DSpace at VNU: Enhanced solubility and modified release of poorly water-soluble drugs via self-assembled gelatin–oleic acid nanoparticles

International Journal of Pharmaceutics 455 (2013) 235–240 Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm Pharmaceutical nanotechnology Enhanced solubility and modified release of poorly water-soluble drugs via self-assembled gelatin–oleic acid nanoparticles Phuong Ha-Lien Tran a , Thao Truong-Dinh Tran a , Beom-Jin Lee b,∗ a b International University, Vietnam National University – Ho Chi Minh City, Viet Nam College of Pharmacy, Ajou University, Suwon 443-749, Republic of Korea a r t i c l e i n f o Article history: Received 24 April 2013 Accepted July 2013 Available online 19 July 2013 Keywords: Gelatin–oleic acid conjugate Self-assembled nanoparticles pH-dependent solubility Poorly water-soluble drugs Enhanced solubility Modified release a b s t r a c t Recently, we synthesized novel amphiphilic gelatin–oleic acid (GO) conjugate to prepare self-assembled nanoparticles for drug delivery The aim of this study was to investigate pharmaceutical potentialities of self-assembled GO nanoparticles for solubility enhancement and modified release of poorly watersoluble drugs Three poorly water-soluble model drugs with different pH-dependent solubility (valsartan and aceclofenac, insoluble at pH 1.2; telmisartan, insoluble at pH 6.8) were chosen to investigate the potential contributions of self-assembled GO nanoparticles to solubility enhancement and controlled release The particle size of the drug-loaded nanoparticles was 200–250 nm Zeta potential was calculated, and instrumental analysis such as powder X-ray diffraction (PXRD) and Fourier transform infrared (FT-IR) spectroscopy were used to investigate the physicochemical properties of the drug-loaded nanoparticles Compared to the drug alone, the drug-loaded nanoparticles showed enhanced solubility Furthermore, the release profiles of the model drugs were modified in a controlled manner The current self-assembled GO nanoparticles can provide a versatile potential in drug delivery and tumor targeting © 2013 Elsevier B.V All rights reserved Introduction Nanomaterial has become an interesting subject of research in many fields including environment, electronics, information and communication, and medicine These materials are expected to have a major impact in the medical field because of having the size between the largest biological molecules and the smallest manmade devices The use of nanoparticles as drug delivery systems is gaining popularity because of a number of advantages such as placing nano-objects at the desired position, increasing the bioavailability of drugs, enhancing solubility and controlling the drug release rate Nanoparticles applied as drug delivery devices or systems are submicron-sized particles (3–200 nm) that can be made using a variety of materials including polymers (polymeric nanoparticles, micelles, or dendrimers), lipids (liposomes), viruses (viral nanoparticles), and even organometallic compounds (nanotubes) (Cho et al., 2008) Regarding polymerbased drug carriers, natural polymers such as albumin, chitosan, gelatin, and heparin have been used for the delivery of oligonucleotides, DNA, proteins, and drugs In addition to synthetic polymers such as N-(2-hydroxypropyl) methacrylamide copolymer ∗ Corresponding author at: Bioavailability Control Laboratory, College of Pharmacy, Ajou University, Suwon 443-749, Republic of Korea Tel.: +82 31 219 3442; fax: +82 31 212 3653 E-mail addresses: beomjinlee@gmail.com, bjl@ajou.ac.kr (B.-J Lee) 0378-5173/$ – see front matter © 2013 Elsevier B.V All rights reserved http://dx.doi.org/10.1016/j.ijpharm.2013.07.025 (HPMA), polystyrene-maleic anhydride copolymer, polyethylene glycol (PEG), and poly-l-glutamic acid, biomaterials such as polyglycolic acid (PGA), polycyanoacrylate, poly-d,l-lactide, polylactic acid, or poly(lactide-co-glycolide) have been introduced as nano drug delivery systems (Kayser et al., 2005; Cho et al., 2008) However, recent researches on various self-assembling delivery systems such as polymeric nanoparticles and branched amphiphilic peptides (surfactant-like peptide) capable of forming nanotubes and nanovesicles have promises in substituting conventional nanoparticles for cellular targeting and multifunctional intelligence of drugs (Motornov et al., 2010; Gudlur et al., 2012) Most of all, a multifunctional nanoparticulate system capable of enhancing the solubility of poorly water-soluble drugs, controlling drug release rates and modifying bioavailability would be more preferable in drug delivery and pharmaceutical applications Recently, we originally developed a novel amphiphilic gelatin–oleic acid (GO) conjugate and investigated its potential pharmaceutical applications in drug delivery by forming self-assembled nanoparticles (Tran et al., 2013a,b) In pharmaceutics, biodegradable and biocompatible polymeric nanoparticles have shown great potential as drug carriers Gelatin is a naturally biodegradable macromolecule with well-documented biocompatible properties over other synthetic polymers, making it a suitable material for use as a nanoparticulate carrier (Lai et al., 2006) Furthermore, gelatin is inexpensive and readily available for various chemical modifications, because gelatin has a primary structure containing functional groups and the presence of multifunctional 236 P.H.-L Tran et al / International Journal of Pharmaceutics 455 (2013) 235–240 charged groups and hydrophobic regions in gelatin molecules (Fitch et al., 1969; Li et al., 1998; Bajpai and Choubey, 2006) Oleic acid, a biocompatible and biodegradable fatty acid, is also used as a stability-inducing agent for many nanoparticle systems (Hosokawa et al., 2002; Ledo-Suárez et al., 2006) In this work, oleic acid was selected to conjugate with gelatin by using a very simple method with monoethanolamine (MEA) in water to form a biocompatible, biodegradable, and stable nanoparticle that self-assembles upon dispersion in an aqueous medium This GO nanoparticle was applied as a carrier to investigate solubility and dissolution rate in a controlled-release fashion for three model drugs such as valsartan (VAL) and aceclofenac (AFC), which have low solubility in simulated gastric fluid (pH 1.2) and telmisartan (TEL), which has low solubility in simulated intestinal fluid (pH 6.8) Particle size distribution, zeta potential, powder X-ray diffraction (PXRD), and Fourier transform infrared (FT-IR) spectroscopy were used to characterize the physicochemical properties of the drug-loaded nanoparticles Materials and methods 2.1 Materials Gelatin was purchased from Kanto Chemical Co., Inc (Tokyo, Japan) Oleic acid was purchased from Shinyo Pure Chemicals Co., Ltd (Osaka, Japan) MEA was purchased from Yakuri Pure Chemicals Co., Ltd Telmisartan and Valsartan were purchased from NJMMM Co (Nanjing, China) and Du-Hope Pharmaceutical Corp (Nanjing, China), respectively Aceclofenac was obtained from Dae Woong Pharmaceutical Co Ltd, (Seoul, Korea) The solvents used were high-performance liquid chromatography (HPLC) grade All other chemicals were of analytical grade and were used without further purification 2.2 Methods 2.2.1 Preparation of drug-loaded GO nanoparticles GO conjugates previously synthesized (Tran et al., 2013a) and the drug (AFC, VAL, or TEL) were dispersed in dichloromethane (loading amount of drug was 10%) The solution (300 ␮L) was then emulsified into 10 mL of distilled water and sonicated for 20 to form an oil/water emulsion Dichloromethane was then evaporated under purged nitrogen gas for 15 The large aggregates, if present, were removed by centrifugation at 1000 rpm for at 37 ◦ C Nanoparticles were then harvested and washed times with distilled water by centrifugation at 40,000 rpm for 20 at 37 ◦ C The pellets were resuspended in water, sonicated for 30 s, and lyophilized and freeze-dried at −50 ◦ C for days Drug-loaded nanoparticles were labeled as VAL-GO, AFC-GO, or TEL-GO, corresponding to the drugs encapsulated in the GO nanoparticles 2.2.2 HPLC analysis After gathering the supernatant and washings collected from the nanoparticle preparation, the drug loading content and encapsulation efficiency in the nanoparticles were determined indirectly by HPLC analysis (WatersTM , USA) with a reversed-phase column (150 × 4.6 mm, Luna 5u C18 100 A) and injection volume of 20 ␮L For AFC analysis, the mobile phase was a mixture of 20 mM phosphate buffer and methanol (35:65, v/v); the flow rate was 1.2 mL/min and the detection wavelength was 282 nm For VAL analysis, the mobile phase consisted of 20 mM phosphate buffer (pH 2, adjusted by phosphoric acid) and acetonitrile (45:55, v/v); the flow rate was 1.2 mL/min, and the detection wavelength was 234 nm For TEL analysis, the mobile phase consisted of a 75:25 (% v/v) mixture of methanol and 51.8 mM ammonium acetate; the flow rate was 1.0 mL/min, and the detection wavelength was 296 nm 2.2.3 In vitro drug release Drug-loaded nanoparticles were dispersed in 10 mL of simulated gastric fluid (pH 1.2; for VAL and AFC) and simulated intestinal fluid (pH 6.8; TEL) in screw-capped tubes, and the tubes were placed in an orbital shaker maintained at 37 ◦ C and shaken at 100 rpm The amount of nanoparticles in 10 mL of media was calculated to be equivalent to the drug amount in dosage form tested in 900 mL of media under the conventional apparatus of a dissolution tester (70 mg for AFC, and 80 mg for VAL and TEL) At predetermined time intervals, the tubes were taken out and centrifuged at 40,000 rpm for 20 The supernatant was saved for HPLC analysis to determine the drug release The precipitated pellets were resuspended in 10 mL of fresh buffer and placed back in the shaker 2.2.4 Solubility study The solubilities of the pure drugs and the drugs loaded in the nanoparticles were determined in simulated gastric fluid (pH 1.2) (VAL, AFC) and simulated intestinal fluid (pH 6.8) (TEL) by adding excess amounts of the drugs to snap-cap Eppendorf tubes (Hamburg, F.R.G) containing mL of media The resulting mixture was sufficiently vortexed and then placed in an incubator at 37 ◦ C for days Aliquots were centrifuged at 15,000 rpm for 10 The supernatant layer was carefully collected and diluted with a solvent for the mobile phase in the HPLC analysis, based on preliminary solubility tests The drug concentration was then quantified by HPLC from a standard calibration curve 2.2.5 Particle size measurements and zeta potential The average particle size of the self-assembled nanoparticles was measured using a PAR-III Laser Particle Analyzer System (Otsuka Electronics, Japan) All measurements were performed in triplicate by using a He-Ne laser light source (5 mW) at a 90◦ angle The zeta potential of nanoparticles was calculated using an Electrophoretic Light Scattering Spectrophotometer 8000 (Otsuka Electronics, Japan) at −28.3 V/cm, −0.1 mA, and 28 ◦ C The sample concentration was maintained at mg/mL in distilled water 2.2.6 Morphology of the nanoparticles A solution of the self-assembled nanoparticles (1 mg/mL) was dropped onto a copper grid to observe the morphology with transmission electron microscopy (TEM; LEO 912AB-100, Carl Zeiss, Korea Basic Science Institute-Chuncheon) After drying in a vacuum dryer at room temperature, the grid was examined using the transmission electron microscope 2.2.7 Fourier transform infrared spectroscopy (FT-IR) The spectra of the samples (Gelatin, OA, conjugates, VAL-GO, AFC-GO, and TEL-GO) were recorded using an IR spectrophotometer (BIO-RAD, USA MODEL EXCALIBER Series UMA-500) KBr pellets were prepared by gently mixing mg of the sample with 200 mg of KBr FT-IR (400–4000 cm−1 ) was performed with a resolution of cm−1 2.2.8 Powder X-ray diffraction (PXRD) PXRD patterns of the samples (Gelatin, OA, conjugates, VAL-GO, AFC-GO, and TEL-GO) were analyzed using a D5005 diffractometer (Bruker, Germany) using Cu K␣ radiation at a voltage of 40 kV and a current of 50 mA The powder samples were scanned in 0.02◦ steps from 5◦ to 60◦ (diffraction angle 2Â) at a rate of s per step by using a zero background sample holder P.H.-L Tran et al / International Journal of Pharmaceutics 455 (2013) 235–240 237 Table Loading content, encapsulation efficiency, and solubility of model drugs in self-assembled GO nanoparticles Samples Loading content of drug (wt.%)a Encapsulation efficiency (%) Solubility at 48 h (37 ◦ C)b (pure drug)/drug encapsulated nanoparticles (␮g/mL) at a specific pH VAL-GO AFC-GO TEL-GO 9.23 ± 0.25 9.16 ± 0.62 9.05 ± 0.5 92.3 ± 2.5 91.6 ± 6.2 90.5 ± 5.0 85.1 ± 2.2/931.6 ± 12.4 (at pH 1.2) 11.8 ± 0.6/384.5 ± 20.4 (at pH 1.2) 0.28 ± 0.04/402.2 ± 9.83 (at pH 6.8) a b Initial loading amount of drug is 10% compared to polymer amount Three model drugs have pH-dependent solubility Thus, solubility was measured at the pH having the lowest solubility Results and discussion 3.1 Dissolution rate of GO bearing poorly water-soluble drugs The solubilities of the drugs selected for the present study were pH-dependent While VAL and AFC showed poor solubility in simulated gastric fluid (pH 1.2), TEL showed very low solubility in simulated intestinal fluid (pH 6.8) (Tran et al., 2008, 2009) The percentage of encapsulation efficiency was over 90% for all drugs with the same ratio of the drug and the conjugate (Table 1) The dissolution rates of VAL, AFC, and TEL were significantly enhanced compared to that of the pure drug in the same conditions (Fig 1), especially the dissolution of VAL, which was almost complete at h The percentage of drug release of TEL encapsulated in nanoparticles also increased by approximately 70% compared to that of pure TEL In the case of AFC, the enhancement of drug dissolution and release reached approximately 70% within the first 10 and then gradually decreased, because of precipitation, a natural spring-like property of AFC (Tran et al., 2009) However, the nanoparticulate drug delivery system showed remarkable effects on the enhancement of these poorly water-soluble drugs with pH-dependent solubility in both acidic and basic media in a controlled-release fashion due to its amphiphilic nature 3.2 Mechanism of enhanced drug release from GO nanoparticles Several commonly known and useful techniques enhance the dissolution rate of poorly water-soluble drugs, such as solubilization (Nunez and Yalkowsky, 1998; Ran et al., 2005), beta-cyclodextrin complexation (Loftsson and Brewster, 2000; Chang and Shojaei, 2004), and solid dispersion (Serajuddin, 1999; Leuner and Dressman, 2000); however, these techniques are associated with several disadvantages, such as environmental concerns, low drug-loading properties, large dosing and limited capacity of solubility and low stability In addition to these techniques, nanoparticular drug delivery systems have emerged as a strategy to overcome some of the problems associated with the aforementioned methods (Radtke, 2001; Muller et al., 2001; Liversidge et al., 2003) One common method to prepare drug encapsulated nanoparticles is the solvent evaporation method In this conventional method, controlled precipitation of polymers containing a drug solubilized in one of the phases of an emulsion is followed by the precipitation of the polymer entrapping the drug in the solvent via solvent evaporation, which results in the drug-loaded particles suspended in the residual solvent (Bajpai and Choubey, 2006) Generally, a surfactant must be used to create smaller nanoparticles in this emulsion solvent evaporation system, but the surfactant can be adsorbed by the nanoparticle surface, significantly affecting particle size, biodegradation rate, biodistribution, and the physicochemical properties of the nanoparticles (Jeong et al., 2002; Cheng et al., 2008) Therefore, development of a surfactant-free nanoparticulate system has been widely suggested Fortunately, the amphiphilic GO conjugates possess surfactant-like properties for stabilization, resulting in spontaneously stabilized nanoparticles without a need for surfactants In the present study, the poorly soluble drugs were introduced into the drug delivery systems through encapsulation in nanoparticles This method was based on the structure of the GO nanoparticle, which possesses a hydrophobic moiety in inner core that adapts to the hydrophobic property of these drugs The entrapment of the drug results in the incorporation of the drug into the hydrophobic inner cores of GO, because of hydrophobic interaction (Jeong et al., 1998; Zhang and Zhuo, 2005) Moreover, as shown in Table 1, the solubilities of VAL, AFC, and TEL were significantly enhanced compared to that of the pure drugs in the same condition, which is attributed to the improved drug dissolution rate for these drugs The particle size and zeta potential of the drug-encapsulated nanoparticles, which are shown in Table 2, are additional factors that can help elucidate this mechanism The particle size for each of the drug-encapsulated nanoparticles, measured through DLS, was approximately 220 nm for VAL and AFC, and 250 nm for TEL, which is considered nanoscale and a factor in the enhancement of drug release These results were slightly different from results obtained by TEM, which were attributed to the different conditions of preparation The size determined by TEM is an actual diameter (dry state) of the nanoparticles; whereas, the size measured by the dynamic laser scattering method is a hydrodynamic diameter (hydrated state) of the nanoparticles Therefore, in the hydrated state, the nanoparticles will have a higher hydrodynamic volume because of the solvent effect; thus, the size measured by the laser light scattering method was higher than that measured using the TEM method The encapsulated drug nanoparticles were also able to maintain their mean diameter for at least weeks without aggregation Moreover, the polydispersity index (PDI) indicated the narrow size distribution of the drug-loaded nanoparticles since PDI values were below 0.2 (Landry et al., 2008) The zeta potential of the drug encapsulated nanoparticles was slightly decreased compared to that of the empty nanoparticles corresponding to each specific pH According to Sahoo et al (2002), the localization of other hydrophobic drugs, including tamoxifen or paclitaxel, within the micelle corona might shield the surface charge by shifting the shear plane further from the micelle surface, resulting in a reduced zeta potential (Sahoo et al., 2002) Furthermore, TEM images of the VAL-loaded nanoparticles, AFC-loaded nanoparticles, and TEL-loaded nanoparticles were also obtained (Fig 2) The round shape of each of these drugloaded nanoparticles was maintained The particle sizes of each of the drug-loaded nanoparticles were greater than those of the Table Particle size and zeta potential of various drug-loaded GO nanoparticles Samples Particle size (nm) Polydispersity index (PI) Zeta potential (mV) VAL-GO (pH 1.2) AFC-GO (pH 1.2) TEL-GO (pH 6.8) 215.77 ± 4.67 221.08 ± 5.51 259.45 ± 3.69 0.05 ± 0.02 0.07 ± 0.03 0.09 ± 0.04 5.29 ± 2.30 6.13 ± 0.54 −32.21 ± 1.64 238 P.H.-L Tran et al / International Journal of Pharmaceutics 455 (2013) 235–240 VAL 100 % drug released 80 60 pure drug VAL-GO nanoparticle 40 20 0 20 40 60 80 100 120 time (min) 80 AFC % drug released 60 40 pure AFC AFC-GO nanoparticle 20 0 20 40 60 80 100 120 time (min) 80 TEL % drug released 60 40 pure TEL TEL-GO nanoparticle 20 Fig TEM images of drug-loaded GO nanoparticles VAL (top); AFC (middle); TEL (bottom) 0 10 20 30 40 50 60 time (hour) Fig Release profiles of drug-loaded GO nanoparticles in different pH having the lowest solubility VAL at pH 1.2 (top); AFC at pH 1.2 (middle); TEL at pH 6.8 (bottom) P.H.-L Tran et al / International Journal of Pharmaceutics 455 (2013) 235–240 239 TEL-GO AFC-GO pure AFC pure TEL VAL-GO pure VAL pure TEL AFC-GO pure AFC VAL-GO pure VAL TEL-GO GO 4000 10 20 30 40 50 60 3000 2000 1000 -1 wavelength (cm ) theta Fig PXRD patterns of pure drugs (VAL, AFC, and TEL), nanoparticles without drug (GO), and nanoparticles encapsulating drugs (GO-VAL, GO-AFC, and GO-TEL) non-drug-loaded nanoparticles This indicates the effect of drug loading into the nanoparticles, because compared to the drug-free micelles, the hydrophobic drug entrapped inside the hydrophobic core leads to an increase in particle size (You et al., 2008) The physicochemical properties of the encapsulated drugs were investigated by PXRD and FT-IR In PXRD analysis, a diffraction pattern of numerous peaks for the pure drug indicates a highly crystalline nature of the drug A lack of distinctive drug peaks or a large reduction in the characteristic peaks indicates an amorphous state of the drug (Tran et al., 2008) In this study, the PXRD results revealed that the drug structures changed to an amorphous state (Fig 3) This was apparent because many characteristic peaks showed the highly crystalline nature of the pure drugs, whereas no peaks appeared on the diffractograms for the drugs encapsulated in the nanoparticle Furthermore, FT-IR showed no interaction between each drug and GO (Fig 4), as demonstrated by the presence of peaks for pure drugs only Therefore, the drugs were encapsulated in the nanoparticles Accordingly, the enhanced drug release can be attributed to the molecular dispersion in a nano-size of the drug delivery system and the change in drug structure from Fig FT-IR spectra of pure drugs (VAL, AFC, and TEL) and nanoparticles encapsulating drugs (GO-VAL, GO-AFC, and GO-TEL) crystalline to amorphous, which has been widely discussed in literature (Chen et al., 2006; Torchilin, 2006; Dhumal et al., 2008) Conclusions GO conjugates appear to be good candidates for drug loading because their hydrophobic cores are suitable for encapsulating many hydrophobic drugs Moreover, GO conjugates are effective for delivery of different poorly water-soluble drugs with differing pH-solubility profiles, 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poorly water-soluble drugs, such as solubilization... self-assembled nanoparticles The entrapment of these poorly water-soluble drugs in GO nanoparticles enhanced their dissolution rates in both acidic and basic conditions with controlled drug release. .. PXRD patterns of pure drugs (VAL, AFC, and TEL), nanoparticles without drug (GO), and nanoparticles encapsulating drugs (GO-VAL, GO-AFC, and GO-TEL) non-drug-loaded nanoparticles This indicates