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Cellulose acetate membranes for transdermal delivery of scopolamine base
Materials Science and Engineering C 20 (2002) 93 – 100 www.elsevier.com/locate/msec
Cellulose acetate membranes for transdermal delivery of scopolamine base Fang-Jing Wang a, Yi-Yan Yang a,*, Xian-Zheng Zhang a, Xiao Zhu b, Tai-shung Chung a,c, Shabbir Moochhala b a Institute of Materials Research and Engineering, No. 3 research Link, Singapore 117602, Singapore Defence Medical Research Institute, #01-06, MD2 National University of Singapore, Singapore 119260, Singapore c Department of Chemical and Environmental Engineering, National University of Singapore, Singapore 119260, Singapore b
Abstract Transdermal delivery is one of the most convenient drug administration routes. In this study, the cellulose acetate membranes were cast with acetone as a solvent at 22 and 40 jC. Polyethylene glycol (PEG, MW 600) was used as a pore-forming agent. The in vitro release rates of scopolamine base as a model drug through the membranes were evaluated in phosphate buffer solution (PBS, pH 7.4) at 32 jC. The membranes were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), thermal mechanical analysis (TMA) and thermogravimetric analysis (TGA). It was observed that the drug permeation through the cellulose acetate membranes was obviously affected by the incorporated PEG content and formed membrane morphology. There was no drug flux from the cellulose acetate membranes prepared without PEG. An increased PEG content resulted in a faster scopolamine release due to a more porous structure created. Both the membrane fabrication temperature and the PEG content can affect the thermal, mechanical and morphological properties of the resultant membranes. With the optimized fabrication conditions, linear in vitro release profiles of scopolamine over 3 days were achieved. The membranes developed would be useful for transdermal delivery of drugs. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Cellulose acetate membranes; Polyethylene glycol (PEG); Transdermal delivery; Scopolamine
1. Introduction Compared with oral and parenteral routes, drug delivery through skin can offer several advantages, for example, (1) bypassing the hepatic ‘‘first pass’’ elimination, (2) maintaining a constant, prolonged and therapeutically effective drug level in the bloodstream or tissues, (3) rapid termination of drug delivery, (4) improved patient compliance [1]. Scopolamine is the first drug marketed in a transdermal delivery form. Transdermal therapeutic scopolamine system (TTS-S, Novartis, Basel, Switzerland) was designed to deliver a total of 0.5 mg scopolamine over a 3-day period, and relieve the signs and symptoms of motion sickness [2,3]. The disadvantage of this design is that it needs 6 to 8 h for a therapeutic plasma level to appear after application. Nachum et al. [4] suggested using the combined oral and transdermal delivery of scopolamine to circumvent this problem.
*
Corresponding author. Tel.: +65-874-8123; fax: +65-872-7528. E-mail address: [email protected] (Y.-Y. Yang).
In the transdermal delivery systems, polymeric membrane is a key component and used to modulate the release rate of a therapeutic drug. Cellulose acetate is a widely used and investigated material both in the industry and in research. However, cellulose acetate, when used as a ratecontrolling membrane material for transdermal drug delivery systems, generally requires plasticizers to improve its mechanical property. A plasticizer is supposed to weaken the intermolecular forces between the polymer chains, resulting in a softened and flexible polymer matrix. Thus, drug permeability through the membranes may also be affected by the addition of a plasticizer. The commonly used plasticizers in membrane formulations include phthalate esters, phosphate esters, fatty acid and glycol derivatives [5]. Polyethylene glycol (PEG) has been widely used in the field of controlled drug release [6]. Rao and Diwan [5] investigated the influence of PEG on the permeability of cellulose acetate films for the use of transdermal patches. It is necessary to investigate the mechanical, thermal and morphological properties of membranes fabricated with various PEG contents and at different temperatures. In this study, PEG (MW 600) was used as a plasticizer as well as a pore-forming
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agent and incorporated into cellulose acetate membranes. Due to its hydrophilicity, PEG can be easily removed by putting the membranes into an aqueous solution before they are assembled into transdermal patches. The cellulose acetate membranes aimed for transdermal delivery systems were fabricated at 22 and 40 jC via a dry casting method to investigate the effect of temperature on membrane morphologies and drug permeation rates. The morphologies and physical properties of resultant membranes were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), thermal mechanical analysis (TMA) and thermogravimetric analysis (TGA). Scopolamine base was used as a model drug. The permeation of scopolamine base through the cellulose acetate membranes fabricated under various conditions was also evaluated.
2. Materials and methods 2.1. Materials Cellulose acetate (approximate 40% acetyl content), scopolamine hydrochloride, and polyethylene glycol (PEG, MW 600) were purchased from Sigma Aldrich (St. Louis, USA). Acetone (A.C.S. reagent) was obtained from Mallinckrodt Baker (Phillipsburg, NJ, USA). Phosphate buffer (PBS, pH 7.4) and monobasic potassium phosphate (KH2PO4) buffer solutions (pH 3.0) were prepared in our laboratory using the chemicals obtained from Merck (Darmstadt, Germany). Scopolamine hydrochloride was neutralized using sodium hydroxide to gain scopolamine base.
2.2. Membrane fabrication Cellulose acetate was dissolved in acetone at a concentration of 3% w/w and the solution was shaken at ambient temperature for 1 day. Twenty milliliters of the polymer solution was poured into a glass petri-dish (100 15 mm2) with a diameter of 9 mm and dried at 22 and 40 jC in an oven for 3 days. The PEG content in the membranes varied from 0%, 10%, 20%, 30%, 40% to 50% (w/w). The collected membranes were stored in a dessicator under vacuum for at least 24 h before use. 2.3. Thermal analysis Differential scanning calorimetry (DSC) studies were carried out by using MDSC 2920 (TA Instruments, DE, USA) with 7– 10 mg of the membranes. Temperature was cycled from 0 to 230 jC at a rate of 10 jC/min under nitrogen atmosphere. The membranes were kept under vacuum conditions before tested. 2.4. Thermal mechanical analysis The properties of cellulose acetate membranes were also characterized by thermal mechanical analysis (TMA 2940, TA Instruments). A constant force of 0.05 N was applied, and the membranes were heated at a constant rate of 5 jC/min from ambient temperature to 200 jC under nitrogen atmosphere. The glass transition temperatures were calculated from the inflection point of the transition.
Fig. 1. DSC curves of membranes fabricated at 22 jC (first heating) with different PEG contents.
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Fig. 2. DSC curves of membranes fabricated at 22 jC (second heating) with different PEG contents.
2.5. Mechanical properties
2.7. Morphological analysis
Mechanical properties were tested by using Instron equipment (Instron Wolpert, Ludwigshafen, Germany) with cellulose acetate membranes (25 mm in length, 5 mm in width and 0.1 mm in thickness). The gauge length used was 10 mm. The films were driven at a speed of 10 mm/min. The load and displacement data at rupture were converted to tensile strength (MPa) and elongation. At least four films were tested for each sample.
The morphologies of the top and bottom surfaces of cellulose acetate membranes were studied by using a JSM6700F field emission scanning electron microscope (FEGSEM, Jeol, Tokyo, Japan). The dried membranes were vacuum-coated under argon atmosphere using a JFC-1200 fine coater (Jeol, Tokyo, Japan). The current was set at 30 mA with a coating time of 20– 30 s. 2.8. Permeation of scopolamine base
2.6. Thermogravimetric analysis The weight loss studies versus temperature were performed by using Thermogravimetric Analyser TGA 7 (Perkin-Elmer Instruments, Wellesley, MA, USA). Five to six milligrams of vacuum dried samples were initially held at 100 jC for 2 min and the temperature was then raised to 450 jC at a rate of 10 jC/min under air condition. The 1% weight loss temperature (T1%), 5% weight loss temperature (T5%), and the derivative decomposition temperature (downward peak, Td) were calculated.
The dissolution test of scopolamine base was carried out in the dissolution test system (VK 7000, Vankel Technology Group, Cary, NC, USA). One milliliter of scopolamine base aqueous solution with a concentration of 100 mg/ml was used as the drug reservoir. The bath temperature was kept at 32 jC and the stirring speed was at 110 rpm. At predetermined time intervals, 1 ml of each sample solution was withdrawn from the buffer vessels and
Table 2 Decomposition temperatures of the membranes fabricated at 22 jC Table 1 Glass transition temperatures (jC) of the membranes measured by TMA
PEG percentage in the membranes (%)
T1% (jC)
T5% (jC)
Td (jC)
PEG content (%)
22 jC membranes
40 jC membranes
0 10 20 30 40 50
206.2 166.9 159.0 145.2 144.2 144.0
201.8 192.7 173.7 173.4 165.4 150.1
0 10 20 30 40 50 Pure PEG
298.7 286.4 276.4 263.5 267.8 262.6 280.9
350.6 331.4 323.0 310.4 314.5 311.7 349.2
393.6 384.1 380.4 378.3 372.8 395.6 425.5
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replaced with 1 ml of fresh buffer solution. The concentration of scopolamine base in the collected sample solutions was measured by high-performance liquid chromatography (HPLC) (Waters 2690D, Milford, MA, USA). The mobile phase consisted of 90% KH2PO4 aqueous solution (pH = 3) and 10% acetonitrile, and was delivered at a rate of 1 ml/min.
3. Results and discussion Fig. 1 shows the DSC data of membranes fabricated at 22 jC, which are obtained during the first heating process. A broad endothermic peak appears within the range of 60– 110 jC. It is nonreversible, which has been evidenced by the modulated DSC. Shieh and Chung [7] demonstrated that the peak was caused by the loss of moisture absorbed in the membranes. The endothermic peak was absent during the second heating process, while it appears again when the sample is placed in air. The TGA studies reveal that the membranes can absorb moisture in air up to 3 – 10% in weight depending on PEG content. According to McBrierty et al. [8], the loss of moisture within the temperature range of 60 –110 jC is due to the h*-relaxation, indicating the existence of water-bound sites in cellulose. As shown in Fig. 1, the membranes with 0%, 10%, 20%, 30%, 40%, and 50% PEG have an endothermic peak at 95.5, 91.2, 88.0, 108.8, 87.5, and 77.9 jC, respectively. The difference in the peak position may reflect the structure of the membranes and the interactions among PEG, polymer and water. However, for membranes with 40% and 50% PEG, the endothermic peak is not as sharp as others. This may be due to the phase separation of PEG and
cellulose acetate. As reported previously [8], glass transition temperature (Tg) of the membranes can be estimated via the transition occurring after the endothermic peak. The glass transition temperatures of membranes fabricated at 22 jC are 198.1, 177.5, 166.0, 162.5, 152.8 and 133.9 jC, respectively, in the order of increased PEG content from 0% to 50%. Clearly, an increased PEG content yields a lower T g. Fig. 2 gives the DSC results obtained from the second heating process of cellulose acetate membranes. After removal of moisture and a thermal history, the melting point of PEG (around 21 jC) appears in the membranes with 40% and 50% PEG, indicating the occurrence of phase separation. Their melting enthalpies are 0.77 J/g and 8.25 J/g, respectively. The DSC results of membranes fabricated at 40 jC are similar to those of membranes fabricated at 22 jC. Their corresponding endothermic peaks in the first heating process are 91.0, 94.2, 82.0, 81.7, 61.6 and 68.7 jC, slightly lower than those of membranes fabricated at 22 jC. Their corresponding glass transition temperatures are 206.7, 196.7, 174.2, 162.6, 130.2 and 128.3 jC, respectively. The enthalpy values of endothermic peaks are also estimated, and the membranes fabricated at 40 jC have a lower value than the membranes fabricated at 22 jC. Since membranes are fabricated at a higher temperature, less moisture is absorbed, probably resulting in lower endothermic temperatures and lower enthalpy values. In particular, the water – polymer interactions may be weakened by higher fabrication temperature. Higher Tg may originate from the denser structures of the membranes, as shown in Figs. 4 and 5. In addition, it is observed that 22 jC membranes are opaque but 40 jC membranes are transparent. In the second heating
Fig. 3. Mechanical properties of membranes fabricated at 22 and 40 jC with different PEG contents (o: membranes fabricated at 22 jC, D: membranes fabricated at 40 jC; full black: mechanical strength, semi-black: elongation at rupture).
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of 40 jC membranes, phase separation also occurs in the membranes with 40% and 50% PEG. The melting enthalpies of PEG in the membranes are 1.20 J/g and 16.2 J/g, respectively. In contrast with the lower values of enthalpy obtained for the membranes fabricated at 22 jC, we would suggest that the membranes fabricated at 40 jC have more PEG in the separated phase. Increasing fabrication temperature may facilitate phase separation and weaken the interactions between PEG and cellulose acetate. This may be another reason yielding higher Tg of membranes fabricated at 40 jC.
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The glass transition temperatures of the membranes were also measured by TMA (Table 1). These data further confirm that the addition of PEG does decrease Tg of the membrane as shown by DSC curves. Moreover, the fabrication temperature also affects Tg of the membrane, in accordance with the results revealed by DSC studies. The weight loss of membranes versus temperature is investigated by TGA, and the results are shown in Table 2. It is found that PEG slightly reduces the degradation temperature of cellulose acetate. However, both cellulose acetate and PEG have no detectable degradation below 200 jC.
Fig. 4. Surface morphologies of membranes fabricated at 22 jC, (A) without PEG, top surface; (B) without PEG, bottom surface; (C) 10% PEG, top surface; (D) 10% PEG, bottom surface; (E) 30% PEG, top surface; (F) 30% PEG, bottom surface. Size of the bar is 1 Am.
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Fig. 3 shows the mechanical properties of membranes. It is found that with the increase of PEG loading, the tensile strength of membrane is decreased but the elongation at rupture is increased. However, when phase separation occurs in membranes with 40% and 50% PEG, their mechanical properties deteriorate significantly. This is evidenced by a tremendous decrease in elongation at rupture and tensile strength. It is also observed that the membranes fabricated at 40 jC have a higher mechanical strength resulting from more homogenous structures (Figs. 4 and 5).
From Fig. 4A and B, it can be seen that the membrane fabricated at 22 jC without PEG has a few pores on the top surface with a size of around 50 nm. In contrast, there are a number of pores with a size of 100 nm on its bottom surface. This may be due to the roughness of petri-dish surface as well as the interfacial tension between the polymer solution and the petri-dish. Fig. 4C and D demonstrates that the addition of PEG leads to a great difference in membrane morphologies. Membranes with 10% and 30% PEG become significantly more porous on the bottom surface. Most of
Fig. 5. Surface morphologies of membranes fabricated at 40 jC, (A) without PEG, top surface; (B) without PEG, bottom surface; (C) 10% PEG, top surface; (D) 10% PEG, bottom surface; (E) 30% PEG, top surface; (F) 30% PEG, bottom surface. Size of the bar is 1 Am.
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the pores are larger than 100 nm and some of them even reach 1 Am. A 30% PEG yields even more pores on both top and bottom surfaces (Fig. 4E and F). PEG is a non-solvent for cellulose acetate and can facilitate the phase inversion of the polymer solution [9]. Faster phase inversion induced by the addition of PEG leads to more porous membrane structures. The morphology difference between the top surface and bottom surface may also arise from the difficulty in solvent transferring during the membrane formation. For 40 jC membranes (Fig. 5), the difference in morphologies between the two surfaces is significantly reduced. The possible reason is that high temperature facilitates solvent transfer. Interestingly, the porosity of membranes fabricated at 40 jC is also decreased as compared with that of membranes fabricated at 22 jC and it decreases with the increase of the PEG content. As presented previously, the addition of PEG decreases the Tg of the membranes, which may, subsequently, result in denser structures due to the relaxation of the polymer chains during the membrane formation process. The more PEG is used, the lower Tg and the denser structure are obtained. Figs. 6 and 7 give the permeation results of scopolamine through the membranes fabricated at 22 and 40 jC. Since the mechanical strength of membranes with 40% and 50% PEG is deteriorated due to the phase separation, the permeation experiments are not performed with these membranes. It can be observed that for the membranes fabricated at both 22 and 40 jC, the permeation rate of scopolamine base increases with an increased PEG content, and the PEGfree membranes do not allow drug permeation throughout the whole period of dissolution tests. The increased drug flux may be attributed to the pores formed by the dissolution of PEG out of the membranes. The formation of a large number of pores on the membrane surfaces after immersed in PBS buffer is observed in SEM scans. Our experimental results reveal that most of PEG is released out of the membranes within 1 h. Therefore, the permeation of scopolamine base through the membranes is enhanced by the pores formed after the dissolution of PEG. More PEG generates
99
Fig. 7. Cumulative amount of scopolamine base permeating through the membranes fabricated at 40 jC.
more pores and forms more channels for the drug to diffuse out. For most of the PEG-incorporated membranes fabricated at 22 jC, there is a high initial drug flux within the first 24 h, followed by a slow drug release. This may be due to the fast consumption of scopolamine base in the drug reservoir, resulting in a decreased driving force for drug permeation. However, for the membranes fabricated at 40 jC, linear release profiles have been obtained with 10% and 20% PEG. This is due to much slower release rate of scopolamine through the membranes, especially when PEG content is low. Thus, the driving force is kept relatively constant throughout the 3-day dissolution tests. Since the membranes fabricated at 22 jC are more porous than those fabricated at 40 jC, the drug release rate through the former membranes is higher. Therefore, PEG content and fabrication temperature should be optimized to yield a desired drug permeation rate.
4. Conclusions In this study, the PEG-incorporated cellulose acetate membranes have been fabricated at 22 and 40 jC and characterized. Both PEG content and fabrication temperature affect the properties of resultant membranes. The structures of membranes fabricated at 40 jC are more homogeneous and denser. The permeation rate of scopolamine base through the membranes fabricated at 40 jC with 10% and 20% PEG is constant over 3 days in vitro. PEG content should be optimized to yield membranes with good mechanical properties and provide a linear release profile of a drug.
References Fig. 6. Cumulative amount of scopolamine base permeating through the membranes fabricated at 22 jC.
[1] Y.W. Chien, Advances in transdermal systemic medium, in: Y.W. Chien (Ed.), Transdermal Controlled Systemic Medications, Marcel Dekker, New York, 1987, pp. 1 – 22.
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[2] S.K. Chandrasekaran, Controlled release of scopolamine for the prophylaxis of motion sickness, Drug Dev. Ind. Pharm. 9 (1983) 627 – 646. [3] S.P. Clissold, R.C. Heel, Transdermal hyoscine (scopolamine): a preliminary review of pharmacodynamic properties and therapeutic efficacy, Drugs 29 (1985) 189 – 207. [4] Z. Nachum, B. Shahal, A. Shupak, O. Spitzer, A. Gonen, I. Beiran, H. Lavon, M. Eynan, S. Dachir, A. Levy, Scopolamine bioavailability in combined oral and transdermal delivery, J. Pharmacol. Exp. Ther. 296 (2001) 121 – 123. [5] P.R. Rao, P.V. Diwan, Permeability studies of cellulose acetate free films for transdermal use: influence of plasticizers, Pharm. Acta Helv. 72 (1997) 47 – 51.
[6] R.L. Cleek, K.C. Ting, S.G. Eskin, A.G. Mikos, Microparticles of poly (DL-lactide-co-glycolide)/poly(ethylene glycol) blends for controlled drug delivery, J. Controlled Release 48 (1997) 259 – 268. [7] J.J. Shieh, T.S. Chung, Effect of liquid – liquid demixing on the membrane morphology, gas permeation, thermal and mechanical properties of cellulose acetate hollow fibers, J. Membr. Sci. 140 (1998) 67 – 79. [8] V.J. McBrierty, C.M. Keely, F.M. Coyle, H. Xu, J.K. Vij, Hydration and plasticization effects in cellulose acetate: molecular motion and relaxation, Faraday Discuss. 103 (1996) 255 – 268. [9] J.H. Kim, K.H. Lee, Effect of PEG additive on membrane formation by phase inversion, J. Membr. Sci. 138 (1998) 153 – 163.
Cellulose acetate membranes for transdermal delivery of scopolamine base Fang-Jing Wang a, Yi-Yan Yang a,*, Xian-Zheng Zhang a, Xiao Zhu b, Tai-shung Chung a,c, Shabbir Moochhala b a Institute of Materials Research and Engineering, No. 3 research Link, Singapore 117602, Singapore Defence Medical Research Institute, #01-06, MD2 National University of Singapore, Singapore 119260, Singapore c Department of Chemical and Environmental Engineering, National University of Singapore, Singapore 119260, Singapore b
Abstract Transdermal delivery is one of the most convenient drug administration routes. In this study, the cellulose acetate membranes were cast with acetone as a solvent at 22 and 40 jC. Polyethylene glycol (PEG, MW 600) was used as a pore-forming agent. The in vitro release rates of scopolamine base as a model drug through the membranes were evaluated in phosphate buffer solution (PBS, pH 7.4) at 32 jC. The membranes were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), thermal mechanical analysis (TMA) and thermogravimetric analysis (TGA). It was observed that the drug permeation through the cellulose acetate membranes was obviously affected by the incorporated PEG content and formed membrane morphology. There was no drug flux from the cellulose acetate membranes prepared without PEG. An increased PEG content resulted in a faster scopolamine release due to a more porous structure created. Both the membrane fabrication temperature and the PEG content can affect the thermal, mechanical and morphological properties of the resultant membranes. With the optimized fabrication conditions, linear in vitro release profiles of scopolamine over 3 days were achieved. The membranes developed would be useful for transdermal delivery of drugs. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Cellulose acetate membranes; Polyethylene glycol (PEG); Transdermal delivery; Scopolamine
1. Introduction Compared with oral and parenteral routes, drug delivery through skin can offer several advantages, for example, (1) bypassing the hepatic ‘‘first pass’’ elimination, (2) maintaining a constant, prolonged and therapeutically effective drug level in the bloodstream or tissues, (3) rapid termination of drug delivery, (4) improved patient compliance [1]. Scopolamine is the first drug marketed in a transdermal delivery form. Transdermal therapeutic scopolamine system (TTS-S, Novartis, Basel, Switzerland) was designed to deliver a total of 0.5 mg scopolamine over a 3-day period, and relieve the signs and symptoms of motion sickness [2,3]. The disadvantage of this design is that it needs 6 to 8 h for a therapeutic plasma level to appear after application. Nachum et al. [4] suggested using the combined oral and transdermal delivery of scopolamine to circumvent this problem.
*
Corresponding author. Tel.: +65-874-8123; fax: +65-872-7528. E-mail address: [email protected] (Y.-Y. Yang).
In the transdermal delivery systems, polymeric membrane is a key component and used to modulate the release rate of a therapeutic drug. Cellulose acetate is a widely used and investigated material both in the industry and in research. However, cellulose acetate, when used as a ratecontrolling membrane material for transdermal drug delivery systems, generally requires plasticizers to improve its mechanical property. A plasticizer is supposed to weaken the intermolecular forces between the polymer chains, resulting in a softened and flexible polymer matrix. Thus, drug permeability through the membranes may also be affected by the addition of a plasticizer. The commonly used plasticizers in membrane formulations include phthalate esters, phosphate esters, fatty acid and glycol derivatives [5]. Polyethylene glycol (PEG) has been widely used in the field of controlled drug release [6]. Rao and Diwan [5] investigated the influence of PEG on the permeability of cellulose acetate films for the use of transdermal patches. It is necessary to investigate the mechanical, thermal and morphological properties of membranes fabricated with various PEG contents and at different temperatures. In this study, PEG (MW 600) was used as a plasticizer as well as a pore-forming
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agent and incorporated into cellulose acetate membranes. Due to its hydrophilicity, PEG can be easily removed by putting the membranes into an aqueous solution before they are assembled into transdermal patches. The cellulose acetate membranes aimed for transdermal delivery systems were fabricated at 22 and 40 jC via a dry casting method to investigate the effect of temperature on membrane morphologies and drug permeation rates. The morphologies and physical properties of resultant membranes were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), thermal mechanical analysis (TMA) and thermogravimetric analysis (TGA). Scopolamine base was used as a model drug. The permeation of scopolamine base through the cellulose acetate membranes fabricated under various conditions was also evaluated.
2. Materials and methods 2.1. Materials Cellulose acetate (approximate 40% acetyl content), scopolamine hydrochloride, and polyethylene glycol (PEG, MW 600) were purchased from Sigma Aldrich (St. Louis, USA). Acetone (A.C.S. reagent) was obtained from Mallinckrodt Baker (Phillipsburg, NJ, USA). Phosphate buffer (PBS, pH 7.4) and monobasic potassium phosphate (KH2PO4) buffer solutions (pH 3.0) were prepared in our laboratory using the chemicals obtained from Merck (Darmstadt, Germany). Scopolamine hydrochloride was neutralized using sodium hydroxide to gain scopolamine base.
2.2. Membrane fabrication Cellulose acetate was dissolved in acetone at a concentration of 3% w/w and the solution was shaken at ambient temperature for 1 day. Twenty milliliters of the polymer solution was poured into a glass petri-dish (100 15 mm2) with a diameter of 9 mm and dried at 22 and 40 jC in an oven for 3 days. The PEG content in the membranes varied from 0%, 10%, 20%, 30%, 40% to 50% (w/w). The collected membranes were stored in a dessicator under vacuum for at least 24 h before use. 2.3. Thermal analysis Differential scanning calorimetry (DSC) studies were carried out by using MDSC 2920 (TA Instruments, DE, USA) with 7– 10 mg of the membranes. Temperature was cycled from 0 to 230 jC at a rate of 10 jC/min under nitrogen atmosphere. The membranes were kept under vacuum conditions before tested. 2.4. Thermal mechanical analysis The properties of cellulose acetate membranes were also characterized by thermal mechanical analysis (TMA 2940, TA Instruments). A constant force of 0.05 N was applied, and the membranes were heated at a constant rate of 5 jC/min from ambient temperature to 200 jC under nitrogen atmosphere. The glass transition temperatures were calculated from the inflection point of the transition.
Fig. 1. DSC curves of membranes fabricated at 22 jC (first heating) with different PEG contents.
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Fig. 2. DSC curves of membranes fabricated at 22 jC (second heating) with different PEG contents.
2.5. Mechanical properties
2.7. Morphological analysis
Mechanical properties were tested by using Instron equipment (Instron Wolpert, Ludwigshafen, Germany) with cellulose acetate membranes (25 mm in length, 5 mm in width and 0.1 mm in thickness). The gauge length used was 10 mm. The films were driven at a speed of 10 mm/min. The load and displacement data at rupture were converted to tensile strength (MPa) and elongation. At least four films were tested for each sample.
The morphologies of the top and bottom surfaces of cellulose acetate membranes were studied by using a JSM6700F field emission scanning electron microscope (FEGSEM, Jeol, Tokyo, Japan). The dried membranes were vacuum-coated under argon atmosphere using a JFC-1200 fine coater (Jeol, Tokyo, Japan). The current was set at 30 mA with a coating time of 20– 30 s. 2.8. Permeation of scopolamine base
2.6. Thermogravimetric analysis The weight loss studies versus temperature were performed by using Thermogravimetric Analyser TGA 7 (Perkin-Elmer Instruments, Wellesley, MA, USA). Five to six milligrams of vacuum dried samples were initially held at 100 jC for 2 min and the temperature was then raised to 450 jC at a rate of 10 jC/min under air condition. The 1% weight loss temperature (T1%), 5% weight loss temperature (T5%), and the derivative decomposition temperature (downward peak, Td) were calculated.
The dissolution test of scopolamine base was carried out in the dissolution test system (VK 7000, Vankel Technology Group, Cary, NC, USA). One milliliter of scopolamine base aqueous solution with a concentration of 100 mg/ml was used as the drug reservoir. The bath temperature was kept at 32 jC and the stirring speed was at 110 rpm. At predetermined time intervals, 1 ml of each sample solution was withdrawn from the buffer vessels and
Table 2 Decomposition temperatures of the membranes fabricated at 22 jC Table 1 Glass transition temperatures (jC) of the membranes measured by TMA
PEG percentage in the membranes (%)
T1% (jC)
T5% (jC)
Td (jC)
PEG content (%)
22 jC membranes
40 jC membranes
0 10 20 30 40 50
206.2 166.9 159.0 145.2 144.2 144.0
201.8 192.7 173.7 173.4 165.4 150.1
0 10 20 30 40 50 Pure PEG
298.7 286.4 276.4 263.5 267.8 262.6 280.9
350.6 331.4 323.0 310.4 314.5 311.7 349.2
393.6 384.1 380.4 378.3 372.8 395.6 425.5
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replaced with 1 ml of fresh buffer solution. The concentration of scopolamine base in the collected sample solutions was measured by high-performance liquid chromatography (HPLC) (Waters 2690D, Milford, MA, USA). The mobile phase consisted of 90% KH2PO4 aqueous solution (pH = 3) and 10% acetonitrile, and was delivered at a rate of 1 ml/min.
3. Results and discussion Fig. 1 shows the DSC data of membranes fabricated at 22 jC, which are obtained during the first heating process. A broad endothermic peak appears within the range of 60– 110 jC. It is nonreversible, which has been evidenced by the modulated DSC. Shieh and Chung [7] demonstrated that the peak was caused by the loss of moisture absorbed in the membranes. The endothermic peak was absent during the second heating process, while it appears again when the sample is placed in air. The TGA studies reveal that the membranes can absorb moisture in air up to 3 – 10% in weight depending on PEG content. According to McBrierty et al. [8], the loss of moisture within the temperature range of 60 –110 jC is due to the h*-relaxation, indicating the existence of water-bound sites in cellulose. As shown in Fig. 1, the membranes with 0%, 10%, 20%, 30%, 40%, and 50% PEG have an endothermic peak at 95.5, 91.2, 88.0, 108.8, 87.5, and 77.9 jC, respectively. The difference in the peak position may reflect the structure of the membranes and the interactions among PEG, polymer and water. However, for membranes with 40% and 50% PEG, the endothermic peak is not as sharp as others. This may be due to the phase separation of PEG and
cellulose acetate. As reported previously [8], glass transition temperature (Tg) of the membranes can be estimated via the transition occurring after the endothermic peak. The glass transition temperatures of membranes fabricated at 22 jC are 198.1, 177.5, 166.0, 162.5, 152.8 and 133.9 jC, respectively, in the order of increased PEG content from 0% to 50%. Clearly, an increased PEG content yields a lower T g. Fig. 2 gives the DSC results obtained from the second heating process of cellulose acetate membranes. After removal of moisture and a thermal history, the melting point of PEG (around 21 jC) appears in the membranes with 40% and 50% PEG, indicating the occurrence of phase separation. Their melting enthalpies are 0.77 J/g and 8.25 J/g, respectively. The DSC results of membranes fabricated at 40 jC are similar to those of membranes fabricated at 22 jC. Their corresponding endothermic peaks in the first heating process are 91.0, 94.2, 82.0, 81.7, 61.6 and 68.7 jC, slightly lower than those of membranes fabricated at 22 jC. Their corresponding glass transition temperatures are 206.7, 196.7, 174.2, 162.6, 130.2 and 128.3 jC, respectively. The enthalpy values of endothermic peaks are also estimated, and the membranes fabricated at 40 jC have a lower value than the membranes fabricated at 22 jC. Since membranes are fabricated at a higher temperature, less moisture is absorbed, probably resulting in lower endothermic temperatures and lower enthalpy values. In particular, the water – polymer interactions may be weakened by higher fabrication temperature. Higher Tg may originate from the denser structures of the membranes, as shown in Figs. 4 and 5. In addition, it is observed that 22 jC membranes are opaque but 40 jC membranes are transparent. In the second heating
Fig. 3. Mechanical properties of membranes fabricated at 22 and 40 jC with different PEG contents (o: membranes fabricated at 22 jC, D: membranes fabricated at 40 jC; full black: mechanical strength, semi-black: elongation at rupture).
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of 40 jC membranes, phase separation also occurs in the membranes with 40% and 50% PEG. The melting enthalpies of PEG in the membranes are 1.20 J/g and 16.2 J/g, respectively. In contrast with the lower values of enthalpy obtained for the membranes fabricated at 22 jC, we would suggest that the membranes fabricated at 40 jC have more PEG in the separated phase. Increasing fabrication temperature may facilitate phase separation and weaken the interactions between PEG and cellulose acetate. This may be another reason yielding higher Tg of membranes fabricated at 40 jC.
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The glass transition temperatures of the membranes were also measured by TMA (Table 1). These data further confirm that the addition of PEG does decrease Tg of the membrane as shown by DSC curves. Moreover, the fabrication temperature also affects Tg of the membrane, in accordance with the results revealed by DSC studies. The weight loss of membranes versus temperature is investigated by TGA, and the results are shown in Table 2. It is found that PEG slightly reduces the degradation temperature of cellulose acetate. However, both cellulose acetate and PEG have no detectable degradation below 200 jC.
Fig. 4. Surface morphologies of membranes fabricated at 22 jC, (A) without PEG, top surface; (B) without PEG, bottom surface; (C) 10% PEG, top surface; (D) 10% PEG, bottom surface; (E) 30% PEG, top surface; (F) 30% PEG, bottom surface. Size of the bar is 1 Am.
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Fig. 3 shows the mechanical properties of membranes. It is found that with the increase of PEG loading, the tensile strength of membrane is decreased but the elongation at rupture is increased. However, when phase separation occurs in membranes with 40% and 50% PEG, their mechanical properties deteriorate significantly. This is evidenced by a tremendous decrease in elongation at rupture and tensile strength. It is also observed that the membranes fabricated at 40 jC have a higher mechanical strength resulting from more homogenous structures (Figs. 4 and 5).
From Fig. 4A and B, it can be seen that the membrane fabricated at 22 jC without PEG has a few pores on the top surface with a size of around 50 nm. In contrast, there are a number of pores with a size of 100 nm on its bottom surface. This may be due to the roughness of petri-dish surface as well as the interfacial tension between the polymer solution and the petri-dish. Fig. 4C and D demonstrates that the addition of PEG leads to a great difference in membrane morphologies. Membranes with 10% and 30% PEG become significantly more porous on the bottom surface. Most of
Fig. 5. Surface morphologies of membranes fabricated at 40 jC, (A) without PEG, top surface; (B) without PEG, bottom surface; (C) 10% PEG, top surface; (D) 10% PEG, bottom surface; (E) 30% PEG, top surface; (F) 30% PEG, bottom surface. Size of the bar is 1 Am.
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the pores are larger than 100 nm and some of them even reach 1 Am. A 30% PEG yields even more pores on both top and bottom surfaces (Fig. 4E and F). PEG is a non-solvent for cellulose acetate and can facilitate the phase inversion of the polymer solution [9]. Faster phase inversion induced by the addition of PEG leads to more porous membrane structures. The morphology difference between the top surface and bottom surface may also arise from the difficulty in solvent transferring during the membrane formation. For 40 jC membranes (Fig. 5), the difference in morphologies between the two surfaces is significantly reduced. The possible reason is that high temperature facilitates solvent transfer. Interestingly, the porosity of membranes fabricated at 40 jC is also decreased as compared with that of membranes fabricated at 22 jC and it decreases with the increase of the PEG content. As presented previously, the addition of PEG decreases the Tg of the membranes, which may, subsequently, result in denser structures due to the relaxation of the polymer chains during the membrane formation process. The more PEG is used, the lower Tg and the denser structure are obtained. Figs. 6 and 7 give the permeation results of scopolamine through the membranes fabricated at 22 and 40 jC. Since the mechanical strength of membranes with 40% and 50% PEG is deteriorated due to the phase separation, the permeation experiments are not performed with these membranes. It can be observed that for the membranes fabricated at both 22 and 40 jC, the permeation rate of scopolamine base increases with an increased PEG content, and the PEGfree membranes do not allow drug permeation throughout the whole period of dissolution tests. The increased drug flux may be attributed to the pores formed by the dissolution of PEG out of the membranes. The formation of a large number of pores on the membrane surfaces after immersed in PBS buffer is observed in SEM scans. Our experimental results reveal that most of PEG is released out of the membranes within 1 h. Therefore, the permeation of scopolamine base through the membranes is enhanced by the pores formed after the dissolution of PEG. More PEG generates
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Fig. 7. Cumulative amount of scopolamine base permeating through the membranes fabricated at 40 jC.
more pores and forms more channels for the drug to diffuse out. For most of the PEG-incorporated membranes fabricated at 22 jC, there is a high initial drug flux within the first 24 h, followed by a slow drug release. This may be due to the fast consumption of scopolamine base in the drug reservoir, resulting in a decreased driving force for drug permeation. However, for the membranes fabricated at 40 jC, linear release profiles have been obtained with 10% and 20% PEG. This is due to much slower release rate of scopolamine through the membranes, especially when PEG content is low. Thus, the driving force is kept relatively constant throughout the 3-day dissolution tests. Since the membranes fabricated at 22 jC are more porous than those fabricated at 40 jC, the drug release rate through the former membranes is higher. Therefore, PEG content and fabrication temperature should be optimized to yield a desired drug permeation rate.
4. Conclusions In this study, the PEG-incorporated cellulose acetate membranes have been fabricated at 22 and 40 jC and characterized. Both PEG content and fabrication temperature affect the properties of resultant membranes. The structures of membranes fabricated at 40 jC are more homogeneous and denser. The permeation rate of scopolamine base through the membranes fabricated at 40 jC with 10% and 20% PEG is constant over 3 days in vitro. PEG content should be optimized to yield membranes with good mechanical properties and provide a linear release profile of a drug.
References Fig. 6. Cumulative amount of scopolamine base permeating through the membranes fabricated at 22 jC.
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