Internal Structure and Size Matters of Polyester Nanoparticles

Aug 8, 2012 - Four PCL-drug nanoparticles were prepared: their internal structures and sizes ... introducing different types of PCL or by changing pol...
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Internal Structure and Size Matters of Polyester Nanoparticles Encapsulating a Bioactive Hydrophobic Drug for the Prevention of Drug Crystals in Aqueous Systems Eun Chul Cho* Department of Chemical Engineering, Division of Chemical, Bioengineering, Hanyang University, Seoul 133-791 Korea S Supporting Information *

ABSTRACT: This study presents a way of preventing a highly hydrophobic bioactive drug encapsulated in polycaprolactone (PCL) nanoparticles from forming drug crystals aqueous systems. Thymol trimethoxycinnamate was selected as a hydrophobic bioactive model drug. Four PCL-drug nanoparticles were prepared: their internal structures and sizes were regulated by introducing different types of PCL or by changing polymer compositions during the preparation of the nanoparticles. The formation of drug crystals from the PCL-drug nanoparticles was observed by optical microscopy at two temperatures (25 and 40 °C) and in three aqueous mediums (deionized water or aqueous solutions containing 5 wt % butylene glycol or ethanol). In deionized water, the formation of drug crystals could be prevented if PCL-drug nanoparticles have highly crystalline cores. In aqueous solutions containing butylene glycol or ethanol, both the internal crystalline core and the size of the nanoparticles could be important in preventing the drug crystal formation. The present study provides both scientific and practical information to those who involve the drug delivery system and pharmaceutical sciences where drugs are engineered to increase the therapeutic efficiency through polymeric nanoparticles.

1. INTRODUCTION Due to their outstanding biocompatibility and biodegradability features,1−4 aliphatic polyesters have been extensively used in drug delivery system (DDS),5−7 in tissue engineering,8,9 and as biomedical devices.1,10,11 In DDS, aliphatic polyesters are used in the form of nanoparticles to encapsulate and carry waterinsoluble or hydrophobic drugs. One important issue concerning aliphatic polyester nanoparticles is how to effectively deliver bioactive drugs to target sites by designing the nanoparticles to have enhanced permeation and retention effects and/or disease specificities.12−18 At the same time, it is also important to preserve the therapeutic doses of the drug in the nanoparticles before they reach the target site: in other words, the hydrophobic drugs in the polyester nanoparticles should not be lost from their significant release to aqueous environments during storage and circulation. However, hydrophobic drugs of a moderate solubility in water are usually released too soon from nano-/microparticles due to a burst effect.19−21 Moreover, highly hydrophobic and water-insoluble drugs can be easily precipitated or crystallized right after being released from particles; hence, drug formulations become unstable. Previous studies have suggested several approaches for controlling the release of drugs from polymer nanoparticles. These include the introduction of functional group(s) which can form hydrogen bond(s) with a drug in polymer chains,22 and the use of hyperbranched polymers.23,24 In addition, it was reported that variation in the crystalline structure of polyester microparticles can alter the release behavior of hydrophobic drugs that have moderate solubility in water.25 However, essentially, no study has been published regarding the effects of the internal structures and sizes of the polyester nanoparticles on the formation of crystals of highly hydrophobic drugs in © 2012 American Chemical Society

aqueous systems. In addition, no studies have suggested an approach for effectively preventing the formation of crystals of these drugs in polymer nanoparticles. Figure 1 is a schematic illustrating the outline of the current study. This research concerns the effects of the internal structure and size of polycaprolactone (PCL) nanoparticles containing a highly hydrophobic drug on the formation of drug crystals in aqueous media. Thymol trimethoxycinnamate was selected as a model hydrophobic drug. The drug has excellent depigmenting activity in animals (e.g., skin tissue)26 and when used as a bioactive ingredient for cosmetic products. However, due to its extremely low solubility in water, this drug is mostly used after being solubilized in butylene glycol or in oil compounds. To overcome this limitation and to extend the use of this drug, preliminary studies were conducted to encapsulate the drug in polymer microparticles or nanoparticles. However, the drug was released from these particles and precipitated to form drug crystals in aqueous systems shortly after preparation of the particles. Therefore, following such observations, the impetus of the current research first involved discovery of the factor(s) influencing the formation of the drug crystals and thus the storage stability of the drug in the polyester nanoparticles. The internal crystalline structures and sizes of the nanoparticles were regulated by changing the molecular weight of PCL or by changing the composition of the nanoparticle constituents during the preparation (Table 1). The formation of the drug crystals in these nanoparticles was observed by optical microscopy in various aqueous media: deionized water and Received: Revised: Accepted: Published: 11137

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Figure 1. Schematic depicting the outline of the present study. Thymol trimethoxycinnamate is highly hydrophobic bioactive drug and forms drug crystals in aqueous media. The study prepared polycaprolactone (PCL)−thymol trimethoxycinnamate nanoparticles for the prevention of the drug crystals. To find factor(s) affecting the formation of drug crystals, nanoparticles regulated with their internal structures and sizes were prepared. Abbreviation: PCL-b-PEG, polycaprolactone-b-poly(ethylene glycol) copolymer.

2. EXPERIMENTAL SECTION 2.1. Materials. PCLs with Mn ≈ 10K and 40K were purchased from Aldrich (Yongin, Korea). PCL-block-poly(ethylene glycol) (PCL-b-PEG) was synthesized according to previous research.27 The molecular weights of PEG and PCL in the block copolymer were 5000 and 9000, respectively. Thymol trimethoxycinnamate was obtained from Leadgene Co. Ltd. (Seongnam, Korea). The melting temperature of the drug is 118 °C from the measurement of differential scanning calorimetry (DSC Q20, TA Instruments) with a scanning rate of 10 °C/min. Butylene glycol and ethanol were purchased from Aldrich (Yongin, Korea). Acetone was obtained from Fisher Scientific. 2.2. Preparation of PCL-Drug Nanoparticles. Four types of PCL-thymol trimethoxycinnamate nanoparticles were prepared. Table 1 shows the sample codes and compositions of the PCL-drug nanoparticles. Typically, PCL, PCL-b-PEG, and thymol trimethoxycinnamate were solubilized in 100 mL of acetone. Subsequently, the mixture was transferred into 150 mL of deionized water. During and after the transfer, the mixture was stirred constantly with an agitator (Matsushita Electric Industrial Co. Ltd.). After 5 min, the acetone and a certain amount of water in the mixture were eliminated using a rotary evaporator at 35 °C for 30 min. After this removal, the concentration of the nanoparticles and drug was 10 wt % in deinoized water. In this preparation, nanoparticles of different sizes and internal structures were prepared by changing the molecular weight of PCL and adjusting the ratio of PCL to PCL-b-PEG, and the concentration of the nanoparticle constituents. PCL10K7-PCG3-Drug1 was the nanoparticle prepared with PCL 10K, with a PCL to PCL-b-PEG weight ratio of 7:3 and a polymer (PCL + PCL-b-PEG) to drug weight ratio of 10:1. As for the other nanoparticles, PCL40K7-PCG3-

Table 1. Composition of Polymers, Drug, and Solvents Used for the Preparation of PCL-Drug Nanoparticlesa composition sample PCL10K7PCG3Drug 1 PCL10K7PCG3 PCL40K7PCG3Drug 1 PCL40K7PCG3 PCL10K6PCG4Drug 1 PCL10K6PCG4 PCL10K14PCG6-Drug2 PCL10K14PCG6

PCL 10K, g

PCL 40K, g

PCL-bPEG,b g

drug,c g

acetone, mL

water, mL

1.75

0.75

0.25

100

150

1.75

0.75

0

100

150

1.75

0.75

0.25

100

150

1.75

0.75

0

100

150

1.5

1.00

0.25

100

150

1.5

1.00

0

100

150

3.5

1.5

0.5

100

150

3.5

1.5

0

100

150

a

See the Experimental Section for the details of the preparation procedure. bPCL-b-PEG: a block copolymer having PCL (Mn ∼ 9000) and PEG (Mn ∼ 5000) blocks. cDrug: thymol trimethoxycinnamate.

aqueous solutions containing butylene glycol or ethanol. On the basis of the results, this research further suggested the optimum conditions for nanoparticles in order to prevent crystal formation of highly hydrophobic drugs for a long storage period of time. 11138

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Drug1 nanoparticles were prepared by replacing PCL 10K with PCL 40K; PCL10K6-PCG4-Drug1 nanoparticles were prepared by changing the weight ratio of PCL 10K to PCL-b-PEG; and PCL10K14-PCG6-Drug2 nanoparticles were prepared by increasing the concentrations of polymers and drugs in acetone by 2-fold. For all the nanoparticles, the polymer-to-drug ratio was kept constant (10:1). In addition, nanoparticles without drugs were also prepared to compare the size and microstructure of these nanoparticles with those containing the drug (see also Table 1). To investigate the formation of drug crystals from the PCLdrug nanoparticles in various aqueous systems, ethanol or butylene glycol (5% (w/w)) was added to the nanoparticles dispersed in deionized water. In such cases, prior to addition, the nanoparticle aqueous dispersions were concentrated further by additional evaporation to keep the concentration of the nanoparticles and drug (10 wt %) constant for all of the samples. 2.3. Morphology of PCL-Drug Nanoparticles. The morphology of the PCL-drug nanoparticles was observed by transmission electron microscopy, TEM (Libra 120, Carl Zeiss, and accelerated voltage of 120 kV). The nanoparticles were stained with 1 wt % phosphotungstic acid aqueous solution, and the TEM image was obtained after the nanoparticles were completely dried. 2.4. Size Measurement of PCL-Drug Nanoparticles. The hydrodynamic diameters of the PCL-drug and PCL (without drug) nanoparticles were determined using photocorrelation spectroscopy (PCS; Malvern Instruments 3000HS). The aqueous dispersions of the PCL-drug nanoparticles were diluted to 1 mg/mL. The samples were irradiated with a 633 nm light from a He−Ne laser, and the intensity of 90°-scattered light was measured. For each specimen, 10 autocorrelation functions were analyzed using the scattered intensity. The mean diameters of the nanoparticles were calculated using the Stokes−Einstein equation. The polydispersity index, showing the degree of scatter for the nanoparticle sizes, was obtained using the CONTIN routine. See Table 2 and Figure 2 for the average diameters, the polydispersity index, and the distribution of the nanoparticle sizes.

Figure 2. TEM image for the PCL10K14-PCG6-Drug2 nanoparticles.

an equal volume of deionized water injected into a reference cell. The cells were sealed tightly (25−30 psi) to prevent the evaporation of water during the experiment. After thermal equilibrium was achieved at 5 °C, the aqueous dispersions were scanned from 5 to 80 °C at a scanning rate of 1 °C/min. During the scan, the heat capacity difference between the sample cell and reference cell was plotted as a function of temperature. 2.6. Observation of PCL-Drug Nanoparticle Aqueous Dispersions. Formation of drug crystallites in the nanoparticle aqueous dispersions was observed by optical microscopy. The nanoparticles in the three aqueous systems were stored in plastic bottles for 2 weeks in thermostatic chambers (JISICO, Seoul, Korea) at 25 and 40 °C with relative humidities of 60 and 75%, respectively. Before and after storage, a drop of the PCL-drug nanoparticle dispersions was taken and placed on a glass slide, and the dispersions were observed by optical microscopy (BX 50, Olympus).

3. RESULTS AND DISCUSSION 3.1. Preparation and Characterization of PCL-Drug Nanoparticles. In the current study, a solvent displacement (or precipitation) method was used for the preparation of PCL nanoparticles containing thymol trimethoxycinnamate. This method is the most commonly used for preparing nanoparticles.28,29 Briefly, a water-miscible organic solvent solubilizing a polymer and a hydrophobic drug was mixed with water. At this time, the polymer and the drug were precipitated to form nanoparticles due to their phase separation from the cosolvent. In the current study, acetone was selected as a watermiscible organic solvent because thymol trimethoxycinnamate, PCL, and PCL-b-PEG were very soluble in this solvent. The stability of the PCL nanoparticles in water was ensured by introducing PCL-b-PEG. The hydrophobic PCL in both the homopolymer and block copolymer made up the core of the nanoparticles, and the hydrophilic PEG stabilized the nanoparticles. Therefore, the resulting structure would comprise PCL core-PEG shell nanoparticles.27 Figure 2 shows a TEM image of the PCL10K14-PCG6-Drug2 nanoparticles. The electron densities of the center and the outside of the nanoparticles were different, indicating the typical core−shell structure.

Table 2. Hydrodynamic Diameters of the PCL-Drug and PCL Nanoparticlesa sample

hydrodynamic diameter, nm

polydispersity index

PCL10K7-PCG3-Drug 1 PCL10K7-PCG3 PCL40K7-PCG3-Drug 1 PCL40K7-PCG3 PCL10K6-PCG4-Drug 1 PCL10K6-PCG4 PCL10K14-PCG6-Drug2 PCL10K14-PCG6

151 135 142 123 141 128 184 176

0.151 0.281 0.257 0.285 0.094 0.257 0.115 0.386

a

Sizes are the hydrodynamic diameters measured in deionized water by using a dynamic light scattering.

2.5. Thermal Analysis of Aqueous Dispersions of PCLDrug Nanoparticles. The internal structures of the aqueous dispersions for the PCL-drug and PCL (no drug) nanoparticles were investigated using microcalorimetry (VP-DSC; MicroCal, Northampton, MA, USA). We loaded 0.6 mL of a nanoparticledrug aqueous dispersion (0.015 wt %) into a sample cell, with 11139

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Four types of nanoparticles were prepared in the current study (Table 1). Among these nanoparticles, PCL10K7-PCG3Drug1, PCL40K7-PCG3-Drug1, and PCL10K6-PCG4-Drug1 nanoparticles had similar hydrodynamic sizes (see Figure 3 and

Figure 4. Microcalorimetry thermograms for the (A) PCL-drug nanoparticles and (b) PCL (without drug) nanoparticles.

Figure 3. Hydrodynamic size distributions of the (A) PCL-drug and (B) PCL (without drug) nanoparticles.

Table 3. Peak Temperatures and Enthalpies (ΔH) of the PCL-Drug and PCL Nanoparticlesa

Table 2). In contrast, the size of the PCL10K14-PCG6-Drug2 nanoparticles was larger by approximately 30 nm. The sizes of the PCL-drug nanoparticles were a little larger than the sizes of the nanoparticles without the drug, undoubtedly due to the inclusion of the drug in the nanoparticle cores. Furthermore, the sizes of the nanoparticles were not significantly altered (within 5 nm) even if the nanoparticles were dispersed in aqueous solutions containing 5 wt % ethanol or butylene glycol (data not shown). The optical microscopy studies, performed immediately following preparation, showed that the drug seemed to be wellincorporated into the PCL cores without any precipitation of the drug crystal (see Figure S1 in the Supporting Information). In addition, it was found that the existence of the polymer nanoparticles themselves did not result in any micrometer-scale crystal (see Figure S2 in the Supporting Information). This observation was consistently observed for all of the nanoparticles prepared in the current study. 3.2. Thermal Analysis of the PCL-Drug Nanoparticles. Figure 4A shows the microcalorimetry thermograms for the PCL-drug nanoparticles, and Table 3 summarizes the results. The thermograms differed from sample to sample. The thermogram of PCL10K7-PCG3-Drug1 nanoparticles showed two peaks at 50.1 and 52.3 °C. The thermogram of PCL10K14PCG6-Drug2 nanoparticles had a main peak at 51.1 °C and a shoulder at 53 °C, and the peak intensity was comparable with that for the PCL10K7-PCG3-Drug1 nanoparticles. In contrast, the peak intensities of the PCL40K7-PCG3-Drug1 and PCL10K6-PCG4-Drug1 nanoparticles were significantly lower than the PCL10K7-PCG3-Drug1 nanoparticles. The same trend was also observed in the absence of the drug in the nanoparticles (Figure 4B). The peak intensities of the

peak temperatures, °C sample b

PCL10K7-PCG3-Drug PCL10K7-PCG3c PCL40K7-PCG3-Drugb PCL40K7-PCG3c PCL10K6-PCG4-Drug 1b PCL10K6-PCG4c PCL10K14-PCG6-Drug2c PCL10K14-PCG6b

first

second

ΔH,d cal/gpolymer

50.1 53.3 50.8 52.6 52.3 54.1 51.1 49.5

52.3

0.186 0.196 0.069 0.071 0.065 0.060 0.173 0.180

53.3 54.7

54.7

a

The values were obtained from the analysis of the thermograms in Figure 4. bTwo peaks were observed in the thermograms. cOne peak was observed in the thermograms. dEnthalpies were estimated from the peak areas of the thermograms.

PCL10K7-PCG3 and PCL10K14-PCG6 nanoparticles were much higher than those of the PCL40K7-PCG3 and PCL10K6PCG4 nanoparticles. The results indicate that PCL10K7PCG3-Drug1 and PCL10K14-PCG6-Drug2 nanoparticles had crystalline cores, whereas there were relatively less PCL crystalline domains in the core of the PCL40K7-PCG3-Drug1 and PCL10K6-PCG4-Drug1 nanoparticles. This was also confirmed by comparing the melting enthalpies of the crystalline regions in the nanoparticles (see Table 3). The enthalpies of PCL40K7-PCG3-Drug1 and PCL10K6-PCG4Drug1 nanoparticles were approximately 37 and 35% of the enthalpy of PCL10K7-PCG3-Drug1 nanoparticles, respectively. The enthalpies of the nanoparticles without containing drug showed the same trend. 11140

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Figure 5. Optical microscope images for the PCL10K7-PCG3-Drug1 nanoparticles dispersed in deionized water (A and B), 5 wt % butylene glycol aqueous solution (C and D), and 5 wt % ethanol aqueous solution (E and F). The images were taken after storing the nanoparticle dispersions for 2 weeks at 25 (A, C, E) and 40 °C (B, D, F).

had a much lower degree of crystallization in the core of the nanoparticles than the PCL10K7-PCG3-Drug1 nanoparticles. As for the effect of the polymer ratio of PCL to PCL-b-PEG, a previous study has shown that the increase in the concentration of PCL-b-PEG decreases in the crystalline domain of the nanoparticles,27 thereby resulting in almost no peaks in the thermogram in the current study. On the basis of a report,34 the PCL chains attached to block copolymers were hindered from crystallizing. Since the miscibility of the PCL in the copolymer and the PCL in the homopolymer is good, the PCL chains in the block copolymer could also prevent the crystallization of the PCL homopolymer.34 Consequently, it was thought that the PCL10K6-PCG4-Drug1 nanoparticles had almost amorphous cores. It is also interesting to discuss the miscibility of the drug and the PCL from the microcalorimetry results. Since thymol trimethoxycinnamate is highly hydrophobic, it is expected that the drug molecules will coexist in the core of the PCL nanoparticles; depending on the miscibility of the drug with the PCL, the drug molecules will be either evenly dispersed in the PCL core matrix or be separated from the PCL. From Figure 4 and Table 3, the PCL10K7-PCG3 and PCL10K14-PCG6 nanoparticles had higher intensities, peak temperatures, and melting enthalpies than the corresponding nanoparticles containing the drugs. The results were probably due to the

When comparing the melting enthalpies between the PCL10K7-PCG3-Drug1 (or PCL10K7-PCG3) and PCL10K14-PCG6-Drug2 (PCL10K14-PCG6), the latter nanoparticles had a little lower value by 7−8% than the former nanoparticles. Combining the results with the size data, it was suggested that the PCL10K14-PCG6-Drug2 nanoparticles were larger than PCL10K7-PCG3-Drug1 nanoparticles, while the crystalline domain in the nanoparticles was a little lower than that in the PCL10K7-PCG3-Drug1 nanoparticles. From the microcalorimetry thermograms, it is possible to discuss the effect of the nanoparticle constituents on the internal structure of the nanoparticles. First, the largest difference in the thermograms for the PCL10K7-PCG3Drug1 (or PCL10K7-PCG3) and PCL40K7-PCG3-Drug1 (or PCL40K7-PCG3) nanoparticles would be caused by using PCLs of different molecular weights. Formation of PCL nanoparticles is the crystallization process of PCL from its random conformation in acetone to the nanosized semicrystalline PCL. The amount of PCL crystallites is reported to vary depending on the kinetics of PCL crystallization.25,32,33 The crystallization kinetics of PCL 40K from its melt or polymer solution to PCL crystallites was slower than that of PCL 10K.25,32 Therefore, since the sizes of the two nanoparticles did not differ too much, the PCL40K7-PCG3-Drug1 nanoparticles 11141

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Figure 6. Optical microscope images for the PCL40K7-PCG3-Drug1 nanoparticles dispersed in deionized water (A and B), 5 wt % butylene glycol aqueous solution (C and D), and 5 wt % ethanol aqueous solution (E and F). The images were taken after storing the nanoparticle dispersions for 2 weeks at 25 (A, C, E) and 40 °C (B, D, F).

of the drug, the drug molecules might readily be precipitated to form drug crystals as soon as they were released from the nanoparticles. As such, it was difficult to obtain release profiles in the current systems (see the discussion in the Supporting Information for more details). On the other hand, it was possible to qualitatively evaluate the formation of drug crystals from optical microscope observations of the nanoparticle dispersions. From these data, more importantly, an effective way of preventing the formation of drug crystals in the PCLdrug nanoparticles could be suggested. Since nanoparticles can be stored in aqueous solutions containing ethanol and/or butylene glycol for antibacterial purposes, the formation of drug crystals under these conditions was also observed. Figure 5 shows the optical microscopy images for the PCL10K7-PCG3-Drug1 nanoparticles after 2 weeks in three aqueous media. As previously mentioned, none of the nanoparticle aqueous dispersions resulted in the formation of any drug crystal immediately after the preparation of the nanoparticles (Figure S1). After 2 weeks, the PCL10K7-PCG3Drug1 nanoparticles did not show significant drug crystal formation when dispersed only in deionized water (Figure 5A,B) at both 25 and 40 °C. However, it was found that a few drug crystals appeared in the aqueous solutions containing 5 wt % butylene glycol or ethanol. In addition, drug crystal formation did not seem to depend on temperature.

good miscibility of the PCL and the drug. The miscibility of the PCL and the drug was further confirmed by estimating the solubility parameters (δ) of the PCL and thymol trimethoxycinnamate and their differences. The solubility parameters of the PCL and thymol trimethoxycinnamate were estimated using the equation suggested by Small;30 that is,

δ=

ρ∑G M

(1)

where ρ is the density of the polymer, M is the molecular weight of the repeating unit in the polymer, and G is the group molar attraction constant derived by Small.30 The δ values for the PCL and thymol trimethoxycinnamate were estimated to be 9.79 and 9.92 (cal/cm3)1/2, respectively, and the difference was 0.13 (cal/cm3)1/2. Since the PCL and the drug had a small difference ( PCL10K7PCG3-Drug1 > PCL40K7-PCG3-Drug1 ≈ PCL10K6-PCG4Drug1.

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ASSOCIATED CONTENT

S Supporting Information *

Figures showing optical microscope images for the as-prepared PC-drug and PCL (without drug) nanoparticles and the calibration curve for thymol trimethoxycinnamate and text describing experiments on the drug release test and discussion on the size control issue. This material is available free of charge via the Internet at http://pubs.acs.org.

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4. CONCLUSIONS The results of the current study suggest an approach for preventing the formation of drug crystals of a highly hydrophobic bioactive drug when encapsulated in polyester nanoparticles. The formation of drug crystals of hydrophobic drugs during storage decreases the therapeutic dose of the drug in the nanoparticles and the stability of the product. In this regard, the formation of drug crystals in these nanoparticles is a practically important issue. This study showed that the internal crystalline structures, and, in some conditions, the sizes of the nanoparticles could play roles in preventing the formation of drug crystals. Due to the limited water solubility of the current drug, this study could only show the microscopic phenomenon of the drug being released from the nanoparticles, and thus did not correlate the release behavior of the drug with the formation of drug crystals. In addition, the resolution of the OM is in micrometers; therefore, it is not known how many nanocrystals were present in the nanoparticle dispersion. Therefore, more systematic future studies are necessary by

AUTHOR INFORMATION

Corresponding Author

*Tel.:+82 2 2220 2332. Fax:+82 2 2298 4101. E-mail: enjoe@ hanyang.ac.kr. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work is supported by the Manpower Development Program for Energy (MKE) and the startup grant from Hanyang University (Grant 201100000000226). The author also acknowledges Jong Kun Ahn at Korea Open National University and Amorepacific Corp. for the technical support.

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dx.doi.org/10.1021/ie300573q | Ind. Eng. Chem. Res. 2012, 51, 11137−11146