A novel nanoparticulate system for sustained delivery of acid-labile lansoprazole

Colloids and Surfaces B: Biointerfaces 111 (2013) 453–459

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Colloids and Surfaces B: Biointerfaces journal homepage: www.elsevier.com/locate/colsurfb

A novel nanoparticulate system for sustained delivery of acid-labile lansoprazole Milind Sadashiv Alai, Wen Jen Lin ∗ Graduate Institute of Pharmaceutical Sciences, School of Pharmacy, National Taiwan University, Taipei 100, Taiwan

a r t i c l e

i n f o

Article history: Received 3 April 2013 Received in revised form 18 June 2013 Accepted 19 June 2013 Available online 26 June 2013 Keywords: Lansoprazole Acid-labile drug Eudragit RS100 Nanoparticles Sustained release

a b s t r a c t In the present study, an effort was made to develop the Eudragit RS100 based nanoparticulate system for sustained delivery of an acid-labile drug, lansoprazole (LPZ). LPZ-loaded Eudragit RS100 nanoparticles (ERSNPs) were prepared by oil-in-water emulsion-solvent evaporation method. The effects of various formulation variables such as polymer concentration, drug amount and solvent composition on physicochemical performance of nanoparticles and in vitro drug release were investigated. All nanoparticles were spherical with particle size 198.9 ± 8.6–376.9 ± 5.6 nm and zeta potential +35.1 ± 1.7 to +40.2 ± 0.8 mV. The yield of nanoparticles was unaffected by change of these three variables. However, the drug loading and encapsulation efficiency were affected by polymer concentration and drug amount. On the other hand, the particle size of nanoparticles was significantly affected by polymer concentration and internal phase composition due to influence of droplet size during emulsification process. All nanoparticles prolonged drug release for 24 h which was dominated by a combination of drug diffusion and polymer chain relaxation. The fastest and the slowest release rates were observed in C2-1002-10/0 and C8-400110/0, respectively, based on the release rate constant (k). Thus, the developed nanoparticles possessed a potential as a nano-carrier to sustain drug delivery for treatment of acid related disorders. © 2013 Elsevier B.V. All rights reserved.

1. Introduction Lansoprazole (LPZ) is a widely used proton pump inhibitor for the treatment of acid related disorders such as gastric and duodenal ulcerative diseases as well as the eradication of Helicobacter pylori [1,2]. The biological half-life of LPZ is 1.5–2 h and it induces gastrointestinal side effects such as diarrhea [3]. LPZ is absorbed from gastrointestinal tract and turns into sulfonamide derivative inside the gastric parietal cells followed by irreversibly binds to cystein residues of the proton pump (H+ /K+ ATPase) to induce its pharmacological effect [1,4]. It is a poorly water-soluble and an acid labile drug [1]. Therefore, it is necessary to protect LPZ from degradation in gastric acid when orally administered. The commercial available solid dosage forms for LPZ include enteric coated granules, tablets and capsules. It has been reported that the LPZ multiparticulates have better absorption than an enteric coated tablet [5]. Recently, the enteric multiparticulates filled capsules [6] and fast disintegrating tablets [7] have been developed. However, the LPZ enteric delayed release dosage form was unable to suppress nocturnal acid secretion in case of acid related disorders [8]. Several

∗ Corresponding author at: F 12 No. 1 Jen Ai Rd. Sec. 1, Graduate Institute of Pharmaceutical Sciences, School of Pharmacy, National Taiwan University, Taipei 100, Taiwan. Tel.: +886 2 23123456x88396; fax: +886 2 23916126. E-mail address: [email protected] (W.J. Lin). 0927-7765/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.colsurfb.2013.06.035

strategies have been attempted to resolve nocturnal acid secretion, but no successful remedies has been achieved yet [9]. Currently, nanostructure-mediated drug delivery system such as polymeric nanoparticles is one of the approaches to achieve a prolonged drug release which is an attractive alternative in the treatment of chronic diseases [10–12]. The polymeric nanoparticles offer many advantages over conventional dosage forms including protection of drugs from enzymatic and gastric degradation in the gastrointestinal tract, site specific property, improved efficacy, reduced toxicity and intersubject variability [13–15]. Thus, the development of nanoparticulate dosage form with controlled release character for LPZ could be useful for treatment of acid reflux related disorders especially to control nocturnal acid secretion. The objective of the present study was to formulate and optimize the nanoparticulate delivery system for LPZ by using Eudragit RS100. Eudragit RS100 is a non-biodegradable polycationic acrylic polymer. It is widely used to control drug delivery such as anti-inflammatory drugs and DNA, etc. [16,17]. The emulsionsolvent evaporation method was applied to prepare LPZ-loaded Eudragit RS100 nanoparticles (ERSNPs). The effects of formulation variables such as polymer concentration, drug amount and solvent composition on yield, particle size, encapsulation efficiency and drug loading were investigated. The influence of nanoparticle characteristics on in vitro drug release was further elucidated.

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Table 1 The component of ERSNPs formulations. Formulationa

Polymer conc. (%w/v)

Drug amount (mg)

Polymer/drug ratio (w/w)

C2-1001-10/0 C4-2001-10/0 C8-4001-10/0 C2-1002-10/0 C2-1005-10/0 C2-1001-8/2 C2-1002-8/2 C2-1005-8/2 C2-1001-5/5 C2-1002-5/5 C2-1005-5/5

2 4 8 2 2 2 2 2 2 2 2

20 20 20 40 100 20 40 100 20 40 100

10/1 20/1 40/1 10/2 10/5 10/1 10/2 10/5 10/1 10/2 10/5

a

Dichloromethane/methanol ratio (v/v) 10/0 10/0 10/0 10/0 10/0 8/2 8/2 8/2 5/5 5/5 5/5

The symbol represents (polymer concentration %w/v)-(polymer/drug w/w ratio)-(dichloromethane/methanol v/v ratio).

2. Materials and methods 2.1. Materials LPZ was kindly provided by Syn-Tech Chem and Pharm. Co. Ltd. (Tainan, Taiwan). Eudragit RS100 was purchased from Evonik Degussa GmbH (Essen, Germany). Polyvinyl alcohol (PVA, MW 22,000 Da, 88% hydrolyzed) was from Acros Organics, Fisher Scientific Co. Inc. (Leicestershire, United Kingdom). Glucose, sodium carbonate (Na2 CO3 ), sodium bicarbonate (NaHCO3 ) and sodium hydroxide (NaOH) were from Wako Pure Chemical Industries Ltd. (Osaka, Japan). Methanol and acetonitrile of HPLC grade were from Merk Millipore (Darmstadt, Germany). 2.2. Preparation of Eudragit nanoparticles (ERSNPs) Eleven batches of ERSNPs were prepared by oil-in-water (o/w) emulsion-solvent evaporation method based on various polymer concentrations (2, 4 and 8%w/v), drug amounts (20, 40 and 100 mg) and solvent composition of internal phase (10/0, 8/2

and 5/5 (v/v) of dichloromethane/methanol) as shown in Table 1. Briefly, Eudragit RS100 and LPZ were previously dissolved in 10 mL dichloromethane/methanol (D/M) mixture which was subsequently added into 100 mL aqueous PVA solution (0.25%w/v, pH 9.0) with a glass dropper at a distance of ∼5 cm above the surface of external aqueous phase drop by drop under sonication at 4 ◦ C for 20 min. The emulsion was magnetically stirred at room temperature for 3 h, and the residual solvent was further removed using a rotarvapor at 35 ◦ C for 5 min. The nanoparticles were collected after centrifugation at 17,000 rpm for 30 min at 4 ◦ C (Avanti J26 XP centrifuge, Beckman Coulter, Miami, USA). The nanoparticles were washed with deionized (DI) water three times followed by re-suspended in 5%w/v glucose aqueous solution. Finally, the nanoparticles were freeze dried at −45 ◦ C using a freeze dryer (EZDRY, FTS Systems Inc., NY, USA). 2.3. Viscosity measurement The viscosity of polymer-drug solution in dichloromethane/methanol mixture was measured at 4 ◦ C using an

Fig. 1. (A) TEM images (30 K X) and (B) particle size distribution of ERSNPs prepared in 2, 4 and 8%w/v polymer concentrations. The symbol represents (polymer concentration %w/v)-(polymer/drug w/w ratio)-(dichloromethane/methanol v/v ratio).

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(A)

v/v) and 0.1%v/v triethylamine (pH 7) at a flow rate of 1 mL/min. The HPLC analytical method was validated prior to sample analysis. It was linear over a concentration range of 5–200 ␮g/mL and the coefficients of determination (R2 ) were ≥0.9999. The accuracy was 99.22–100.91%, and the precision was 0.99–7.32%. The drug loading (DL) and encapsulation efficiency (EE) were calculated by Eqs. (3) and (4).

Yield (%)

NS

Yield (%)

500

*

100

80

400

60

300

40

200

20

100

Particle size ( m)

Particle size ( m)

Yield (%) =

total amount of nanoparticles recovered total amount of drug and polymer added initially × 100%

2

4

8

Polymer concentraon (%w/v)

DL(%) =

determined amount of drug in nanoparticles × 100% (3) total amount of nanoparticles

EE(%) =

determined amount of drug in nanoparticles total amount of drug used for nanoparticles preparation × 100%

Drug loading (%)

Drug loading (%)

8

80

*

6

60

4

40

2

20

0

0 2

4

Fig. 2. Effect of polymer concentration on (A) yield (%) as well as particle size (nm) and (B) drug loading (%) as well as encapsulation efficiency (%) of ERSNPs prepared at 20 mg drug amount in dichloromethane/methanol 10/0 (v/v) ratio. The values represent mean ± SD (n = 3). *Indicates p < 0.05 and ‘NS’ indicates p > 0.05.

Ostwald glass capillary viscometer (Cannon Instrument Company, Pennsylvania, USA). The viscosity was calculated using Eq. (1). Where ps is the viscosity of polymer-drug solution, w is the viscosity of water, tps is the flow time of polymer-drug solution, tw is the flow time of water, ps is the density of polymer-drug solution and w is the density of water. w × tps × ps tw × w

2.5. Fourier transform infrared spectroscopy (FT-IR) The pure LPZ, Eudragit RS100, physical mixture of LPZ and Eudragit RS100 (1/10 w/w), and ERSNPs (C2-1001-10/0) were analyzed by FT-IR spectrophotometer (410, Jasco International Co. Ltd., Tokyo, Japan). Briefly, the sample (3 mg) and potassium bromide (150 mg) were mixed well followed by compressed into a disk at 3000 psi for 45 s using a hydraulic press (12 ton E-Z PressTM , International Crystal Laboratory Co. Ltd., Garfield, USA). 100 scans were carried out in wavenumber 400–4000 cm−1 at a resolution of 4 cm−1 . 2.6. Thermal analysis

8

Polymer concentraon (%w/v)

ps =

(4)

100

*

Encapsulation efficiency (%)

Encapsulation efficiency (%)

10

(2)

0

0

(B)

455

(1)

2.4. Characterization of Eudragit nanoparticles The mean particle size and zeta potential of nanoparticles were measured by Zetasizer (Nano ZS, Malvern Co. Ltd., Worcestershire, UK). The morphology of nanoparticles was observed by using transmission electron microscope (TEM, H7100, Hitachi High-technologies Corporation, Tokyo, Japan). The freeze dried nanoparticles were dispersed in deionized water and placed on the carbon-coated copper grids for TEM. The yield of nanoparticles was calculated using Eq. (2). The amount of drug encapsulated in the nanoparticles was determined by dissolving 5 mg of nanoparticles in 10 mL methanol and analyzed by HPLC (Jasco International Company Ltd., Tokyo, Japan) at 285 nm. A reversed phase silica column (C-18, 4.6 mm × 250 mm, 5 ␮m, Phenomenex Inc., USA) was used. The mobile phase was comprised by water and acetonitrile (50:50,

Thermal analysis of LPZ, Eudragit RS100, physical mixture of LPZ and Eudragit RS100 (1/10w/w), and ERSNPs (C2-1001-10/0) was performed using differential scanning calorimetry (Diamond DSC, Perkin Elmer, Massachusetts, USA). Samples (5 mg) were weighed and sealed into aluminum pans. Each sample was conducted over the range of 25–220 ◦ C at a heating rate of 10 ◦ C/min. 2.7. In vitro drug release Nanoparticles equivalent to 1 mg LPZ were suspended in 5 mL pH 9.68 carbonate buffer solution in a dialysis bag (MWCO 6000–8000 Da) which was immersed in 100 mL of the same release medium and maintained at 37 ± 0.5 ◦ C in a shaker bath with a speed of 75 rpm. Samples (1 mL) were collected at time intervals of 0.5, 1, 2, 4, 6, 8, 12 and 24 h, and the same volume of fresh release medium was replaced. The concentration of LPZ in each sample was determined by HPLC at 285 nm. The LPZ release profiles was analyzed by Korsmeyer–Peppas release model using Eq. (5), where k is the release rate constant, Mt /M∞ is the percentage of drug released, t is the release time and n is the release exponent to indicate the drug release mechanism [18,19]. In this model, n = 0.43 indicates a diffusion-dominated drug release; 0.43 < n < 0.85 indicates the anomalous transport or non-Fickian diffusion where the drug release associates a combination of drug diffusion and polymer chain relaxation when the release medium diffuses into polymer matrix; n  0.85 indicates a supercase-II transport where the drug release is dominated by polymer relaxation. Mt = kt n M∞

(5)

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Fig. 3. Effect of drug amount (20, 40, 100 mg) and dichloromethane/methanol compositions (10/0, 8/2, 5/5 v/v) on (A) yield (%), (B) particle size (nm), (C) drug loading (%) and (D) encapsulation efficiency (%) of ERSNPs. All formulations were prepared in 2%w/v polymer concentration. The values represent mean ± SD (n = 3). *Indicates p < 0.05 and ‘NS’ indicates p > 0.05.

In addition, the difference factor (f1 ) and the similarity factor (f2 ) were used to compare the release profiles of ERSNPs. They were computed by Eqs. (6) and (7), where n is the number of time points, Rt and Tt are the mean percent of drug released at each time point from the reference and test release profiles, respectively. Generally, the f2 value in the range of 50–100 and the f1 value in the range of 0–15 ensure the similarity between two comparative release profiles [4,20].

 n f1 =



t=1

|Rt − Tt |

n

f2 = 50 × log

× 100

R t=1 t

⎧

⎨ ⎩

1+

n 1

n

t=1

(6)

−0.5 (Rt − Tt )2

⎫ ⎬

× 100

⎭

(7)

3. Results and discussion 3.1. Characterization of Eudragit nanoparticles The emulsion-solvent evaporation method was employed for encapsulation of LPZ in Eudragit® RS100 nanoparticles. The aqueous PVA solution (pH 9.0) was used as an external phase to avoid LPZ degradation during encapsulation process. A number of formulation parameters such as polymer concentration, drug amount and solvent composition of internal phase were modified to achieve nanoparticles with acceptable drug loading and particle size ∼200 nm. The prepared ERSNPs had spherical morphology (Fig. 1). The particle size of nanoparticles was ranged from 198.9 ± 8.6 nm to 376.9 ± 5.6 nm with polydispersity indexes 0.085 ± 0.01–0.263 ± 0.02. All nanoparticles exhibited positive zeta potential in the range of +35.1 ± 1.7 to +40.2 ± 0.8 mV. The effects of formulation parameters on the characteristics of nanoparticles and in vitro drug release were investigated as follows.

2.8. Statistical analysis The Student t-test was conducted for statistical analysis. Data were expressed as mean ± standard deviation. A p value less than 0.05 was assumed for the statistically significant difference.

3.1.1. Polymer concentration effect Increase in polymer concentration from 2%w/v to 8%w/v did not affect the yield of ERSNPs while the particle size was increased (Fig. 2A). The drug loading of nanoparticles was significantly decreased from 4.79 ± 0.15% to 2.36 ± 0.19% while the

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encapsulation efficiency of nanoparticles was prominently increased from 54.58 ± 1.83% to 70.12 ± 6.29% as increase of polymer concentrations (Fig. 2B). The viscosity of internal phase containing 2, 4 and 8%w/v polymer concentration was measured to be 0.86, 2.04 and 4.10 mPa, respectively. Increase in internal phase viscosity as increase of polymer concentration decreased the net shear stress during emulsification and the larger droplet was formed [21,22]. On the other hand, high viscosity at high polymer concentration decreased drug diffusion into external aqueous phase which resulted in higher encapsulation efficiency as shown in Fig. 2B [23,24]. 3.1.2. Drug amount effect Increase in drug amount from 20 mg to 100 mg did not affect the yield and particle size of ERSNPs (p > 0.05) (Fig. 3A and B). However, the drug loading and the encapsulation efficiency were enhanced proportionally to the amount of drug added initially in three different dichloromethane/methanol volume ratios (p < 0.05) (Fig. 3C and D). The limited solubility of LPZ in the external aqueous phase hindered drug loss during encapsulation process which resulted in increase in drug loading and encapsulation efficiency as increase in drug amount in the formulation [16]. 3.1.3. Solvent composition effect The solvent composition of internal phase did not significantly affect yield, drug loading and encapsulation efficiency of ERSNPs (p < 0.05) (Fig. 3A, C and D). However, it did affect the particle size of ERSNPs which was prominently decreased with increase in volume ratio of methanol in the internal phase from 10/0 to 5/5 (Fig. 3B). The similar result has been reported by changing the volume ratio of polar/non-polar solvent (e.g., acetone/dichloromethane and ethanol/ethyl acetate) to prepare celecoxib-loaded PLGA nanoparticles and poly(ε-caprolactone) nanospheres [25,26]. The polar organic solvent (e.g., methanol) had high affinity toward water to facilitate its diffusion into external aqueous phase which decreased the interfacial tension of the droplet and reduced the droplet size. On the other hand, the presence of more non-polar solvent (e.g., dichloromethane) increased the restoring stress and the interfacial tension of the droplets which resulted in larger droplet size. Thus, the decrease of nanoparticle size by change of dichloromethane/methanol volume ratio from 10/0 to 5/5 was due to decrease of interfacial tension to facilitate methanol diffusion into external aqueous phase.

Fig. 4. (A) FT-IR spectra and (B) DSC thermograms of Eudragit RS100, LPZ, physical mixture of LPZ and Eudragit RS100 (1/10 w/w) and ERSNPs (C2-1001-10/0).

120

100

Fig. 4A shows the FT-IR spectra of LPZ, Eudragit RS100, physical mixture of LPZ and Eudragit RS100 (1/10 w/w) and ERSNPs (C21001-10/0). The characteristic peaks of LPZ appeared at 3232.11, 1578.45, 1273.75 and 1118.58 cm−1 denoted NH, C C of aromatic ring, C N on the pyridyl ring and the ether bond, respectively. The FT-IR spectrum of Eudragit RS100 showed a strong C O vibration at 1731.76 cm−1 . All of these indicating bands were observed in both ERSNPs and physical mixture of LPZ and Eudragit RS100 without changing their positions. These results indicated no specific interaction between LPZ and Eudragit RS100.

Cumulative drug release (%)

3.2. FT-IR analysis

80

60 C2-1005-10/0 C2-1005-8/2 C2-1005-5/5 C2-1002-10/0 C2-1002-8/2 C2-1002-5/5 C2-1001-10/0 C2-1001-8/2 C2-1001-5/5 C4-2001-10/0 C8-4001-10/0

40

20

3.3. DSC analysis Fig. 4B shows the DSC thermograms of LPZ, Eudragit RS100, their physical mixture (1/10 w/w) and ERSNPs (C2-1001-10/0). Both LPZ and physical mixture exhibited a single endothermic peak at ∼177 ◦ C corresponding to the melting temperature of the drug followed by a sharp exothermic decomposition peak at 183.1 ◦ C. However, these peaks were not appeared in the DSC thermogram

0 0

4

8

12

16

20

24

Time (h) Fig. 5. In vitro release of LPZ from ERSNPs in pH 9.68 carbonate buffer solutions at 37 ± 0.5 ◦ C. The values represent mean ± SD (n = 3).

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500

40

400

30

300

20

200

10

100 0

0

Particle size (nm)

50

50

Release rate constant (k) 30 Drug loading (%)

40

25 20

30

15 20

10

10

5

0

0

Drug loading (%)

(B) Release rate constant (k) Particle size (nm)

Release rate constant (%h-n)

Release rate constant (%h-n)

(A)

C8-4001-10/0 C4-2001-10/0 C2-1001-10/0 C2-1001-8/2 C2-1001-5/5 C2-1002-10/0 C2-1002-8/2 C2-1002-5/5 C2-1005-10/0 C2-1005-8/2 C2-1005-5/5

C8-4001-10/0 C4-2001-10/0 C2-1001-10/0 C2-1001-8/2 C2-1001-5/5 C2-1002-10/0 C2-1002-8/2 C2-1002-5/5 C2-1005-10/0 C2-1005-8/2 C2-1005-5/5

Fig. 6. Correlations of LPZ release rate constant (k) and (A) particle size and (B) drug loading. The values represent mean ± SD (n = 3).

of ERSNPs. It seemed that the LPZ was encapsulated in Eudragit RS100 nanoparticles as an amorphous form. 3.4. In vitro drug release Fig. 5 illustrates in vitro LPZ release from Eudragit nanoparticles in pH 9.68 carbonate buffer solution. All nanoparticles revealed slow drug release up to 24 h. The fastest and the slowest release rates were observed in C2-1002-10/0 and C8-4001-10/0, respectively, based on the release rate constant (k). Eudragit RS100 is widely used as a water-insoluble carrier to control drug release [13,19]. The drug release from polymeric nanoparticles could be dominated by diffusion, polymer swelling or polymer erosion. To further elucidate the release mechanism involved in LPZ loaded Eudragit nanoparticles, the in vitro drug release data were analyzed by Korsmeyer-Peppas release model [18]. All nanoparticles had n values in the range of 0.44 ± 0.01–0.65 ± 0.02 with correlation coefficients 0.8640 ± 0.011–0.9725 ± 0.015. These results indicated that the release of LPZ from Eudragit nanoparticles was governed by a combination of drug diffusion and polymer chain relaxation during polymer swelling [27]. The difference factor (f1 ) and similarity factor (f2 ) were further applied to compare the drug release profiles [4,20]. The differences in release profiles in terms of f1 > 15 and f2 < 50 were observed between C2-1001-10/0 and C4-2001-10/0, C2-1001-10/0 and C8-4001-10/0, as well as C2-1001-8/2 and C2-1005-8/2. In other words, the nanoparticles prepared in various polymer concentrations (e.g., 2, 4 and 8%w/v) or polymer/drug ratios (e.g., 10/1 and 10/5 w/w) showed a significant impact on drug release. The reason accounted for this result was discussed further based on the drug loading and the particle size of nanoparticles. The drug release rate constant (k) derived from Korsmeyer–Peppas equation was selected as the target release character being evaluated. Fig. 6A illustrates the relationship between particle size and drug release rate constant (k). There was no significant difference in the drug release rate among nanoparticles with particle size <∼235 nm while it was prominently decreased as increase in particle size from ∼235 nm to ∼375 nm (e.g., C2-1001-10/0, C4-2001-10/0 and C84001-10/0). In other words, the quite different release performance of nanoparticles prepared in various Eudragit RS100 concentrations could be due to particle size dominated. Increase in polymer concentrations from 2%w/v to 8%w/v produced nanoparticles with larger particle size which decreased the surface area exposed to the release media and further decreased drug release rate [28]. Fig. 6B illustrates the relationship between drug loading and LPZ release rate constant (k), and there was a positive correlation of all nanoparticles. Increase in drug loading from 2.36 ± 2.13% to 24.45 ± 1.04%

increased drug release rate constant (k) from 12.35 ± 0.31%h−n to 33.41 ± 1.71%h−n . Since the increase in drug loading enhanced the driving force for drug diffusion which accelerated drug release rate [29]. 4. Conclusion A series of LPZ-loaded Eudragit RS100 nanoparticles were prepared by emulsion-solvent evaporation method based on three formulation parameters (e.g., polymer concentration, drug amount, and solvent composition). All nanoparticles had particle size in the range of 198.9 ± 8.6–376.9 ± 5.6 nm with positive zeta potential (+35.1 ± 1.7 to +40.2 ± 0.8 mV). Increase in polymer concentration increased particle size and drug encapsulation efficiency but decreased drug loading in nanoparticles. Increase in drug amount did not affect the particle size of nanoparticles while enhanced the drug loading and the encapsulation efficiency. Furthermore, the change of solvent composition only affected the particle size of nanoparticles. The Eudragit nanoparticles extended LPZ release over 24 h which was dominated by a combination of drug diffusion and polymer chain relaxation during polymer swelling. The characteristics of nanoparticles in terms of particle size and drug loading made a definitely important impact on LPZ release rate. Acknowledgements This work was supported by National Science Council in Taiwan. The authors appreciated Professor Fu Hsiung Chang from the Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan, for kindly lending us the Zetasizer. References [1] M.N. Singh, H.K.S. Yadav, M. Ram, H.G. Shivakumar, Freeze dried chitosan/poly(glutamic acid) microparticles for intestinal delivery of lansoprazole, Curr. Drug Deliv. 9 (2012) 95–104. [2] H. Satoh, Discovery of lansoprazole and its unique pharmacological properties independent from anti-secretory activity, Curr. Pharm. Design 19 (2013) 67–75. [3] S. Shimura, N. Hamamoto, N. Yoshino, Y. Kushiyama, H. Fujishiro, Y. Komazawa, K. Furuta, S. Ishihara, K. Adachi, Y. Kinoshita, Diarrhea caused by proton pump inhibitor administration: comparisons among lansoprazole, rabeprazole, and omeprazole, Curr. Ther. Res. Clin. E 73 (2012) 112–120. [4] M. Alai, W.J. Lin, A novel once daily microparticulate dosage form comprising lansoprazole to prevent nocturnal acid breakthrough in the case of gastro-esophageal reflux disease: preparation, pharmacokinetic and pharmacodynamic evaluation, J. Microencapsul. 1 (2013) 11, http://dx.doi.org/10.3109/02652048.2012.758180. [5] S. Missaghi, C. Young, K. Fegely, A.R. Rajabi-Siahboomi, Delayed release film coating applications on oral solid dosage forms of proton pump inhibitors: case studies, Drug Dev. Ind. Pharm. 36 (2010) 180–189.

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