. 4C). For a simple mixture of original ciprofloxicine and doxycycline, the phase transitions observed in individual samples were present (i.e. endothermic water loss of ciprofloxacin at 1558C, endothermic melt of doxycycline at 1798C and exothermal crystallisation peak of doxycycline at 2228C). The cospray dried formulation had a broad exothermic response at DOI 10.1002/jps

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Figure 3. XRPD of raw and spray dried antibiotics. (A) Ciprofloxacin, (B) doxycycline and (C) cospray dried ciprofloxacin and doxycycline.

1148C, suggesting a recrystallisation of the ciprofloxacin at an elevated temperature to that of the single spray dried ciprofloxacin. To further understand the relative solid-state stability of the spray dried formulation components, as individual entities and as cospray dried powders, the influence of humidity on moisture sorption was investigated. DOI 10.1002/jps

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Figure 4. DSC thermogram of raw and spray dried antibiotics. (A) Ciprofloxacin, (B) doxycycline and (C) cospray dried ciprofloxacin and doxycycline (exothermic—down).

Representative moisture sorption isotherms for spray dried ciprofloxacin, doxycycline and combination antibiotics are shown in Figure 5A– C, respectively. In general the two spray dried antibiotics had very different gravimetric JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 8, AUGUST 2008

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dramatic weight loss in the spray dried ciprofloxacin. Such observations are characteristic of the loss of water during crystallisation, related to the expulsion of plasticising water. Furthermore, subsequent sorption and desorption isotherms suggested a reversible moisture sorption profile with a mass difference of 2%, over the range 0–90% RH (Fig. 5A). Analysis of the sample using polarised light microscopy before and after DVS analysis indicated a crystallisation phenomena had occurred. In comparison, moisture sorption of spray dried doxycycline showed a reversible sorption curve, with a mass increase of 25% (w/w) over the range 0–90% RH. The lack of any detectable hysterisis, or characteristic mass loss suggested the spray dried doxycycline to be stable in the amorphous form under such conditions. Again, such observations were in good agreement with the DSC thermograms where no detectable exothermic response was observed below 2008C. Moisture sorption profiles of the cospray dried antibiotic formulation indicated that, although a phase transition hysterisis was observed, it occurred at elevated relative humidities (90% RH). By comparing the relative changes in mass versus time for each formulation through the first adsorption cycle (Fig. 6), it can be seen that mass

Figure 5. DVS isotherm of the single and cospray dried antibiotics. (A) Ciprofloxacin, (B) doxycycline and (C) cospray dried ciprofloxacin and doxycycline.

responses to moisture sorption. Analysis of the moisture sorption isotherm of spray dried ciprofloxacin (Fig. 5A), indicated a rapid increase in the moisture uptake between 0 and 50% RH (8%, w/w). Furthermore, increasing the partial water vapour pressure above 50% RH led to a JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 8, AUGUST 2008

Figure 6. Mass change as a function of time for the three spray dried formulations during the first DVS cycle. DOI 10.1002/jps

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loss, due to recrystallisation, for the ciprofloxacin occurs after exposure to 50% RH. The characteristic mass loss in the combination powder occurs at a much greater RH (around 90%), suggesting that a greater amount of adsorbed moisture is required to induce enough molecular mobility for crystallisation.

In Vitro Aerosolisation Efficiency of the Single and Cospray Dried Antibiotics System The in vitro drug deposition of the single and cospray dried formulation of antibiotics were analysed. Data is reported as drug concentrations remaining in the device/capsule and deposited on each stage of MSLI (Fig. 7). In addition, the cumulative drug deposition from stage 3 to filter of the MSLI was calculated as the fine particle dose

Figure 7. In vitro drug deposition of antibiotics using Aerolizer1 at flow rate of 60 L min1. (A) Single spray dried formulation and (B) cospray dried formulation. DOI 10.1002/jps

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(particles with an aerodynamic diameter less than 6.8 mm). The percentage of the fine particle dose as a function of drug recovered from all components (including device) was calculated and expressed as the fine particle fraction (FPF). The deposition of the single spray dried antibiotic powders, from individual MSLI studies, are shown side by side in Figure 7A. In general, the single spray dried formulation of doxycycline had a statistically significant higher drug deposition compared to the ciprofloxacin spray dried powder ( p < 0.05), where FPFs of 31.5  2.3% and 21.3  3.6% were observed for the doxycycline and ciprofloxacin formulations, respectively. The results suggested that the ciprofloxacin powder may be more cohesive. Subsequently, during aerosolisation, many particles remain agglomerated and are deposited on the MSLI throat. When ciprofloxacin was cospray dried with the doxycycline, the FPF was significantly increased from 21.3% to 33.6% (an increase in efficiency of 12%), when compared to the single spray dried ciprofloxacin alone ( p < 0.05). In comparison, no significant change in FPF of doxycycline was observed after cospray drying ( p < 0.05), suggesting the doxycycline component to dominate aerosolisation efficiency. As expected, analysis of the simultaneous deposition of ciprofloxacin and docxycycline from a cospray dried formulation indicated similar deposition patterns (Fig. 7B). Statistical analysis of the aerosolisation efficiency of the cospray dried of antibiotics suggested no significant difference in FPF ( p < 0.05) where FPFs of 33.6  2.3% and 33.9  2.2% were observed for ciprofloxacin and doxycycline, respectively. Similarity between the deposition profiles for the two antibiotics suggests that the cospray dried formulation consists of a homogeneous mixture of both components, indicating no molecular segregation occurs during the spray drying process. Furthermore, total recovered, emitted and fine particle doses were consistent with the proportion of each component in the original aqueous spray drying solution (ratio of 1:1). It is important to note, that due to the use of the readily commercially available Aerolizer1 device, the formulation loading used in this study was limited to 20 mg. Although, limited research has been conducted on clinically effective dose ranging of antibiotics via DPI, recent studies have indicated that 150–300 mg, would have a clinical effect31–34 comparable to the same dose given via a nebuliser or intravenously. Although, previous JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 8, AUGUST 2008

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Table 1. Zone Diameter of Staphylococcus aureus, Pseudomonas aeruginosa and Streptococcus pyrogenes against Original and Spray Dried Antibiotics Inhibition Zone Diameter (mm) Staphylococcus aureus

Streptococcus pyrogenes

Pseudomonas aeruginosa

Raw ciprofloxacin Raw doxycycline Combined raw ciprofloxacin and doxycyline Spray dried ciprofloxacin Spray dried doxycycline Cospray dried ciprofloxacin and doxycyline

45 42 44 44 42 44

44 41 43 42 41 42

47 15 46 47 15 47

studies using dry powder antibiotics have administered multiple concurrent dosing (up to 32 inhalations),34 the authors recognize that the large number of inhalations required as a result of present device design limitations would be not ‘patient friendly’. The authors are aware that future formulations and delivery systems having greater drug delivery efficiency are not unrealistic and would make the delivery of antibiotics from DPI a practical alternative to nebulisers.35,36

observed in the S. aureus, P. aeruginosa and Streptococcus pyogenes.

Antimicrobial Agent

Antibiotic Susceptibility Test In order to assess the antimicrobial activity of the antibiotics (ciprofloxacin and doxycycline) before and after spray drying, the disk diffusion test was performed. S. aureus, P. aeruginosa and S. pyrogenes were selected as model bacteria because of their ability to cause respiratory infections. Results of the zone diameter from the inhibited bacteria growth around the antibiotic disk are summarised in the Table 1. The results showed that the spray dried antibiotics had similar zone diameter compared to the original antibiotics, for example, similar zone diameters were observed for the S. aureus with 45 mm and 44 mm for the original ciprofloxacin and spray dried ciprofloxacin, respectively. Similarly, no difference in the zone diameter was observed in the S. pyrogenes when spray dried and original doxycyclines were used (Tab. 1). Although no synergic effect was found (possibly due to the 1:1 dose ratio chosen for this specific study) the cospray drying process did not change the antimicrobial activity of the ciprofloxacin and doxycyline compared to the original mixture of antibiotics, since similar zone diameters were JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 8, AUGUST 2008

CONCLUSIONS In this study the authors investigated the physical stability and aerosolisation efficiency of a cospray dried antibiotic formulation containing ciprofloxacin and doxycycline as a dry powder inhaler formulation providing a feasible and potentially attractive alternative to nebulisation or oral and systemic dosage. The combination of these particular two chemical entities as a cospray dried formulation suggested that a physically stable powder could be produced that facilitated simultaneous and identical in vitro drug deposition profiles, when compared to deposition patterns from the individual formulations. The use of a synergistic, multiple drug, formulation strategy is a logical step to treat pathological infection, however it must be noted that the local and topical efficacy of a combination therapy will only be effective if both antibiotics reach the same action site simultaneously. Thus, this approach of coengineering particles for inhalation warrants further investigation. In addition, the antimicrobial activity of the spray dried antibiotics was proven to be similar to the original antibiotics for S. aureus, P. aeruginosa and S. pyrogenes. The study has shown that delivery of antibiotics via DPI is feasible and could, with further improvement, ultimately be used to improve therapeutic outcomes for patients suffering from pulmonary critical illnesses. Furthermore, the formulation of a cospray dried antibiotic inhalation powder may provide simultaneous delivery of the two pharmaceutical components to the same DOI 10.1002/jps

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site of action increasing the potential synergistic functionality of combined therapy.

ACKNOWLEDGMENTS The authors would like to thank the Pharmacy Trust of New South Wales for the monetary support.

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DOI 10.1002/jps