Hydrogels containing redispersible spray-dried melatonin-loaded nanocapsules: a formulation for transdermal-controlled delivery
© Hoffmeister et al.; licensee Springer. 2012
Received: 21 March 2012
Accepted: 26 April 2012
Published: 15 May 2012
The aim of the present study was to develop a transdermal system for controlled delivery of melatonin combining three strategies: nanoencapsulation of melatonin, drying of melatonin-loaded nanocapsules, and incorporation of nanocapsules in a hydrophilic gel. Nanocapsules were prepared by interfacial deposition of the polymer and were spray-dried using water-soluble excipients. In vitro drug release profiles were evaluated by the dialysis bag method, and skin permeation studies were carried out using Franz cells with porcine skin as the membrane. The use of 10% (w/v) water-soluble excipients (lactose or maltodextrin) as spray-drying adjuvants furnished redispersible powders (redispersibility index approximately 1.0) suitable for incorporation into hydrogels. All formulations showed a better controlled in vitro release of melatonin compared with the melatonin solution. The best controlled release results were achieved with hydrogels prepared with dried nanocapsules (hydrogels > redispersed dried nanocapsules > nanocapsule suspension > melatonin solution). The skin permeation studies demonstrated a significant modulation of the transdermal melatonin permeation for hydrogels prepared with redispersible nanocapsules. In this way, the additive effect of the different approaches used in this study (nanoencapsulation, spray-drying, and preparation of semisolid dosage forms) allows not only the control of melatonin release, but also transdermal permeation.
KeywordsHydrogels Maltodextrin Melatonin Nanocapsules Spray-drying Lactose Skin permeation Transdermal delivery
Melatonin (N-acetyl-5-methoxytryptamine) is a hormone secreted by the pineal gland of mammals at nighttime, and it is involved in the regulation of the sleep-wake cycle as well as in several biological functions, including the regulation of mood, the control of seasonal reproduction, and the circadian rhythm, in animals and humans. The administration of dosage forms containing exogenous melatonin has been used to treat circadian rhythm disorders such as jet lag and insomnia . Besides being a potent antioxidant, melatonin is a free scavenger [1, 2]; it protects against lipid peroxidation in several models  and against oxidative stress in some neurodegenerative diseases such as Alzheimer's disease [1, 4]. Furthermore, it protects against ischemia/reperfusion injury  and has antitumor activity .
Melatonin has a very short half-life and low and variable oral bioavailability presumably due to variable degrees of absorption and/or an extensive metabolism by the liver [7, 8]. Furthermore, melatonin is a poorly water-soluble substance and has slow dissolution characteristics . Hence, melatonin is not a good candidate for conventional oral immediate-release dosage forms . Thus, melatonin-sustained release formulations have been developed for oral [8–14], intranasal , transdermal [16–18], and transmucosal [18, 19] administrations. Modified release tablets containing melatonin, including β-cyclodextrin , microparticles [8, 13, 15], hydroxypropylmethylcellulose matrix tablets , and lecithin/chitosan nanoparticles , have been also successfully prepared. Transdermal administration of melatonin could be a very attractive alternative resulting in sustained drug plasma levels that can be tailored to the normal physiological range and avoid the first pass effect . Additionally, transdermal delivery could overcome the low oral bioavailability of melatonin . In this context, the skin protecting and non-irritant nature of melatonin supports its candidature for transdermal delivery .
Over the past few decades, there has been considerable interest in studying polymeric nanostructures as effective drug delivery devices. Nanocapsules are vesicular systems composed of an oil-filled cavity surrounded by a polymeric wall presenting narrow particle size distribution, and they are stabilized by surfactants at the particle/water interface [21–23]. In nanocapsules (<1 μm), the drug can be dissolved, entrapped, encapsulated, and/or adsorbed or attached to the polymeric particles [21, 22]. Despite the huge variety of promising applications of polymeric nanocapsules, in the area of transdermal delivery, these carriers have not yet been explored. This via is advantageous because it is minimally invasive, therefore avoids pain and risk of infections.
Previous studies have demonstrated that melatonin-loaded Eudragit® S100 nanocapsule suspensions were able to improve the antioxidant effect of melatonin in both in vitro and in vivo experiments [24, 25]. In some cases, these aqueous suspensions present limited physicochemical stability under storage due to the possibility of particle aggregation , the degradation of components such as the polymer [27–29] or drug leakage [29–31]. Freeze-drying [23, 29] and spray-drying techniques [32, 33] have been reported as alternatives to improve the stability of nanoparticle suspensions by means of their conversion into powders. Spray-dried powders containing melatonin-loaded Eudragit® S100 nanocapsules were prepared using silicon dioxide as drying adjuvants, showing a controlled drug release profile in comparison with the pure drug . In addition, redispersible drug-free spray-dried poly(ϵ-caprolactone)-nanocapsules were developed using lactose as the excipient .
Although the results of previous studies have demonstrated the feasibility of preparing redispersible dried polymeric nanocapsules, there is a lack of information in the literature on the use of these powders for the development of nanomedicines or nanocosmetics as final dosage forms. In this context, the aim of this study was to control the in vitro transdermal delivery of melatonin by means of a strategy based on hydrogel formulations containing spray-dried melatonin-loaded nanocapsules. We hypothesized that the nanocarriers dried with the aid of a water-soluble excipient and incorporated into the semisolid formulation could modulate the transdermal delivery of melatonin.
Melatonin was obtained from Acros Organics (Geel, Belgium). Poly(methacrylic acid-co-methyl methacrylate) (Eudragit S100®) was supplied by Almapal (São Paulo, Brazil). The caprylic/capric triglyceride mixture was obtained from Brasquim (Porto Alegre, Brazil). Sorbitan monooleate (Span 80®), polysorbate 80 and triethanolamine were acquired from Delaware (Porto Alegre, Brazil). Carbopol 940® was obtained from BF Goodrich (Charlotte, NC, USA). Lactose and maltodextrin were purchase from Henrifarma (São Paulo, Brazil) and Roquette (Lestrem, France), respectively. All other chemicals and solvents were of pharmaceutical grade and used as received.
Preparation and characterization of nanocapsule suspensions
Melatonin-loaded polymeric nanocapsules (NC) were prepared (n = 3) by interfacial deposition of the preformed polymer according to the method described by Fessi and co-workers . The organic phase consisted of melatonin (0.0125 g), caprylic/capric triglyceride mixture (0.8 mL), Eudragit S100® (0.25 g), and Span 80® (0.1915 g) in acetone. This lipophilic solution was poured into a hydrophilic phase containing polysorbate 80 (0.1915 g). Acetone was removed, and the suspensions were concentrated by evaporation under reduced pressure to obtain a final volume of 25 mL (0.5 mg mL−1 of melatonin) .
The mean size and polydispersity of the nanocapsules were determined at 25 ± 2°C by photon correlation spectroscopy (Zetasizer Nano ZEN3600, Malvern, UK). Suspensions were diluted 500-fold in MilliQ® water (Millipore Co., Billerica, MA, USA). Zeta potential was measured by an eletrophoretic technique, using the same equipment. For these measurements, the suspensions were diluted (1:500) with 10 mM NaCl aqueous solution. The pH measurements were carried out directly in the samples using a Micronal B474 potentiometer (Micronal, São Paulo, Brazil).
The melatonin content of the nanocapsules was determined after their dissolution in acetonitrile and assayed by high-performance liquid chromatography (HPLC) . The system consisted of an SPD-10A Shimadzu detector, LC-10 AD Shimadzu pump, SIL-10A Shimadzu injector (Shimadzu Corporation, Nakagyo-ku, Kyoto, Japan), and Lichrospher® RP-18 column provided by Merck (Darmstadt, Germany). The mobile phase consisted of acetonitrile/water (55:45, v/v) at a flow rate of 0.7 mL min−1. Melatonin was detected at 229 nm. The encapsulation efficiency (percentage) was calculated by difference between the total content and free melatonin concentration in the nanocapsule suspension. The free melatonin concentration was determined using the ultrafiltration-centrifugation technique (Microcon 10,000 KDa, Millipore) .
Preparation and characterization of spray-dried polymeric nanocapsules
Spray-dried melatonin-loaded nanocapsules were prepared (n = 3) using an MSD® 1.0 spray dryer (Labmaq, São Paulo, Brazil). Lactose and maltodextrin at 10% (w/v) were evaluated individually as drying adjuvants. The drying adjuvant was added to the nanocapsule suspension under magnetic stirring. The stirring was maintaining for 10 min before the formulation was fed into the spray dryer. A two-fluid nozzle with a cap orifice diameter of 0.7 mm and a co-current flow was used. The inlet temperature in the drying chamber was maintained at 150 ± 10°C, and the feeding rate was set at 0.3 L/h . Powders prepared with lactose and maltodextrin were named as D-NC-L and D-NC-M, respectively.
The process yield (percentage) was calculated as the ratio between the total weight of powder recovered in the sample collector and the total dry mass of the components used. The residual moisture content (percentage) of each spray-dried product was measured by Karl Fischer titration in dry methanol (Titro Matric 1 S, Crison Instruments, Barcelona, Spain). Measurements were performed in triplicate. In order to determine the melatonin content in the spray-dried powders, samples were dispersed in methanol and kept under magnetic stirring for 10 min. After centrifugation, melatonin was assayed by HPLC according to the method described above.
where dRP is the mean particle size of the redispersed spray-dried powder and dS is the mean particle size of the original nanocapsule suspension.
Morphological analysis of spray-dried powders was carried out by scanning electron microscopy (JEOL scanning microscope JSM-5800, Tokyo, Japan). Samples were analyzed after they had been gold sputtered (JEOL Jee 4B SVG IN, Tokyo, Japan), and the analysis was performed at the Electron Microscopy Center of the Federal University of Rio Grande de Sul State (Centro de Microscopia Eletrônica - UFRGS).
Preparation and characterization of hydrophilic gels
Hydrogels were prepared using 0.5% of Carbopol 940®, 0.2% of diazolinidyl urea, and triethanolamine. Four different formulations were prepared: (a) a hydrogel prepared by adding Carbopol 940® directly to the nanocapsule suspension (G-NC), (b) a hydrogel prepared by adding the spray-dried nanocapsules (prepared with lactose) to a preformed hydrogel (G-NC-L), (c) a hydrogel prepared by adding the spray-dried nanocapsules (prepared with maltodextrin) to a preformed hydrogel (G-NC-M), and (d) a hydrogel prepared by adding directly the melatonin dispersed in water containing polysorbate 80 at 0.77% to preformed hydrogels (G-M). All formulations were prepared at a final concentration of 0.5 mg g−1 of melatonin. Hydrogels containing redispersed spray-dried nanocapsules (G-NC-L and G-NC-M) were prepared by adding 1.57 g of powder in 10 g of each hydrogel previously prepared, reaching a final concentration of 0.5 mg g−1 of melatonin. The pH values of the gels were determined using a potentiometer (Micronal B474, São Paulo, Brazil) through the direct immersion of the electrode in semisolids (n = 3). The physical stability of the hydrogels was evaluated by multiple light scattering (Turbiscan Lab, Formulaction, L'Union, France). The samples were poured into glass cells without any dilution and analyzed using scan mode every 6 min for 20 h at room temperature.
In vitro drug release profiles
In vitro drug release profiles (n = 3) from all formulations (nanocapsule suspensions, dried nanocapsules, and hydrogels) were studied under sink conditions using a cellulose dialysis bag (MWCO = 12,000 to 14,000 Da, Sigma-Aldrich Corporation, St. Louis, MO, USA). Nanocapsule suspensions (10 mL) and the hydrogels (10 g) were transferred directly to the dialysis bags, which were placed in a beaker containing 150 mL of 5% polysorbate 80 aqueous solution (at 37°C) with slow magnetic stirring. For the spray-dried nanocapsules, the powders were previously redispersed in 10 mL of water. The initial concentration of melatonin in the dialysis bag was 0.5 mg mL−1 for all samples. Aliquots of 2 mL were withdrawn periodically and replaced with the same volume of fresh medium. The concentration of melatonin released at each time was determined by HPLC using a validated methodology previously described . Drug release profiles were analyzed by model-dependent methods (mono-exponential and bi-exponential models) using the software MicroMath Scientist® (St. Louis, MO, USA). The best model to describe the release profile was selected based on the highest model selection criterion (MSC) and the highest correlation coefficient (r), as well as the best curve fitting.
In vitro skin permeation studies
The in vitro permeation experiments were performed using Franz type diffusion cells and pig abdomen skin at 37°C. Pig skin was obtained from a local slaughterhouse. The skin was cleaned to remove the hair and adipose tissue and kept at −20°C until use. The thickness of the skin piece (1.5 to 2 mm) was measured using a micrometer (Dial Thickness Gage, 2046 S, Mitutoyo Corporation, Kanagawa, Japan). The dermal side of the porcine flank skin was exposed to the receptor fluid (5.0% (v/v) polysorbate 80 aqueous solution), and the stratum corneum was exposed to the air (non-occlusive conditions). The effective permeation area was 16 cm2, and the volume of the receiver chamber was around 50 mL.
The hydrogels were applied and weighed in the donor compartment (50 mg/cm2). The flux of melatonin from the nanocapsules through the skin was calculated by determining the drug concentration in the receptor medium at predetermined times (2, 4, 6, 8, 12, and 24 h) by liquid chromatography (as previously described). Results represent the mean of six independent replicates (n = 6). The cumulative amounts of melatonin per diffusion area were calculated for each time point and plotted versus the sampling time points. Flux corresponds to the slope calculated by the linear regression of these data points.
All analyses were carried out in triplicate. Results are expressed as the mean ± standard deviation. Parameters of the mathematical modeling (k, A, α, B, and β) and the data of in vitro melatonin permeation were statistically evaluated using one-way analysis of variance at a significance level of 5% (StatGraphics Plus 5.1, STATPOINT TECHNOLOGIES, INC., Warrenton, VA, USA).
Results and discussion
Polymeric nanocapsule suspensions
The melatonin-loaded nanocapsule suspension revealed a mean particle size of 186 ± 24 nm with a low polydispersity index (0.16 ± 0.03) and a pH of 3.87 ± 0.14. The zeta potential was negative (−11.2 ± 5.1 mV) because of the negative surface charge density at the particle/water interface as a consequence of the presence of oxygen atoms in the polymer backbone [37, 38]. Drug content in the final nanocapsule suspension was 0.477 ± 0.003 mg ml−1 with an encapsulation efficiency of 63 ± 2%. All these results are in accordance with the method of preparation, drug and materials used, as previously reported by our group .
Spray-dried polymeric nanocapsules
Nanocapsule suspensions were spray-dried using lactose or maltodextrin. The process yields were of 52 ± 8% and 50 ± 6% for spray-dried formulations using lactose (D-NC-L) or maltodextrin (D-NC-M), respectively. The operational conditions of the spray-drying process were appropriate for the drying of the nanocapsules, as demonstrated by the low moisture content of the dried formulations (1.1 ± 0.1% and 1.7 ± 0.3% for D-NC-L and D-NC-M, respectively).
Melatonin content in the spray-dried nanocapsules was 3.17 and 3.36 mg g−1, for D-NC-L and D-NC-M, respectively, corresponding to a complete recovery of the drug after the drying process (99% and 105%, respectively). However, some previous reports have described that a segregation of the drug/materials during the spray-drying process can occur, depending on the raw material  or the parameters of the process .
To fully characterize the nanoscopic population, formulations were also analyzed by photon correlation spectroscopy. D-NC-L and D-NC-M showed z-averaged diameters of 192 ± 50 nm and 181 ± 27 nm with polydispersity indexes of 0.33 ± 0.03 and 0.25 ± 0.10, respectively. In order to determine the redispersibility efficiency, the values for the ratio between the mean diameter of D-NC-L or D-NC-M and the mean size of the original nanocapsules were calculated. The results obtained were close to unity (1.03 and 0.97 for D-NC-L and D-NC-M, respectively), demonstrating that the dehydration-rehydration process did not lead to significant changes in the nanometric size of the systems, regardless of the adjuvant added.
Hydrogels containing spray-dried melatonin-loaded nanocapsules
Melatonin-loaded nanocapsule suspensions and spray-dried nanocapsules (D-NC-L and D-NC-M) were incorporated into semisolid hydrogels (G-NC, G-NC-L, and G-NC-M, respectively). Hydrogels were white and bright with pH values being close to neutral for G-NC-L (7.11 ± 0.02) and for G-NC-M (7.10 ± 0.01); while for G-NC, a slightly acid pH was observed (5.8 ± 0.04).
In vitro melatonin release studies
Calculated release parameters of different formulations containing melatonin-loaded nanocapsules, according to the bi-exponential model
0.88 ± 0.10
0.15 ± 0.11
0.0073 ± 0.0005
0.0017 ± 0.0011
0.80 ± 0.02
0.28 ± 0.00
0.0058 ± 0.0002
0.0003 ± 0.0000
0.78 ± 0.01
0.24 ± 0.02
0.0043 ± 0.0004
0.0004 ± 0.0001
0.27 ± 0.04
0.0120 ± 0.0011
0.0016 ± 0.0001
0.84 ± 0.00
0.1647 ± 0.0012
0.0012 ± 0.0000
0.21 ± 0.10
0.74 ± 0.01
0.0072 ± 0.0002
0.0008 ± 0.0000
In vitro permeation studies
In general, the results of the permeation study corroborate those obtained in the drug release studies, showing lower melatonin release/skin permeation for the hydrogels prepared with the spray-dried nanocapsules as well as the synergistic effect of the strategies employed in this study (nanoencapsulation, spray-drying, and preparation of semisolid dosage forms). In addition, with a view to industrial production, spray-dried powders present the advantages of being less susceptible to microbiological contamination and more appropriate for storage and transport.
Redispersible spray-dried melatonin-loaded nanocapsules were prepared using water-soluble excipients as drying adjuvants (lactose or maltodextrin). Different techniques showed the redispersion efficiency of spray-dried nanocapsules. Laser diffraction, photon correlation spectroscopy, and nanoparticle tracking analysis showed similar results. The hydrogels prepared with melatonin-loaded nanocapsules were able to control the release rate of melatonin as well as to delay its permeation across the pig skin. An additive effect of the nanoencapsulation, spray-drying, and incorporation in semisolid dosage forms explains the better control of the transdermal delivery of melatonin. This study represents a promising strategy for the use of spray-dried nanocapsules in the development of semisolid dosage forms for transdermal-controlled delivery nanomedicines.
powders prepared with lactose
powders prepared with maltodextrin
hydrogel prepared by adding directly the melatonin dispersed in water containing polysorbate 80
hydrogel prepared by adding Carbopol 940® directly to the nanocapsule suspension
hydrogel prepared by adding the spray-dried nanocapsules (prepared with lactose)
hydrogel prepared by adding the spray-dried nanocapsules (prepared with maltodextrin)
model selection criterion
melatonin-loaded polymeric nanocapsules
nanoparticle tracking analysis
photon correlation spectroscopy
measure of the width of the distribution of particle size..
The authors gratefully acknowledge the financial support from CNPq, FAPERGS, CAPES, Rede Nanocosméticos, INCT_if and PRONEX-FAPERGS/CNPq.
- Beyer CE, Steketee JD, Saphier D: Antioxidant properties of melatonin – an emerging mystery. Biochem Pharmacol 1998, 56: 1265–1272. 10.1016/S0006-2952(98)00180-4View ArticleGoogle Scholar
- Brömme HJ, Mörke W, Peschke E, Ebelt H, Peschke D: Scavenging effect of melatonin on hydroxyl radicals generated by alloxan. J Pineal Res 2000, 29: 201–208. 10.1034/j.1600-0633.2002.290402.xView ArticleGoogle Scholar
- Teixeira A, Morfim MP, de Cordova CAS, Charão CCT, de Lima VR, Creczynski-Pasa TB: Melatonin protects against pro-oxidant enzymes and reduces lipid peroxidation in distinct membranes induced by the hydroxyl an ascorbyl radicals and by peroxynitrite. J Pineal Res 2003, 35: 262–268. 10.1034/j.1600-079X.2003.00085.xView ArticleGoogle Scholar
- Pappolla MA, Simovich MJ, Bryant-Tomas T, Chyan Y-J, Poeggler B, Dubocovich M, Bick R, Perry G, Cruz-Samchez F, Simith MA: The protective activities of melatonin against the Alzheimer β-protein are not mediated by melatonin membrane receptors. J Pineal Res 2002, 32: 135–142. 10.1034/j.1600-079x.2002.1o838.xView ArticleGoogle Scholar
- Reiter RJ, Tan D-X: Melatonin: a novel protective agent against oxidative injury of the ischemic/reperfused heart. Cardiovasc Res 2003, 58: 10–19. 10.1016/S0008-6363(02)00827-1View ArticleGoogle Scholar
- Vijayalaximi CRT, Reiter RJ, Herman TS: Melatonin: from basic research to cancer treatment clinics. J Clin Oncol 2002, 20: 2575–2601. 10.1200/JCO.2002.11.004View ArticleGoogle Scholar
- Lee B-J, Ryu S-G, Cui J-H: Formulation and release characteristics of hydroxypropyl methylcellulose matrix tablet containing melatonin. Drug Dev Ind Pharm 1999, 25: 493–501. 10.1081/DDC-100102199View ArticleGoogle Scholar
- El-Gibaly I, Meki AMA, Abdel-Ghaffar SK: Novel B melatonin-loaded chitosan microcapsules: in vitro characterization and antiapoptosis efficacy for aflatoxin B1-induced apoptosis in rat liver. Int J Pharm 2003, 260: 5–22. 10.1016/S0378-5173(03)00149-2View ArticleGoogle Scholar
- Kumar A, Agarwal SP, Khanna R: Modified release bi-layered tablet of melatonin using β-cyclodextrin. Pharmazie 2003, 58: 642–644.Google Scholar
- Lee B-J, Parrot KA, Ayres JW, Sack RL: Design and evaluation of an oral controlled release delivery system form melatonin in human subjects. Int J Pharm 1995, 124: 119–127. 10.1016/0378-5173(95)00088-ZView ArticleGoogle Scholar
- Lee B-J, Mim G-H: Oral controlled release of melatonin using polymer-reinforced and coated alginate beads. Int J Pharm 1996, 144: 37–46. 10.1016/S0378-5173(96)04723-0View ArticleGoogle Scholar
- Lee B-J, Parrot KA, Ayres JW, Sack RL: Development and characterization of an oral controlled-release delivery system for melatonin. Drug Dev Ind Pharm 1996, 22: 269–274. 10.3109/03639049609058571View ArticleGoogle Scholar
- Lee B-J, Choe JS, Kim C-K: Preparation and characterization of melatonin-loaded stearyl alcohol microspheres. J Microencapsul 1998, 15: 775–787. 10.3109/02652049809008260View ArticleGoogle Scholar
- El-Gibaly I: Development and in vitro evaluation of novel floating chitosan microcapsules for oral use: comparison with non-floating chitosan microspheres. Int J Pharm 2002, 249: 7–21. 10.1016/S0378-5173(02)00396-4View ArticleGoogle Scholar
- Mao S, Chen J, Wei Z, Liu H, Bi D: Intranasal administration of melatonin starch microspheres. Int J Pharm 2004, 272: 37–43. 10.1016/j.ijpharm.2003.11.028View ArticleGoogle Scholar
- Dubey V, Mishra D, Jain NK: Melatonin loaded ethanolic liposomes: physicochemical characterization and enhanced transdermal delivery. Eur J Pharm Biopharm 2007, 67: 398–405. 10.1016/j.ejpb.2007.03.007View ArticleGoogle Scholar
- Dubey V, Mishra D, Asthana A, Jain NK: Transdermal delivery of a pineal hormone: melatonin via elastic liposomes. Biomaterials 2006, 27: 3491–3496. 10.1016/j.biomaterials.2006.01.060View ArticleGoogle Scholar
- Bénès L, Claustrat B, Horrière F, Geoffriau M, Konsil J, Parrott KA, DeGrande G, McQuinn RL, Ayres JW: Transmucosal, oral controlled-release, and transdermal drug administration in human subjects: a crossover study with melatonin. J Pharm Sci 1997, 86: 1115–1119. 10.1021/js970011zView ArticleGoogle Scholar
- Hafner A, Lovrić J, Voinovich D, Filipović-Grčić J: Melatonin-loaded lecithin/chitosan nanoparticles: physicochemical characterization and permeability through Caco-2 cell monolayers. Int J Pharm 2009, 381: 205–213. 10.1016/j.ijpharm.2009.07.001View ArticleGoogle Scholar
- Kandimalla KK, Kanikkannan N, Singh M: Optimization of a vehicle mixture for the transdermal delivery of melatonin using artificial neural networks and response surface method. J Contr Release 1999, 61: 71–82. 10.1016/S0168-3659(99)00107-8View ArticleGoogle Scholar
- Sahoo SK, Labhasetwar V: Nanotech approaches to drug delivery and imaging. Drug Discov Today 2003, 8: 1112–1120. 10.1016/S1359-6446(03)02903-9View ArticleGoogle Scholar
- Garcia-Garcia E, Andrieux K, Gil S, Couvreur P: Colloidal carriers and blood–brain barrier (BBB) translocation: a way to deliver drugs to the brain? Int J Pharm 2005, 298: 274–292. 10.1016/j.ijpharm.2005.03.031View ArticleGoogle Scholar
- Schaffazick SR, Guterres SS, Lucca-Freitas L, Pohlmann AR: Caracterização e estabilidade físico-química de sistemas poliméricos nanoparticulados para administração de fármacos. Quim Nova 2003, 26: 726–737. 10.1590/S0100-40422003000500017View ArticleGoogle Scholar
- Schaffazick SR, Pohlmann AR, Cordova CAS, Creczyniski-Pasa TB, Guterres SS: Protective properties of melatonin-loaded nanoparticles against lipid peroxidation. Int J Pharm 2005, 289: 209–213. 10.1016/j.ijpharm.2004.11.003View ArticleGoogle Scholar
- Schaffazick SR, Siqueira IR, Badejo AS, Jornada DS, Pohlmann AR, Netto CA, Guterres SS: Incorporation in polymeric nanocapsules improves the antioxidant effect of melatonin against lipid peroxidation in mice brain and liver. Eur J Pharm Biopharm 2008, 69: 64–71. 10.1016/j.ejpb.2007.11.010View ArticleGoogle Scholar
- Molpeceres J, Aberturas MR, Chacón M, Berges L, Guzmán M: Stability of cyclosporine-loaded poly-epsilon-caprolactone nanoparticles. J Microencapsul 1997, 14: 777–787. 10.3109/02652049709006828View ArticleGoogle Scholar
- Guterres SS, Fessi H, Barratt G, Devissaguet J-P, Puisieux P: Poly(dl-lactide) nanocapsules containing diclofenac: I. Formulation and stability study. Int J Pharm 1995, 113: 57–63. 10.1016/0378-5173(94)00177-7View ArticleGoogle Scholar
- Calvo P, Vila-Jato JL, Alonso MJ: Comparative in vitro evaluation of several colloidal systems, nanoparticles, nanocapsules and nanoemulsions, as ocular drug carriers. J Pharm Sci 1996, 85: 530–536. 10.1021/js950474+View ArticleGoogle Scholar
- Abdelwahed W, Degobert G, Fessi H: A pilot study of freeze-drying of poly(ϵ-caprolactone) nanocapsules stabilized by poly(vinyl alcohol): formulation and process optimization. Int J Pharm 2006, 309: 178–188. 10.1016/j.ijpharm.2005.10.003View ArticleGoogle Scholar
- Lacoulonche F, Gamisans F, Chauvet A, García ML, Espina M, Egea MA: Stability and in vitro drug release of flurbiprofen-loaded poly-ϵ-caprolactone nanospheres. Drug Dev Ind Pharm 1999, 25: 983–993. 10.1081/DDC-100102261View ArticleGoogle Scholar
- Schaffazick SR, Pohlmann AR, Guterres SS: Nanocapsules, nanoemulsion and nanodispersion containing melatonin: preparation, characterization and stability evaluation. Pharmazie 2007, 62: 354–360.Google Scholar
- Guterres SS, Beck RCR, Pohlmann AR: Spray-drying technique to prepare innovative nanoparticulate formulations for drug administration: a brief overview. Braz J Phys 2009, 39: 205–209. 10.1590/S0103-97332009000200013View ArticleGoogle Scholar
- Domingues GS, Guterres SS, Beck RCR, Pohlmann AR: Micropartículas nanorrevestidas contendo um fármaco modelo hidrofóbico: preparação em etapa única e caracterização biofarmacêutica. Quim Nova 2008, 31: 1966–1972. 10.1590/S0100-40422008000800009View ArticleGoogle Scholar
- Schaffazick SR, Pohlmann AR, Mezzalira G, Guterres SS: Development of nanocapsule suspensions and nanocapsule spray-dried powders containing melatonin. J Braz Chem Soc 2006, 17: 562–569. 10.1590/S0103-50532006000300020View ArticleGoogle Scholar
- Tewa-Tagne P, Briaçon S, Fessi H: Preparation of redispersible dry nanocapsules by means of spray-drying: Development and characterization. Eur J Pharm Sci 2007, 30: 124–135. 10.1016/j.ejps.2006.10.006View ArticleGoogle Scholar
- Fessi H, Puisieux F, Devissaguet JP, Ammoury N, Benita S: Nanocapsule formation by interfacial polymer deposition following solvent displacement. Int J Pharm 1989, 55: R1-R4. 10.1016/0378-5173(89)90281-0View ArticleGoogle Scholar
- Fontana MC, Coradini K, Guterres SS, Pohlmann AR, Beck RCR: Nanoencapsulation as a way to control the release and to increase the photostability of clobetasol propionate: influence of the nanostructured system. J Biomed Nanotechnol 2009, 5: 254–263. 10.1166/jbn.2009.1030View ArticleGoogle Scholar
- Jager E, Venturini CG, Poletto F, Colomé LM, Pohlmann JPU, Bernardi A, Battastini AMO, Guterres SS, Pohlmann AR: Sustained release from lipid-core nanocapsules by varying the core viscosity and the particle surface area. J Biomed Nanotechnol 2009, 5: 130–140. 10.1166/jbn.2009.1004View ArticleGoogle Scholar
- Beck RCR, Hass SE, Guterres SS, Ré MI, Benvenutti EV, Pohlmann AR: Nanoparticle-coated organic–inorganic microparticles: experimental design and gastrointestinal tolerance evaluation. Quim Nova 2006, 29: 990–996. 10.1590/S0100-40422006000500019View ArticleGoogle Scholar
- Jakubowicz J: Particle analysis and properties of mechanically alloyed Nd16Fe76-xTixB8. Superlattice and Microst 2008, 43: 315–323. 10.1016/j.spmi.2008.01.006View ArticleGoogle Scholar
- Le TT, Saveyn P, Hoa HD, Meeren PV: Determination of head-induced effects on the particle size distribution of casein micelles by dynamic light scattering and nanoparticle tracking analysis. Int Dairy J 2008, 18: 1090–1096. 10.1016/j.idairyj.2008.06.006View ArticleGoogle Scholar
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