Evaluation of water uptake and mechanical properties of blended polymer films for preparing gas‐generated multiple‐unit floating drug delivery systems

RESEARCH ARTICLE Evaluation of Water Uptake and Mechanical Properties of Blended Polymer Films for Preparing Gas-Generated Multiple-Unit Floating Drug Delivery Systems YING-CHEN CHEN,1 LIN-WEN LEE,2,3 HSIU-O HO,1 CHEN SHA,1 MING-THAU SHEU1,4 1

School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

2

Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

3

Research Center for Biomedical Devices and Prototyping Production, Taipei Medical University, Taipei, Taiwan

4

Clinical Research Center and Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei, Taiwan

Received 19 December 2011; revised 25 June 2012; accepted 6 July 2012 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.23279 ABSTRACT: Among various strategies of gastroretentive drug delivery systems (DDSs) developed to prolong the gastric residence time and to increase the overall bioavailability, effervescent multiple-unit floating DDSs (muFDDSs) were studied here. These systems consist of drug (losartan)- and effervescent (sodium bicarbonate)-containing pellets coated with a blended polymeric membrane, which was a mixture of gastrointestinal tract (GIT)-soluble and GITinsoluble polymers. The addition of GIT-soluble polymers, such as hydroxypropyl methylcelluR IR, greatly increased the water lose, polyethylene glycol (PEG) 6000, PEG 600, and Kollicoat R R NE, RS, and RL; Surelease ; and uptake ability of the GIT-insoluble polymers (Eudragit R  Kollicoat SR) and caused them to immediately initiate the effervescent reaction and float, but the hydrated films should also be impermeable to the generated CO2 to maintain floatation and sufficiently flexible to withstand the pressure of carbon dioxide to avoid rupturing. The study demonstrated that the water uptake ability and mechanical properties could be applied as screening tools during the development of effervescent muFDDSs. The optimized system R SR and 5% PEG 600) with a 20% coating of SRT(5)P600(5) (i.e., a mixture of 5% Kollicoat level began to completely float within 15 min and maintained its buoyancy over a period of 12 h with a sustained-release effect. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci Keywords: gastrointestinal transit; mechanical properties; permeability; dissolution rate; formulation; floating ability; effervescent; water uptake

INTRODUCTION Sustained-release drug delivery systems (DDSs) offer several advantages over immediate-release DDSs, including the minimization of fluctuations in drug concentrations in the plasma with reduced side effects, prolonged periods of action resulting in maximized therapeutic efficiencies, and a reduction in the administration frequency, which leads to improved patient compliance.1,2,3 However, sustained-release Correspondence to: Ming-Thau Sheu (Telephone: +886-223771942; Fax: +886-2-23771942; E-mail: [email protected]) Ying-Chen Chen and Lin-Wen Lee contributed equally to this article. Journal of Pharmaceutical Sciences © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association

DDSs limit the advantage of drugs with a narrow absorption window in the stomach or upper part of the small intestine. Variable and short gastric residence times result in incomplete drug release or exposure in the absorption zone and lead to diminished efficacy of the dose.4,5,6 In order to increase the bioavailability, the gastric residence time of sustained-release dosage forms should be prolonged. Therefore, gastroretentive DDSs (GRDDSs), which retain in the stomach and release the drug in a controlled manner, were invented to resolve this problem.4,5,6 They are also particularly suitable for drugs with a narrow absorption window,7,8,9 for drugs that act locally in a part of gastrointestinal tract (GIT) such as antibiotic administration for Helicobacter pylori eradication for treating peptic ulcers,10,11,12 for drugs that are unstable in JOURNAL OF PHARMACEUTICAL SCIENCES

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intestinal fluid,7,13,14 and for drugs that exhibit poor solubility in the intestinal tract.15,16 Over the past few decades, several GRDDS approaches were designed and developed, including floating DDSs (FDDSs),7,11,17,18 mucoadhesive systems that cause bioadhesion to the stomach mucosa,19 and extendible or swellable systems that prevent from emptying of the dosage forms through the pyloric sphincter of stomach.20 FDDSs can be further divided into non-effervescent and effervescent systems. Upon contact with gastric fluid, the fluid penetrates the outer membrane and reacts with the effervescent components [e.g., sodium bicarbonate (NaHCO3 ) alone or combined with citric acid or tartaric acid]. Carbon dioxide (CO2 ) is liberated causing the formulation to float in the stomach because of its lower bulk density. Previously reported FDDSs were prepared as single-unit systems such as tablets and capsules.21 Nevertheless, the disadvantage of single-unit systems is the intersubject/intrasubject variability of the gastrointestinal transit time because of its all-or-nothing emptying processes10,22–25 ; moreover, single-unit systems raise the possibility of dose dumping.26 Hence, the concept of multiple-unit dosage forms, such as granules, pellets, or minitablets, were developed by dividing the dose into a number of subunits, each one containing the drug. Various effervescent multipleunit FDDSs (muFDDSs) were reported to prolong the gastric residence time and increase the overall bioavailability of the dosage form. Those systems R RL alone or a demonstrated that using Eudragit R  combination of Eudragit RL and RS as the polymeric layer could cause floating for desirable periods and with controlled-release properties, and would remain in the stomach for about 5 h in vivo as determined by radiograms. The development of effervescent muFDDSs is a promising area in pharmaceutical research concerning the control of release in the stomach with a sustained-release rate coupled with a high flexibility for adjusting the dose and reducing individual subject variations. An ideal membrane for effervescent muFDDSs should be highly water permeable to immediately initiate the effervescent reaction to prevent the dosage form from transiting into the small intestine,27 but hydrated films should also be impermeable to the generated CO2 to maintain floatation and remain sufficiently flexible to withstand the pressure of CO2 to R RL was avoid rupture.28 To the present, Eudragit the only single polymer that could fulfill all those requirements. Because most of single-polymer material is unable to fulfill all of the requirements desired for being an ideal membrane of effervescent muFDDSs, it was thought to utilize a combination of polymers with different physicochemical characteristics (e.g., water and drug permeabilities, GIT solubilities, and mechanical properties) to overcome such JOURNAL OF PHARMACEUTICAL SCIENCES

limitations. By simply choosing polymer types and adjusting the blended ratio, various properties of resulting films can be gained, including the drug release pattern, water uptake ability, and mechanical strength. Unfortunately, the use of polymer blends as coating materials is not straightforward, and complicated phenomena can occur. Application of polymer blends as coating materials in effervescent muFDDSs is accompanied by more-complex processes compared with dosage forms coated with only one type of polymer. Consequently, a thorough evaluation of the underlying mechanisms and time-/cost-saving screening methods would be highly desirable. In this study, a gas-entrapping membrane to fulfill the requirements for effervescent muFDDSs was characterized based on the water uptake ability and mechanical properties. Free films composed of various R combinations of GIT-insoluble polymers [Eudragit R  NE, RL, and RS; ethycellulose (EC); Surelease ; and R SR] and GIT-soluble polymers [hydroxKollicoat ypropyl methylcellulose (HPMC) 6 cP, polyethylene R IR] were glycol (PEG) 6000, PEG 600, and Kollicoat evaluated in both the dry and wet states, and optimal polymer blends of gas-entrapping polymeric films were selected. Spherical core pellets containing the drug and effervescent (NaHCO3 ) were prepared by an extrusion-spheronization process followed by the optimal coating of a gas-entrapping polymeric film. Losartan was chosen as the model drug because effervescent muFDDSs were designed to prolong the gastric retention time and provide enhanced bioavailability.29 The floating ability (floating lag time and duration) and drug release profiles of the resulting muFDDSs coated with the optimally selected gasentrapping polymeric film were studied.

MATERIALS AND METHODS Materials Losartan potassium (IPCA, Bangalore, India) was chosen as the model drug. NaHCO3 (Merck, Darmstadt, Germany) was used as an effervescent agent to generate gas, and microcrystalline cellulose (MCC 102; Wei-Ming Pharmaceutical, Taipei, Taiwan) was the pelletization aid. The gas-entrapping polymeric films used were mixtures of GIT-soluble polymers of HPMC (Pharmacoat 606; Shin-Etsu, Tokyo, Japan), PEG 6000 (Fluka, Buchs, Switzerland), PEG 600 R IR (BASF, (Fluka, Buchs, Switzerland), or Kollicoat Ludwigshafen, Germany), and GIT-insoluble polymers of an aqueous colloidal polymethacrylate disperR NE, RS 30D, and RL 30D; Evonik, sion (Eudragit Darmstadt, Germany), EC (10 cP; Aqualon, WilmR (Colorcon, Indianapolis, ington, USA), Surelease R  USA), and Kollicoat SR 30D (BASF, Ludwigshafen, Germany) plasticized with diethyl phthalate (DEP; DOI 10.1002/jps

WATER UPTAKE AND MECHANICAL PROPERTIES OF GAS-GENERATED FLOATING DRUG DELIVERY SYSTEMS

Merck, Darmstadt, Germany) or triethyl citrate (TEC; Merck, Darmstadt, Germany). Glyceryl monostearate (GMS; Sasol, Johannesburg, South Africa) was an antiadhesive agent to prevent coalescence during pellet coating. Tween 80 (polysorbate 80; Riedelde Ha¨en, Seelze, Germany) was used as a dispersing agent. All other reagents were of analytical grade.

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R R (Colorcon), S; Kollicoat SR 30D (BASF), Surelease SR; Diethyl phthalate, D; Triethyl citrate, T; R IR (BASF), IR; PEG 600, P600. For exKollicoat ample, SRT(5)P600(10) means that the GIT-insoluble R SR 30D (BASF) with 5% TEC polymer was Kollicoat as the plasticizer, and the GIT-soluble polymer was 10% PEG 600.

Preparation and Characterization of Free Films

Preparation and Floating Ability Test of Pellets

First, the plasticizer (TEC or DEP) was thoroughly mixed in the aqueous solution with GIT-soluble polyR mers (HPMC, PEG 600, PEG 6000, and Kollicoat IR (BASF) at 5%, 10%, and 15% levels, w/w). Then, R NE, RS, and the GIT-insoluble polymers [Eudragit R R  RL (Evonik); Surelease (Colorcon); and Kollicoat SR (BASF)] were added as an aqueous dispersion solution at a final polymer level of 15% (w/w) and blended for 30 min for plasticizing. Dried free films were prepared by pouring the resultant mixture onto the parafilm-sealed bottom of a polyarylic column, dried at 40◦ C for 12 h, and further cured at 50◦ C R RL for 12 h. The free film prepared with Eudragit (Evonik) was used as a reference for the evaluation of water uptake amount, mechanical properties, and drug release rate. Wet films were prepared by soaking the dried free films in 500 mL of simulated gastric fluids (SGFs, 0.1 M HCl solution) at 37◦ C for 4 h to simulate the films in vivo conditions. Both free films cut in a circle with a diameter of 30 mm were placed in a glass filter of a modified Enslin apparatus30 at a temperature of 37◦ C. Water uptake amount at 15 min was read from a graduated pipette and recorded (n = 4). The mechanical strengths of both free films (10 × 3 mm2 with a thickness of 0.20–0.40 mm) were measured (dynamic mechanical analyzer, DMA7e; PerkinElmer, Massachusetts, USA) by monitoring the time-modulus curve conducted at ambient temperature. The initial applied force was 5 mN, with an extension rate of 100 mN/min. From the stress–strain curves, mechanical properties including elongation at break and tensile strength were obtained, and Young’s modulus was calculated as the slope of the linearly region of the stress–strain curve. Statistically significant differences in the water uptake amount at 15 min among the addition of different levels of GIT-soluble polymers were examined using one-way analysis of variance followed by Student–Newman–Keul test. All p values were two sided, and a p value of less than0.05 was accepted as indicating statistical significance. All analyses were performed using the statistical software package STATISTICA, version 5.5 (StatSoft Incorporation, Tulsa, Oklahoma).

The pellet cores composed of losartan potassium (25%, w/w; IPCA), MCC (55%, w/w), and NaHCO3 (20%, w/w) were produced by extrusion through a screen size of 1 mm and spheronization at 700 rpm for 5 min (Shang Yuh Machine, New Taipei City, Taiwan). The coating solution was prepared the same as that for free films with the slight modification of adding 8% GMS as an antiadhesive to prevent coalescence during pellet coating. Pellet coating with different combinations of GIT-soluble and GIT-insoluble polymers was performed using a rotor-type fluidized-bed system (GPCG-1; Glatt, Binzen, Germany) at respective optimal conditions to achieve a weight gain of 5%, 10%, 15%, and 20% (w/w) to obtain the effervescent muFDDS. All coating efficiencies exceeded 90%. After coating, pellets were further cured at 50◦ C for 12 h, and pellets in the size range of 0.71–1.25 mm were collected for further experiments. One hundred pellets were placed in the medium, and the time to float (floating lag time) and floating duration (the duration when a certain percentage pellets float) were determined by visual observation. Floating lag time was defined as the time for that 100 pellets completely floated on the top surface of 900 mL of SGF at 37◦ C with a stirring rate of 50 rpm. The percentage of floating pellets was defined as the floating pellets (%) based on the following equation:

Abbreviations of Blended Films R R Eudragit NE (Evonik), N; Eudragit RL 30D R  RS 30D (Evonik), RS; (Evonik), RL; Eudragit

DOI 10.1002/jps

Floating pellet(%) = number of floating pellets at the measured time × 100 (1) initial number of the pellets

Drug Release Studies Drug dissolution from the coated pellets was conducted in 900 mL of SGF at 37 ± 0.5◦ C and 50 rpm based on the apparatus II method (United States Pharmacopeia XXIX) (VK7020; Vankel, North Carolina, USA). The medium (5 mL) was sampled at predetermined times and replaced with fresh medium of the same volume. The drug concentration was measured by an ultraviolet–visible spectrophotometer (V550; Jasco, Japan) at a wavelength of 254 nm that had been validated to have acceptable precision and accuracy. Each in vitro release study was performed in triplicate. JOURNAL OF PHARMACEUTICAL SCIENCES

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R Figure 1. Water uptake amount of blending polymers at 15 min. (a) Eudragit NE (Evonik), R R R (Colorcon), (d) Eudragit RS (Evonik), (e) Kollicoat SR (b) ethylcellulose, (c) Surelease ∗ ∗∗ (BASF) (mean ± SD; n = 4). p 0.05, p 0.01.

Correlation Analysis The correlation analysis was carried out with linear regression (PASW Statistics 18.0, IBM, New York, USA) to assess the relationship between independent or log-transform variables (water uptake amount at 15 min or tensile strength in wet state) with all dependent or log-transform variables (floating lag time, floating duration, and drug release rate) of different formulations [RLD(15), SRT(5)P600(10), NIR (10), ST(30)IR(10), RSD(15)IR(10), SRT(5)P600(5), NIR (20), ST(30)IR(5), and RSD(15)IR(20)] by multivariant analysis with stepwise regression. p values of less than 0.05 were considered as statistically significant.

RESULTS AND DISCUSSION Preparation and Characterization of the Free Films Because ideal effervescent muFDDSs are not achievable by single-polymeric films, GIT-soluble polymers JOURNAL OF PHARMACEUTICAL SCIENCES

blended with GIT-insoluble polymers were used as coating materials in this study, and several evaluations were conducted to identify whether they provided the desired properties of rapid floating and maintenance of buoyancy in the stomach.

Water Uptake Amount Permeation of liquid through the polymeric film into the core and the subsequent generation of CO2 may play major roles in the floating and drug-release characteristics. The gastric emptying time ranges from 15 min to 3 h,31 FDDSs should float within 15 min. So, the water uptake amount at 15 min was evaluated, and Figure 1 shows the results of the water upR take amount of GIT-insoluble polymers [Eudragit  NE, RL 30D, and RS 30D (Evonik); EC; Surelease R R (Colorcon); and Kollicoat SR 30D (BASF)] intermixed with different GIT-soluble polymers [HPMC, R IR (BASF)]. PEG 6000, PEG 600, and Kollicoat DOI 10.1002/jps

WATER UPTAKE AND MECHANICAL PROPERTIES OF GAS-GENERATED FLOATING DRUG DELIVERY SYSTEMS

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R Table 1. Mechanical Properties of Gastrointestinal Tract (GIT)-Insoluble Polymers [Eudragit NE (Evonik), NE; Ethylcellulose, EC; R  Surelease (Colorcon), S] Blended with Different GIT-Soluble Materials in the Wet and Dry States (in Parentheses) (Mean ± SD; n = 5)

Elongation at Break (%)

Tensile Strength (Mpa) 2.77 ± 0.39 (1.75 ±

Young’s Modulus (kpa)

RLD(15)

230.74 ± 6.51 (296.35 ±

NE NH(5) NH(10) NH(20) NP6000(5) NP6000(10) NP6000(20) NP600(5) NP600(10) NP600(20) NIR(5) NIR(10) NIR(20)

651.25 ± 68.21 (697.93 ± 55.27) 690.97 ± 42.64 (711.36 ± 44.12) 709.56 ± 29.33 (693.54 ± 64.01) 854.91 ± 40.58 (802.12 ± 48.17) 594.03 ± 53.27 (527.18 ± 30.98) 676.93 ± 35.02 (696.06 ± 40.67) 593.22 ± 37.27 (607.89 ± 55.77) 630.60 ± 27.59 (586.60 ± 38.51) 714.17 ± 17.96 (628.06 ± 56.48) 645.64 ± 51.72 (609.04 ± 64.21) 697.43 ± 48.10 (676.85 ± 44.42) 679.73 ± 17.56 (669.86 ± 44.04) 689.89 ± 29.55 (674.22 ± 17.11)

NB NB NB NB NB NB NB NB NB NB NB NB NB

3.27 ± 1.53 (1.25 ± 0.23) NB NB NB NB NB NB NB NB NB 11.06 ± 3.24 (3.33 ± 0.32) 3.96 ± 0.15 (10.37 ± 0.21) 3.14 ± 0.34 (15.16 ± 0.84)

EC ED(30) ET(30) ED(30)H(5) ED(30)H(10) ED(30)H(20) ED(30)P6000(5) ED(30)P6000(10) ED(30)P6000(20) ED(30)P600(5) ED(30)P600(10) ED(30)P600(20) ED(30)IR(5) ED(30)IR(10) ED(30)IR(20)

7.04 ± 2.52 (5.66 ± 2.25) 27.84 ± 17.41 (49.20 ± 33.07) 19.32 ± 1.20 (32.76 ± 1.81) 22.87 ± 4.30 (12.88 ± 1.97) 26.48 ± 2.03 (12.94 ± 1.19) 30.41 ± 8.05 (11.48 ± 1.29) 35.09 ± 2.37 (22.50 ± 1.61) 40.11 ± 12.36 (28.33 ± 1.87) 36.54 ± 3.10 (26.85 ± 1.65) 89.87 ± 11.79 (46.32 ± 10.27) 94.56 ± 14.70 (66.13 ± 17.21) 100.67 ± 14.75 (76.28 ± 10.25) 28.44 ± 6.71 (13.23 ± 1.08) 32.40 ± 1.61 (20.77 ± 1.86) 39.20 ± 3.09 (25.44 ± 2.72)

NB NB 11.38 ± 1.28 (10.38 ± 3.61) 7.31 ± 0.95 (7.92 ± 1.00) 5.52 ± 0.95 (6.00 ± 1.69) 4.76 ± 1.45 (6.00 ± 1.69) 5.94 ± 1.27 (8.77 ± 1.33) 5.54 ± 1.83 (8.69 ± 1.24) 4.56 ± 1.43 (6.46 ± 1.61) 8.73 ± 1.10 (11.16 ± 2.02) 8.05 ± 0.76 (9.01 ± 0.74) 6.77 ± 0.91 (7.90 ± 0.88) 6.83 ± 0.57 (6.45 ± 1.04) 6.23 ± 0.65 (6.05 ± 1.49) 5.32 ± 0.23 (4.67 ± 0.28)

2000.00 ± 21.13 (175.00 ± 50.00) 162.91 ± 7.23 (NB) 1666.67 ± 577.35 (994.60 ± 12.07) 634.28 ± 84.86 (461.88 ± 291.29) 90.00 ± 12.10 (823.82 ± 171.42) 58.49 ± 25.68 (200.15 ± 90.52) 49.60 ± 13.71 (497.69 ± 156.13) 247.98 ± 97.71 (742.96 ± 265.85) 166.95 ± 70.46 (671.93 ± 66.39) 35.45 ± 12.07 (12.60 ± 2.35) 10.62 ± 0.34 (769.52 ± 6.85) 20.05 ± 11.99 (46.02 ± 26.10) 665.97 ± 62.04 (223.80 ± 0.14) 402.00 ± 84.17 (96.32 ± 39.31) 53.20 ± 14.17 (80.59 ± 31.22)

S SD(30) ST(30) ST(30)H(5) ST(30)H(10) ST(30)H(20) ST(30)P6000(5) ST(30)P6000(10) ST(30)P6000(20) ST(30)P600(5) ST(30)P600(10) ST(30)P600(20) ST(30)IR(5) ST(30)IR(10) ST(30)IR(20)

29.10 ± 11.64 (27.83 ± 9.72) 42.40 ± 7.04 (64.85 ± 4.25) 75.80 ± 3.46 (92.31 ± 5.06) 55.65 ± 11.41 (13.18 ± 6.95) 57.99 ± 18.89 (15.78 ± 1.83) 64.25 ± 5.90 (19.29 ± 0.97) 96.07 ± 12.41 (49.70 ± 8.26) 111.80 ± 20.97 (52.30 ± 5.66) 139.33 ± 35.59 (54.81 ± 9.37) 138.51 ± 7.46 (116.81 ± 8.47) 204.44 ± 55.31 (128.89 ± 14.09) 217.37 ± 45.98 (149.10 ± 13.42) 219.51 ± 22.90 (35.47 ± 2.90) 287.99 ± 12.61 (40.33 ± 3.26) 323.99 ± 33.66 (53.15 ± 2.43)

1.10 ± 0.05 (1.22 ± 0.52) 1.08 ± 0.06 (0.88 ± 0.03) 1.15 ± 0.02 (0.51 ± 0.3) 0.16 ± 0.04 (0.17 ± 0.08) 0.15 ± 0.02 (0.20 ± 0.06) 0.14 ± 0.01 (0.38 ± 0.05) 0.54 ± 0.03 (0.56 ± 0.06) 0.47 ± 0.04 (0.50 ± 0.05) 0.36 ± 0.09 (0.45 ± 0.04) 0.52 ± 0.03 (0.55 ± 0.04) 0.44 ± 0.04 (0.49 ± 0.06) 0.44 ± 0.04 (0.48 ± 0.03) 0.85 ± 0.03 (0.57 ± 0.03) 0.72 ± 0.05 (0.37 ± 0.01) 0.63 ± 0.01 (0.31 ± 0.02)

14.53 ± 1.34 (71.15 ± 27.10) 28.61 ± 2.08 (7.46 ± 2.57) 111.96 ± 16.52 (21.14 ± 2.23) 3.68 ± 0.30 (13.40 ± 1.35) 3.07 ± 0.54 (7.98 ± 2.33) 7.53 ± 1.44 (41.54 ± 17.65) 11.01 ± 0.76 (11.95 ± 2.43) 5.39 ± 0.87 (NB) 5.81 ± 0.50 (21.33 ± 5.35) 12.34 ± 5.21 (5.49 ± 1.71) 7.33 ± 0.40 (4.96 ± 1.05) 10.60 ± 7.90 (5.35 ± 1.77) 14.72 ± 1.87 (26.91 ± 11.65) 11.23 ± 1.93 (13.07 ± 7.06) 5.11 ± 1.94 (24.16 ± 3.08)

55.34)a

0.63)a

125.22 ± 63.89 (40.13 ± 10.09)a

NB, not break till the limit of the dynamic mechanical analyzer. a Wet state (dry state).

Water uptake amount significantly increased (p < 0.01) after the addition of GIT-soluble polymers in all formulations. The ability to take up water by R R (Colorcon) and Kollicoat SR (BASF) was Surelease R IR greatly enhanced when combined with Kollicoat (BASF) and PEG 600, respectively, and was as high as R RL (Evonik). Water uptake amount that of Eudragit by GIT-soluble polymers was in the following orR IR (BASF) ≈ PEG 600 > PEG 6000 > der: Kollicoat HPMC. HPMC swells prior to dissolving when in contact with liquids and hence exhibited a lag time compared with other GIT-soluble polymers. DOI 10.1002/jps

Mechanical Properties An ideal film for FDDSs should be impermeable to the gas, and flexible in the wet state to resist the pressure of CO2 so that floatation can be maintained. The stress–strain curve was recorded, and their corresponding mechanical properties were calculated and are listed in Tables 1 and 2. Because tensile strength measures the ability of films to withstand rupture, the tensile strength decreased with the increasing ratio of GIT-soluble materials, indicating the easy break of the film. There were two findings noted for all JOURNAL OF PHARMACEUTICAL SCIENCES

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CHEN ET AL. R R RS (Evonik), RSD; Kollicoat Table 2. Mechanical Properties of Gastrointestinal Tract (GIT)-Insoluble Polymers [Eudragit SR, SR (BASF)] Blended with Different GIT-Soluble Materials in the Wet and Dry States (in Parentheses) (mean ± SD; n = 5)

Elongation at Break (%)

Tensile Strength (Mpa)

Young’s Modulus (kpa)

RSD(15) RSD(15)H(5) RSD(15)H(10) RSD(15)H(20) RSD(15)P6000(5) RSD(15)P6000(10) RSD(15)P6000(20) RSD(15)P600(5) RSD(15)P600(10) RSD(15)P600(20) RSD(15)IR(5) RSD(15)IR(10) RSD(15)IR(20)

401.78 ± 72.32 (506.14 ± 667.03 ± 26.25 (100.55 ± 13.88) 719.58 ± 52.18 (115.57 ± 10.97) 722.37 ± 16.21 (123.06 ± 9.91) 710.11 ± 70.04 (210.96 ± 37.31) 719.40 ± 29.71 (212.53 ± 22.91) 733.80 ± 25.22 (260.46 ± 23.51) 712.14 ± 41.69 (279.31 ± 30.12) 765.72 ± 25.70 (325.23 ± 38.79) 758.84 ± 20.09 (379.02 ± 31.73) 685.99 ± 24.98 (561.76 ± 25.51) 709.11 ± 8.64 (637.27 ± 35.17) 715.57 ± 19.85 (670.57 ± 46.31)

1.62 ± 0.15 (1.24 ± 1.03 ± 0.22 (2.29 ± 0.06) 0.73 ± 0.11 (2.75 ± 0.20) 0.51 ± 0.07 (3.35 ± 0.69) 0.89 ± 0.12 (1.30 ± 0.07) 0.89 ± 0.07 (1.10 ± 0.02) 0.69 ± 0.09 (0.76 ± 0.04) 0.98 ± 0.05 (1.58 ± 0.16) 0.91 ± 0.07 (1.08 ± 0.15) 0.64 ± 0.06 (0.89 ± 0.08) 1.20 ± 0.23 (1.33 ± 0.11) 1.24 ± 0.07 (1.84 ± 0.06) 1.17 ± 0.05 (2.24 ± 0.08)

12.51 ± 1.60 (13.28 ± 4.32)a 14.67 ± 4.95 (11.56 ± 0.91) 4.97 ± 1.29 (76.37 ± 6.36) 1.38 ± 0.17 (69.60 ± 13.35) 10.12 ± 2.29 (13.98 ± 3.96) 12.69 ± 4.57 (58.33 ± 19.31) 3.98 ± 0.64 (2.10 ± 0.19) 12.32 ± 0.23 (12.93 ± 1.91) 10.28 ± 2.94 (5.39 ± 0.81) 6.69 ± 0.58 (3.20 ± 0.38) 15.71 ± 3.05 (12.72 ± 4.16) 17.46 ± 4.38 (31.70 ± 10.41) 12.12 ± 3.81 (41.30 ± 18.57)

SR SRT(5) SRT(5)H(5) SRT(5)H(10) SRT(5)H(20) SRT(5)P6000(5) SRT(5)P6000(10) SRT(5)P6000(20) SRT(5)P600(5) SRT(5)P600(10) SRT(5)P600(20) SRT(5)IR(5) SRT(5)IR(10) SRT(5)IR(20)

652.41 ± 27.98 (654.46 ± 29.84) 691.18 ± 4.90 (685.22 ± 6.83) 659.09 ± 27.84 (650.13 ± 37.94) 640.82 ± 8.27 (622.60 ± 10.20) 663.35 ± 16.92 (668.23 ± 24.48) 676.68 ± 16.92 (659.30 ± 13.34) 681.82 ± 7.68 (666.57 ± 19.83) 692.17 ± 5.24 (644.72 ± 22.22) 664.99 ± 10.73 (652.34 ± 7.27) 670.75 ± 11.10 (665.27 ± 2.16) 679.22 ± 6.09 (670.99 ± 4.82) 672.03 ± 10.79 (652.01 ± 10.67) 672.52 ± 7.98 (660.56 ± 6.07) 686.18 ± 6.64 (677.83 ± 10.03)

NB NB NB NB 1.05 ± 0.03 (NB) NB NB 0.95 ± 0.03 (NB) NB NB 0.40 ± 0.03 (NB) NB NB 0.46 ± 0.04 (NB)

0.20 ± 0.03 (6.83 ± 1.22) 0.16 ± 0.02 (2.81 ± 0.49) 0.14 ± 0.01 (4.95 ± 0.47) 0.16 ± 0.00 (7.30 ± 0.12) 0.02 ± 0.00 (15.84 ± 0.42) 0.04 ± 0.00 (2.27 ± 1.50) 0.05 ± 0.00 (11.28 ± 3.49) 0.04 ± 0.00 (2.59 ± 0.68) 0.06 ± 0.01 (0.26 ± 0.16) 0.11 ± 0.03 (0.32 ± 0.03) 0.18 ± 0.03 (0.12 ± 0.07) 0.12 ± 0.02 (1.09 ± 0.08) 0.10 ± 0.03 (2.05 ± 0.32) 0.08 ± 0.00 (4.00 ± 0.56)

97.03)a

0.19)a

NB, not break till the limit of the dynamic mechanical analyzer. a Wet state (dry state).

formulations when comparing the results in the wet and dry states. First, the elongation of the film declined in the wet state and it agreed with those reported by Sungthongjeen et al.21 This was thought to be due to the additional plasticizer effect of water after soaking; thus, hydration of the polymer and the resulting interference of water with interchain hydrogen bonding were responsible for the results.32 The other one was with the addition of GIT-soluble polymers that dissolved as well as did the plasticizers; moreover, GIT-soluble polymers formed pores. Therefore, the film with GIT-soluble polymers added in the wet state displayed increased elongation, which masked the effect of the plasticizers. However, the mechanical properties varied depending on the GITinsoluble polymers used. R NE In both the dry and wet states, Eudragit (Evonik) films were hard to break when up to 20% GIT-soluble polymers was added. This is because R NE (Evonik) is a neutral ester polymer Eudragit with no hydrogen bonds or other intermolecular forces, and the glass transition temperature value is approximately 5◦ C; therefore, it was flexible with low Young’s modulus of 3.27 ± 1.53 kpa and high elongation of 651.25 ± 68.21% in the wet state at room temperature. Our results were consistent with R those reported by Sungthongjeen et al.,21 Eudragit JOURNAL OF PHARMACEUTICAL SCIENCES

NE (Evonik) film was observed to have the highest elongation values in both the dry and wet states. This polymer dispersion has a low minimum film formation temperature and does not require plasticizers, resulting in flexible films.28 The films preR RL (Evonik) or RS also had pared from Eudragit high elongation values and low Young’s modulus, indicating their good flexibility. In the wet state, the R NE (Evonik) films value of elongation of Eudragit decreased to less extent than those of the films preR RL (Evonik) or RS. This can be pared with Eudragit R explained by the hydrophobic character of Eudragit R  NE (Evonik), compared with Eudragit RL and RS (Evonik).32 Ethylcellulose possesses very low elongation (5.66 ± 2.25% and 7.04 ± 2.52% in the dry and wet states, respectively) and high Young’s modulus (175.0 ± 50.0 and 2000.0 ± 21.1 kpa in the dry and wet states, respectively), and it was difficult to break when no plasticizers or GIT-soluble materials were added; however, even with pore formation after the addition of GIT-soluble polymers in the wet state, the enhanced extendibility was still not as good as R RL (Evonik). The intermolecular that of Eudragit hydrogen bonds and sugar-based three-dimensional obstacles might have resulted in the poor extendibility of EC. This was also confirmed by Sungthongjeen DOI 10.1002/jps

WATER UPTAKE AND MECHANICAL PROPERTIES OF GAS-GENERATED FLOATING DRUG DELIVERY SYSTEMS

et al.,21 who determined that EC is a mechanically weak and brittle polymer and hence can easily rupture once CO2 pressure forms. According to our results, EC is rigid and brittle so is not a suitable candiR (Colorcon) in date for FDDSs. Otherwise, Surelease a 25% EC aqueous dispersion with dibutyl sebacate and oleic acid as plasticizers exhibited higher elongation (27.83 ± 9.72% and 29.10 ± 11.64% in the dry and wet states, respectively) and lower Young’s modulus (71.15 ± 27.10 and 14.53 ± 1.34 kpa in the dry and wet states, respectively) than that for EC alone. R (Colorcon) combined with either PEG 600 Surelease R IR (BASF) had ideal extendibility as or Kollicoat R  Eudragit RL (Evonik) did in the wet state. However, the same situation of fragility and easy rupture with R (Collow tensile strength was found for Surelease orcon) due to basic structure of EC, intermolecular hydrogen bonds, and sugar-based three-dimensional obstacles. R R SR (BASF) and Eudragit NE Both Kollicoat (Evonik) are very good materials with elongation up to 600% without bursting, but the flexibility of R SR (BASF) was not as good as that of Kollicoat  Eudragit R NE (Evonik) because the shape of the former was hard to restore after extension. The good R SR (BASF) was because of extendibility of Kollicoat it being a soft film, but also because with up to 20% GIT-soluble polymers added, the film with extremely many pores easily broken. In addition, enhanced elongation was seen in formulations with PEG, and in formulations with smaller molecular weights, the strain was higher with PEG 600 than that with PEG 6000. Because PEG also acts as a plasticizer, the plasticizing capacity decreases as its molecular weight increases.33 Films with 20% GIT-soluble polymers were so soft that the shapes were hard to maintain, so the formulations with 10% GIT-soluble polymers were preferred. On the basis of the results of water uptake amount at 15 min and mechanical strength, RLD(15), NIR(10), ST(30)IR(10), RSD(15)IR(10), and SRT(5)P600(10) were selected for further studies on the floating ability and dissolution. Preparation and Floating Characterization of the Pellets The systems consisted of a drug-containing core (losartan) pellet with an effervescent (NaHCO3 ) and pelletization aid (MCC), and a gas-entrapping polymeric membrane (a mixture of GIT-insoluble and GIT-soluble polymers). To develop a successful effervescent muFDDS, rapid formation of a low-density system within minutes after contact with gastric fluid and maintenance of the buoyancy in the stomach with controlled release are required, and the results of the floating lag time measurement are shown in Figure 2, the percentage of floating pellet is shown in Figure 3, and the release profile is plotted in Figure 4. DOI 10.1002/jps

7

Figure 2. Floating lag times of various formulations combined by GIT-soluble and GIT-insoluble polymers R R SR (BASF) and PEG 600, Surelease (Color[Kollicoat   R R con) and Kollicoat IR (BASF), Eudragit NE (Evonik) R R IR (BASF), and Eudragit RS (Evonik) and and Kollicoat  R Kollicoat IR (BASF)] with different ratios in panels (a) and (b) (mean ± SD; n = 3).

Floating Ability On the basis of the results of water uptake amount at 15 min, these formulations could be simply divided into two groups: a lower water uptake ability, NIR(10) and RSD(15)IR(10), for which the floating lag time far exceeded 20 min even with the lowest 5% coating level, and no floating effect occurred with a more than 10% coating level. The floating lag time of NIR(10) was shorter than that of RSD(15)IR(10) [90.5 ± 2.8 min for NIR(10) and 131.7 ± 2.3 min for RSD(15)IR(10)] because of the higher water uptake amount of NIR(10) than that of RSD(15)IR(10). The results were in accordance with previous studies,21,34–36 and they demonstrated that R Eudragit RS and NE (Evonik) might not be permeable enough to induce the effervescent reaction and generate a sufficient amount of CO2 to make the formulations float in the dissolution medium. JOURNAL OF PHARMACEUTICAL SCIENCES

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CHEN ET AL.

R R Figure 3. Floating percentage of Eudragit NE (Evonik) and Kollicoat IR (BASF) (a), R R R RS (Evonik) and Kollicoat IR (BASF) (b), Kollicoat SR (BASF) and PEG 600 Eudragit R R (Colorcon) and Kollicoat IR (BASF) (d) at different ratios with various (c), and Surelease coating levels in SGF (mean ± SD; n = 3).

On the contrary, formulations with higher water uptake abilities, SRT(5)P600(10) and ST(30)IR(10), were able to float within 20 min; in particular, SRT(5)P600(10) floated within 10 min. With an inR SR (BASF) and creasing coating level of Kollicoat R  Surelease (Colorcon), the floating began later because of the delayed water permeation through the thicker coating layer, and this result agreed with those of previous studies.22,28 Although their ability to take up water was not as good as that of RLD(15), the films were so soft that pores were formed rapidly and liquid was entered easily; hence, gas was immediately generated, thus shortening the floating lag time. The order of floating lag times was RSD(15)IR(10) > NIR(10) > ST(30)IR(10) > SRT(5)P600(10), and it was well correlated with water uptake amount. A linear plot of log [floating lag time] versus log [water uptake amount at 15 min] was shown in Figure 5a (r2 = 0.818, p < 0.001). Greater water uptake amount with JOURNAL OF PHARMACEUTICAL SCIENCES

a shorter floating lag time was observed. However, the generated gas also ruptured the soft film easily, and thus floating was maintained for only a brief time. The duration of 60% floating pellets of SRT(5)P600(10) was quite short, and the film was so soft that no CO2 was entrapped. The mechanical properties reflected the duration of floating well. Figure 5b shows that r2 for log [duration of 80%, 60%, 50%, and 20% floating pellets] versus log [tensile strength (in the wet state)] was 0.984, 0.960, 0.967, and 0.960, respectively, with a p value of less than 0.001. Stronger tensile strength made the floating duration longer because of better ability of gas entrapping. The reason that NIR(10) and RSD(15)IR(10) were unable to float rapidly is because of poor water uptake ability, so a more ratio of GIT-soluble polymers R NE (Evonik) was comwas added. When Eudragit R IR (BASF), the bined with 10% and 20% Kollicoat floating lag time was reduced from 90.5 ± 2.8 to DOI 10.1002/jps

WATER UPTAKE AND MECHANICAL PROPERTIES OF GAS-GENERATED FLOATING DRUG DELIVERY SYSTEMS

9

R R Figure 4. Drug release profiles of Eudragit NE (Evonik) and Kollicoat IR (BASF) (a),    R R R Eudragit RS (Evonik) and Kollicoat IR (BASF) (b), Kollicoat SR (BASF) and PEG 600 (c), R R (Colorcon) and Kollicoat IR (BASF) (d) at different ratios with various coating and Surelease levels in SGF (mean ± SD; n = 3).

51.6 ± 0.7 min, respectively; and in formulations of R R RS (Evonik) with 10% and 20% Kollicoat Eudragit IR (BASF), the floating lag time was also shortened from 131.7 ± 2.3 to 72.4 ± 1.1 min, respectively. Similar results were shown in those with a 10% coating level; however, the goal of a floating lag time of less than 15 min was still not reached for films with R NE and RS (Evonik). On the contrary, it Eudragit was difficult to maintain long-term floating with those containing SRT(5)P600(10) and ST(30)IR(10) because of excessive water uptake ability; therefore, we reduced the amount of GIT-soluble polymers. The floating lag time was extended with a reduction in the ratio of GIT-soluble polymers. SRT(5)P600(5) with a 20% coating level floated within 15 min; moreover, over 60% of pellets remained floating for 12 h.

Drug Release Studies Effervescent muFDDSs not only have the ability to float, but also necessarily possess a sustained-release DOI 10.1002/jps

effect, so in vitro dissolution tests were conducted. Because effervescent muFDDSs mainly stay in the stomach, SGF was used to simulate drug release in the stomach. RLD (15) had a very good floating ability as previously described, but had no controlled-release effect even at a 20% coating level (data not shown). The effect of the coating level on drug release agreed with previous studies.21,34–36 The higher coating level of film represented a greater thickness and caused lower water uptake ability, and this resulted in retarded water permeation and slightly decreased drug release. RSD(15)IR(10) released the drug more slowly than NIR(10) did because of its poor water uptake ability. As a greater amount of GIT-soluble polymers was added, a faster release pattern was seen. The high water uptake ability created a better floating ability, but also made losartan release more rapid and abrogated the sustained-release effect in SRT(5)P600(10) and ST(30)IR(10) even with a 15% coating level. R2 for the correlation analysis between log [time when JOURNAL OF PHARMACEUTICAL SCIENCES

10

CHEN ET AL.

Figure 5. A correlation plot of log [floating lag time] (h) versus log [water uptake amount at 15 min] (mL/g) (a), log [duration of 50% and 80% floating pellet] (h) versus log [tensile strength] (MPa) (b), log [time when 50% and 90% drug being released] (min) versus log [water uptake amount at 15 min] (mL/g) (c).

50% and 90% of drug being released] versus log [water uptake amount at 15 min] was 0.810 and 0.798, respectively, with a p value of less than 0.001 (Fig. ¨ 5c). Strubing et al.37 once demonstrated that popraR nolol HCl-containing tablets coated with Kollicoat R  SR (BASF) and Kollicoat IR (BASF) in an 8.5:1.5 ratio exhibited the shortest floating lag time, and drug release was efficiently delayed within a time period of 24 h. In this study, the optimum system of SRT(5)P600(5) with a 20% coating level completely floated within 15 min and maintained its buoyancy over a period of 12 h with a sustained-release effect. Correlation Analysis After the multivariant analysis by stepwise regression, the results showed that floating lag time was explained by water uptake ability regardless of the coating level. A linear plot of log [floating lag time] versus JOURNAL OF PHARMACEUTICAL SCIENCES

log[water uptake amount at 15 min] was observed in Figure 5a. Statistically acceptable correlation was determined to be between log [duration of 50% and 80% floating pellet] and log [tensile strength] (Fig. 5b). The correlation analysis further showed a statistically significant linear relationship of log [time when 50% or 90% drug being released] between log [water uptake amount at 15 min] in Figure 5c.

CONCLUSIONS Both rapid-floating and sustained-release properties were achieved with the effervescent muFDDSs developed in the present study. The systems consisted of drug (losartan)- and effervescent (NaHCO3 )-containing pellets coated with a polymeric membrane, which was a mixture of GIT-soluble and GIT-insoluble polymers. The floating ability and drug DOI 10.1002/jps

WATER UPTAKE AND MECHANICAL PROPERTIES OF GAS-GENERATED FLOATING DRUG DELIVERY SYSTEMS

release of the systems were dependent on the composition and coating level of the polymeric membrane. The addition of GIT-soluble polymers, such R IR as HPMC, PEG 6000, PEG 600, and Kollicoat (BASF), greatly increased the water uptake ability of R NE, RS, and RL GIT-insoluble polymers [Eudragit R R  (Evonik); Surelease (Colorcon); and Kollicoat SR (BASF)] and rendered them capable of being used in effervescent FDDSs. The result of correlation analyses showed that floating lag time and drug release rate was explained by water uptake amount and floating duration by tensile strenth regardless of the coating level, so the water uptake ability and mechanical properties could be applied as screening tools during the development of effervescent muFDDSs. The optimized system of SRT(5)P600(5) [i.e., a mixture of 5% R SR (BASF) with 5% TEC and 5% PEG 600] Kollicoat at a 20% coating level began to completely float within 15 min and maintained its buoyancy over a period of 12 h with a sustained-release effect.

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DOI 10.1002/jps