- Email: [email protected]
Preparation and in vitro release of spray-dried chitosan microspheres for levofloxacin delivery
e70
Abstracts / Journal of Controlled Release 152 (2011) e1–e132
Conclusion In summary, a clear correlation was found between the changes in size, charge, and drug release behavior of BSA/PVP and BSA/PVP/GA when the temperature and pH were changed. The phase transition temperature for these parameters was approximately 30 °C which is close to the body's normal temperature. Being soft and flexible, small molecular weight compounds, such as drugs or other substances, can easily be impregnated into these core–shell microspheres. With the advantages of controlled drug-release behavior, dual stimuli–responsive properties and a biocompatible skeleton, this biomaterial is an attractive candidate for application in the medical and biomedical fields. Acknowledgments The project was supported by the NSFC (20964002; 20804031), NCET, RFDP and SRF for ROCS of MOE of China, Lanzhou Sci Techn Bureau (2009-1-14) and NWNU-kjcxgc-03-63. References [1] K.S. Soppimath, T.M. Aminabhavi, A.R. Kulkarnia, W.E. Rudzinski, Biodegradable polymeric nanoparticles as drug delivery devicesJ. Control. Release 70 (2001) 1–20. [2] N. Nath, A. Chilkoti, Creating “smart” surfaces using stimuli responsive polymers, J. Adv. Mater. 14 (2002) 1243–1247. [3] R.M. Wang, G. Li, H.F. Zhang, Y.F. He, N.P. He, Z.Q. Lei, Preparation of albumin-PAA nanocapsules and their controlled release behavior for drugs, Polym. Adv. Technol. (2010) (online available).
doi:10.1016/j.jconrel.2011.08.128
Preparation and in vitro release of spray-dried chitosan microspheres for levofloxacin delivery Jiayu Cai, Yin Zhang, Wennan Du, Kaihui Nan Eye Hospital, Wenzhou Medical College, Wenzhou 325027, China E-mail address: [email protected] (K. Nan). Abstract summary Levofloxacin (LOF) was incorporated into chitosan microspheres for controlled release. The microspheres were prepared by spray-drying technology combined with glutaraldehyde cross-linking. The drugloaded microspheres showed a golf ball-like particles with a size distribution between 0.5 and 2 μm. The encapsulation efficiency of LOF within microspheres was up to 88.78%. The in vitro release behavior of LOF-CS microspheres was investigated and showed two distinct stages. The present investigation provides a scope for using levofloxacin-loaded chitosan microspheres for combating ocular surface infections.
mucoadhesive and biodegradable polymer that possesses penetrationenhancing properties and an adequate toxicity profile [4,5]. The objective of this work was to explore the possibility to prepare chitosan microspheres using spray-drying technology combined with glutaraldehyde cross-linking for controlled release of levofloxacin as a hydrophilic model drug, as well as to study the in vitro release behavior of the microspheres. Experimental methods Microspheres Preparation. Chitosan microspheres containing LOF were prepared via the spray-drying method. Chitosan (900 mg) was dissolved in aqueous acetic acid solution (100 mL, 1%, v/v) and filtered through a nylon cloth to remove insolubles. Then, LOF was dispersed directly into the chitosan solution to a final concentration of 25% (w/w of chitosan). The prepared formulations were subsequently spray-dried using a mini spraydryer equipped with a high performance cyclone (Büchi B-290, Büchi Labortechnik AG, Switzerland) with a 0.7 mm two-fluid nozzle, using the following standard operating conditions: inlet temperature, 180 °C; spray flow rate, 600 L/h; pump setting, 10% (3.2 mL/min); aspirator setting, 85% (34 m3/h). These conditions resulted in an outlet temperature of 92–95 °C. The spray-dried microspheres were subsequently dispersed in a dehydrated alcohol solution containing 0.1%, 0.5% and 1% (v/v) of glutaraldehyde to cross-link for 2 h. Afterwards, the final product was obtained by centrifugation (4000 rpm, 5 min) and freeze-drying. In Vitro Release. Microsphere samples (50 mg) were placed into dialysis bags and suspended in 35 mL BSS (balanced salt solution) as the release media at 37 ± 0.1 °C and stirred at 100 rpm using the USP 23 paddle method. At predetermined times, samples (2 mL) were withdrawn with a syringe filter (0.45 μm pore size) from the release media and replaced with an equal volume of the corresponding fresh media to maintain a constant volume. The test solution was analyzed by spectrophotometry and the amount of LOF released from the microspheres was calculated as a percentage of the initial amount of LOF incorporated in the microspheres prior to the dissolution test. Results and discussion Spray-drying technology offers the potential to incorporate a range of excipients into the formulation to be spray-dried, and provides a good control over particle size, particle morphology and microsphere density. In our work, using of the high performance cyclone resulted in the collection of high yields of spray-dried
a
b
c
d
Keywords: Chitosan, Levofloxacin, Spray-dry, Controlled release Introduction There are a number of challenges associated to the treatment of ocular diseases. In the case of systemic administration, a major drawback is that only 1–2% of the administered drug reaches the vitreous cavity [1]. Topical instillation is the method of preference for the administration of drugs used in the treatment of ocular disorders, affecting the ocular surface and both the anterior and posterior segment of the eye. It presents several advantages over the invasive routes, such as an easy administration and better patient compliance. However, topical drug delivery to the eye is often impaired by the innate protective characteristics of the eye against the entry of foreign compounds. Due to the removal mechanisms (blinking, tears) and to the complex composition and dynamic character of the lachrymal fluid the bioavailability of an instilled compound is generally low, with only a small fraction reaching the target site [2]. Chitosan is a natural polysaccharide derived from chitin by alkaline deacetylation, and it is the second most abundant biopolymer after cellulose [3]. Chitosan exhibits several favorable biological properties that make it an interesting polymer for use in pharmaceutical formulations, as demonstrated by the number of scientific reports published. It is a
Fig. 1. Representative scanning electron micrographs of spray-dried microspheres undergoing glutaraldehyde cross-linking with different concentrations. (a) drugunloaded microspheres, (b) drug-loaded microspheres, (c) drug-loaded microspheres undergoing 0.1% glutaraldehyde cross-linking, (d) drug-loaded microspheres undergoing 1% glutaraldehyde cross-linking. Bar = 1 μm.
Abstracts / Journal of Controlled Release 152 (2011) e1–e132
microspheres (the yields ranged from 57% to 63%). Analysis of the levofloxacin content of the spray-dried microspheres indicated that the drug loading ranged from 25% to 50% with good concordance. Scanning electron microscopy was used to visualize the particle diameter, structural and surface morphology of the spray-dried microspheres (Fig. 1). Interestingly, the micrograph of the microspheres without glutaraldehyde cross-link did not show spherical particles (Fig. 1a and b); rather, the particles appear to have undergone fusion and partial recrystallization, which is in accordance with what has been described in the literature [6]. In contrast, the micrographs of the microspheres undergoing glutaraldehyde crosslinking (Fig. 1c and d) indicated that the microspheres comprised uniform particles possessing a golf ball-like surface and a diameter of less than 3 μm. It is unclear whether this phenomenon is occurring by the addition of levofloxacin in spray-dried microspheres, or because of contraction during spray-drying. In vitro release tests were used to provide a comparison between the release profile of the spray-dried microsphere with and without glutaraldehyde cross-linking. As expected, the microspheres without cross-links underwent very rapid dissolution, with 100% levofloxacin released after approximately 2 h (Fig. 2). The cross-linked microspheres exhibited delayed release characteristics; however, increasing the concentration of glutaraldehyde was not associated with a more sustained release profile. The cross-linked microspheres with 25% drugloading released about 80% levofloxacin after 6 h, and it needed 12 h to release its entire loaded drug. The results suggest that the levofloxacin loaded cross-linked chitosan microspheres can be used as major constituents of eye drops to improve the bioavailability of levofloxacin.
e71
[2] P. Paolicelli, M. de la Fuente, A. Sanchez, B. Seijo, M.J. Alonso, Chitosan nanoparticles for drug delivery to the eye, Expert Opin. Drug Deliv. 6 (2009) 239–253. [3] M.N.V. Ravi Kumar, A review of chitin and chitosan applications, React. Funct. Polym. 46 (2000) 1–27. [4] I.A. Sogias, A.C. Williams, V.V. Khutoryanskiy, Why is chitosan mucoadhesive? Biomacromolecules 9 (2008) 1837–1842. [5] V. Dodane, M. Amin Khan, J.R. Merwin, Effect of chitosan on epithelial permeability and structure, Int. J. Pharm. 182 (1999) 21–32. [6] T.P. Learoyd, J.L. Burrows, E. French, P.C. Seville, Chitosan-based spray-dried respirable powders for sustained delivery of terbutaline sulfate, Eur. J. Pharm. Biopharm. 68 (2008) 224–234.
doi:10.1016/j.jconrel.2011.08.129
Investigation on the preparation and application of chitosan/alginate microcapsules Dongzhi Yang, Shuang Guo, Jing Qiao, Jun Nie Key Laboratory of Carbon Fiber and Functional Polymers, Ministry of Education, State Key Laboratory of Chemical Resource Engineering, College of Materials Science and Engineering, Beijing University of Chemical and Technology, Beijing 100029, China E-mail address: [email protected] (J. Nie). Abstract summary Chitosan/sodium alginate microcapsules were prepared by highvoltage electrostatic spray method. Multi-layer chitosan–sodium alginate microcapsules were prepared through layer-by-layer self-assembly. The release of ofloxacin from microcapsules was studied. The results showed that the electrostatic spray was a simple, highly efficient and convenient method for preparation of microcapsules. The prepared microcapsules had a smooth surface with uniform particle size. The drug release results indicated that the prepared microcapsules were not sensitive to pH and the rate of release did not change with layer number. Keywords: Chitosan, Sodium alginate, Electrospraying, Controlled delivery, Layer-by-layer self-assembly
Fig. 2. In vitro release profile of levofloxacin loaded chitosan microspheres.
Conclusion In our investigation, chitosan microspheres containing levofloxacin were successfully prepared using spray-drying technology combined with glutaraldehyde cross-linking. The microspheres had golf ball-like surfaces and uniform sizes. The release profiles of levofloxacin from the microspheres with cross-links showed distinct differences as compared to microspheres without cross-links. The cross-linked chitosan microspheres can extend the levofloxacin release time to 12 h, whereas the release time of this drug from uncross-linked microspheres was only 2 h. Thus, controlled release of levofloxacin will provide a more effective and continuous supply of levofloxacin when these microspheres are used for eye drops. References [1] E. Mannermaa, K.S. Vellonen, A. Urtti, Drug transport in corneal epithelium and blood– retina barrier: emerging role of transporters in ocular pharmacokinetics, Adv. Drug Deliv Rev. 58 (2006) 1136–1163.
Introduction Chitosan and alginate are natural cationic or anionic polysaccharides, respectively. They have been frequently in the biomedical field for their good biocompatibility, biodegradability, and their abundance in nature [1], e.g. their complex was used as carrier for the drug release [2]. Among the preparation techniques for chitosan microencapsulation, electrospraying is a convenient way in which an electric field is used to control the formation and deposition of polymer microcapsules. Above a critical voltage between a needle capillary end and a collector, droplets will be produced by the electrostatic repulsion force of surface charges and the droplets are received in a collector [3,4]. Due to the opposite charges of chitosan and alginate, multi-layer microcapsules can be fabricated through repeated deposition by the layer-by-layer (LbL) self-assembly technique [5–7]. The thickness and composition can be controlled by the layer number and type of polymer used [8,9]. The purpose of this work was to fabricate chitosan/alginate microcapsules by electrospraying at room temperature, which is a simple and mild operation, and to encapsulate enzymes or proteins in the prepared microcapsules in order to preserve their activity. Experimental methods A solution of sodium alginate was placed in a 5 mL medical plastic syringe fitted with a stainless steel needle. The needle with solution was attached to the electrospraying apparatus. The collecting solution was an aqueous chitosan solution. Then a layer-by-layer (LbL) self-assembly method was used to make multi-layer microcapsules, because chitosan and sodium alginate as polysaccharides were directly deposited on the
Abstracts / Journal of Controlled Release 152 (2011) e1–e132
Conclusion In summary, a clear correlation was found between the changes in size, charge, and drug release behavior of BSA/PVP and BSA/PVP/GA when the temperature and pH were changed. The phase transition temperature for these parameters was approximately 30 °C which is close to the body's normal temperature. Being soft and flexible, small molecular weight compounds, such as drugs or other substances, can easily be impregnated into these core–shell microspheres. With the advantages of controlled drug-release behavior, dual stimuli–responsive properties and a biocompatible skeleton, this biomaterial is an attractive candidate for application in the medical and biomedical fields. Acknowledgments The project was supported by the NSFC (20964002; 20804031), NCET, RFDP and SRF for ROCS of MOE of China, Lanzhou Sci Techn Bureau (2009-1-14) and NWNU-kjcxgc-03-63. References [1] K.S. Soppimath, T.M. Aminabhavi, A.R. Kulkarnia, W.E. Rudzinski, Biodegradable polymeric nanoparticles as drug delivery devicesJ. Control. Release 70 (2001) 1–20. [2] N. Nath, A. Chilkoti, Creating “smart” surfaces using stimuli responsive polymers, J. Adv. Mater. 14 (2002) 1243–1247. [3] R.M. Wang, G. Li, H.F. Zhang, Y.F. He, N.P. He, Z.Q. Lei, Preparation of albumin-PAA nanocapsules and their controlled release behavior for drugs, Polym. Adv. Technol. (2010) (online available).
doi:10.1016/j.jconrel.2011.08.128
Preparation and in vitro release of spray-dried chitosan microspheres for levofloxacin delivery Jiayu Cai, Yin Zhang, Wennan Du, Kaihui Nan Eye Hospital, Wenzhou Medical College, Wenzhou 325027, China E-mail address: [email protected] (K. Nan). Abstract summary Levofloxacin (LOF) was incorporated into chitosan microspheres for controlled release. The microspheres were prepared by spray-drying technology combined with glutaraldehyde cross-linking. The drugloaded microspheres showed a golf ball-like particles with a size distribution between 0.5 and 2 μm. The encapsulation efficiency of LOF within microspheres was up to 88.78%. The in vitro release behavior of LOF-CS microspheres was investigated and showed two distinct stages. The present investigation provides a scope for using levofloxacin-loaded chitosan microspheres for combating ocular surface infections.
mucoadhesive and biodegradable polymer that possesses penetrationenhancing properties and an adequate toxicity profile [4,5]. The objective of this work was to explore the possibility to prepare chitosan microspheres using spray-drying technology combined with glutaraldehyde cross-linking for controlled release of levofloxacin as a hydrophilic model drug, as well as to study the in vitro release behavior of the microspheres. Experimental methods Microspheres Preparation. Chitosan microspheres containing LOF were prepared via the spray-drying method. Chitosan (900 mg) was dissolved in aqueous acetic acid solution (100 mL, 1%, v/v) and filtered through a nylon cloth to remove insolubles. Then, LOF was dispersed directly into the chitosan solution to a final concentration of 25% (w/w of chitosan). The prepared formulations were subsequently spray-dried using a mini spraydryer equipped with a high performance cyclone (Büchi B-290, Büchi Labortechnik AG, Switzerland) with a 0.7 mm two-fluid nozzle, using the following standard operating conditions: inlet temperature, 180 °C; spray flow rate, 600 L/h; pump setting, 10% (3.2 mL/min); aspirator setting, 85% (34 m3/h). These conditions resulted in an outlet temperature of 92–95 °C. The spray-dried microspheres were subsequently dispersed in a dehydrated alcohol solution containing 0.1%, 0.5% and 1% (v/v) of glutaraldehyde to cross-link for 2 h. Afterwards, the final product was obtained by centrifugation (4000 rpm, 5 min) and freeze-drying. In Vitro Release. Microsphere samples (50 mg) were placed into dialysis bags and suspended in 35 mL BSS (balanced salt solution) as the release media at 37 ± 0.1 °C and stirred at 100 rpm using the USP 23 paddle method. At predetermined times, samples (2 mL) were withdrawn with a syringe filter (0.45 μm pore size) from the release media and replaced with an equal volume of the corresponding fresh media to maintain a constant volume. The test solution was analyzed by spectrophotometry and the amount of LOF released from the microspheres was calculated as a percentage of the initial amount of LOF incorporated in the microspheres prior to the dissolution test. Results and discussion Spray-drying technology offers the potential to incorporate a range of excipients into the formulation to be spray-dried, and provides a good control over particle size, particle morphology and microsphere density. In our work, using of the high performance cyclone resulted in the collection of high yields of spray-dried
a
b
c
d
Keywords: Chitosan, Levofloxacin, Spray-dry, Controlled release Introduction There are a number of challenges associated to the treatment of ocular diseases. In the case of systemic administration, a major drawback is that only 1–2% of the administered drug reaches the vitreous cavity [1]. Topical instillation is the method of preference for the administration of drugs used in the treatment of ocular disorders, affecting the ocular surface and both the anterior and posterior segment of the eye. It presents several advantages over the invasive routes, such as an easy administration and better patient compliance. However, topical drug delivery to the eye is often impaired by the innate protective characteristics of the eye against the entry of foreign compounds. Due to the removal mechanisms (blinking, tears) and to the complex composition and dynamic character of the lachrymal fluid the bioavailability of an instilled compound is generally low, with only a small fraction reaching the target site [2]. Chitosan is a natural polysaccharide derived from chitin by alkaline deacetylation, and it is the second most abundant biopolymer after cellulose [3]. Chitosan exhibits several favorable biological properties that make it an interesting polymer for use in pharmaceutical formulations, as demonstrated by the number of scientific reports published. It is a
Fig. 1. Representative scanning electron micrographs of spray-dried microspheres undergoing glutaraldehyde cross-linking with different concentrations. (a) drugunloaded microspheres, (b) drug-loaded microspheres, (c) drug-loaded microspheres undergoing 0.1% glutaraldehyde cross-linking, (d) drug-loaded microspheres undergoing 1% glutaraldehyde cross-linking. Bar = 1 μm.
Abstracts / Journal of Controlled Release 152 (2011) e1–e132
microspheres (the yields ranged from 57% to 63%). Analysis of the levofloxacin content of the spray-dried microspheres indicated that the drug loading ranged from 25% to 50% with good concordance. Scanning electron microscopy was used to visualize the particle diameter, structural and surface morphology of the spray-dried microspheres (Fig. 1). Interestingly, the micrograph of the microspheres without glutaraldehyde cross-link did not show spherical particles (Fig. 1a and b); rather, the particles appear to have undergone fusion and partial recrystallization, which is in accordance with what has been described in the literature [6]. In contrast, the micrographs of the microspheres undergoing glutaraldehyde crosslinking (Fig. 1c and d) indicated that the microspheres comprised uniform particles possessing a golf ball-like surface and a diameter of less than 3 μm. It is unclear whether this phenomenon is occurring by the addition of levofloxacin in spray-dried microspheres, or because of contraction during spray-drying. In vitro release tests were used to provide a comparison between the release profile of the spray-dried microsphere with and without glutaraldehyde cross-linking. As expected, the microspheres without cross-links underwent very rapid dissolution, with 100% levofloxacin released after approximately 2 h (Fig. 2). The cross-linked microspheres exhibited delayed release characteristics; however, increasing the concentration of glutaraldehyde was not associated with a more sustained release profile. The cross-linked microspheres with 25% drugloading released about 80% levofloxacin after 6 h, and it needed 12 h to release its entire loaded drug. The results suggest that the levofloxacin loaded cross-linked chitosan microspheres can be used as major constituents of eye drops to improve the bioavailability of levofloxacin.
e71
[2] P. Paolicelli, M. de la Fuente, A. Sanchez, B. Seijo, M.J. Alonso, Chitosan nanoparticles for drug delivery to the eye, Expert Opin. Drug Deliv. 6 (2009) 239–253. [3] M.N.V. Ravi Kumar, A review of chitin and chitosan applications, React. Funct. Polym. 46 (2000) 1–27. [4] I.A. Sogias, A.C. Williams, V.V. Khutoryanskiy, Why is chitosan mucoadhesive? Biomacromolecules 9 (2008) 1837–1842. [5] V. Dodane, M. Amin Khan, J.R. Merwin, Effect of chitosan on epithelial permeability and structure, Int. J. Pharm. 182 (1999) 21–32. [6] T.P. Learoyd, J.L. Burrows, E. French, P.C. Seville, Chitosan-based spray-dried respirable powders for sustained delivery of terbutaline sulfate, Eur. J. Pharm. Biopharm. 68 (2008) 224–234.
doi:10.1016/j.jconrel.2011.08.129
Investigation on the preparation and application of chitosan/alginate microcapsules Dongzhi Yang, Shuang Guo, Jing Qiao, Jun Nie Key Laboratory of Carbon Fiber and Functional Polymers, Ministry of Education, State Key Laboratory of Chemical Resource Engineering, College of Materials Science and Engineering, Beijing University of Chemical and Technology, Beijing 100029, China E-mail address: [email protected] (J. Nie). Abstract summary Chitosan/sodium alginate microcapsules were prepared by highvoltage electrostatic spray method. Multi-layer chitosan–sodium alginate microcapsules were prepared through layer-by-layer self-assembly. The release of ofloxacin from microcapsules was studied. The results showed that the electrostatic spray was a simple, highly efficient and convenient method for preparation of microcapsules. The prepared microcapsules had a smooth surface with uniform particle size. The drug release results indicated that the prepared microcapsules were not sensitive to pH and the rate of release did not change with layer number. Keywords: Chitosan, Sodium alginate, Electrospraying, Controlled delivery, Layer-by-layer self-assembly
Fig. 2. In vitro release profile of levofloxacin loaded chitosan microspheres.
Conclusion In our investigation, chitosan microspheres containing levofloxacin were successfully prepared using spray-drying technology combined with glutaraldehyde cross-linking. The microspheres had golf ball-like surfaces and uniform sizes. The release profiles of levofloxacin from the microspheres with cross-links showed distinct differences as compared to microspheres without cross-links. The cross-linked chitosan microspheres can extend the levofloxacin release time to 12 h, whereas the release time of this drug from uncross-linked microspheres was only 2 h. Thus, controlled release of levofloxacin will provide a more effective and continuous supply of levofloxacin when these microspheres are used for eye drops. References [1] E. Mannermaa, K.S. Vellonen, A. Urtti, Drug transport in corneal epithelium and blood– retina barrier: emerging role of transporters in ocular pharmacokinetics, Adv. Drug Deliv Rev. 58 (2006) 1136–1163.
Introduction Chitosan and alginate are natural cationic or anionic polysaccharides, respectively. They have been frequently in the biomedical field for their good biocompatibility, biodegradability, and their abundance in nature [1], e.g. their complex was used as carrier for the drug release [2]. Among the preparation techniques for chitosan microencapsulation, electrospraying is a convenient way in which an electric field is used to control the formation and deposition of polymer microcapsules. Above a critical voltage between a needle capillary end and a collector, droplets will be produced by the electrostatic repulsion force of surface charges and the droplets are received in a collector [3,4]. Due to the opposite charges of chitosan and alginate, multi-layer microcapsules can be fabricated through repeated deposition by the layer-by-layer (LbL) self-assembly technique [5–7]. The thickness and composition can be controlled by the layer number and type of polymer used [8,9]. The purpose of this work was to fabricate chitosan/alginate microcapsules by electrospraying at room temperature, which is a simple and mild operation, and to encapsulate enzymes or proteins in the prepared microcapsules in order to preserve their activity. Experimental methods A solution of sodium alginate was placed in a 5 mL medical plastic syringe fitted with a stainless steel needle. The needle with solution was attached to the electrospraying apparatus. The collecting solution was an aqueous chitosan solution. Then a layer-by-layer (LbL) self-assembly method was used to make multi-layer microcapsules, because chitosan and sodium alginate as polysaccharides were directly deposited on the