International Journal of Biological Macromolecules 77 (2015) 207–213
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International Journal of Biological Macromolecules journal homepage: www.elsevier.com/locate/ijbiomac
Modified hydroxypropyl methyl cellulose: Efficient matrix for controlled release of 5-amino salicylic acid Raghunath Das, Sagar Pal ∗ Polymer Chemistry Laboratory, Department of Applied Chemistry, Indian School of Mines, Dhanbad 826004, India
a r t i c l e
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Article history: Received 30 November 2014 Received in revised form 20 February 2015 Accepted 7 March 2015 Available online 19 March 2015 Keywords: 5-Amino salicylic acid Controlled drug release HPMC
a b s t r a c t Hydroxypropyl methyl cellulose has been modified by grafting synthetic polyacrylamide chains [g-HPMC (M)] in presence of microwave irradiation, which has used as carrier for controlled release of 5-amino salicylic acid (5-ASA). The FTIR and UV–vis–NIR studies reveal the excellent compatibility between g-HPMC (M) and 5-ASA. Field emission scanning electron microscopy (FESEM) and UV–vis–NIR analyses suggest that physical interaction predominates between the drug and matrix. % equilibrium swelling ratio (% ESR) of g-HPMC (M) decreased with addition of salt solutions and follow the order: Na+ > K+ > Mg2+ > Ca2+ > Al3+ . The in vitro 5-ASA release studies indicate that g-HPMC (M) delivers the drug preferentially in colonic region in more sustained way than that of HPMC. The 5-ASA release follows first order kinetics and nonFickian diffusion mechanism. These favorable features make the graft copolymer a potential matrix for colon specific delivery of 5-ASA. © 2015 Elsevier B.V. All rights reserved.
1. Introduction In recent years, polymeric materials have gained significant attention for the delivery of various therapeutic agents. Biodegradable polymers are widely used for encapsulating drugs and their subsequent release behaviour [1–6]. Recently, targeted or sitespecific drug delivery [7–9] is one of the major challenge in disease therapy. Among the various modes of drug delivery, oral mode is the most suitable and commonly employed route owing to its ease of administration, cost effectiveness, high patient compliance, and flexibility in the design of dosage form [10–14]. Site-specific drug delivery to the colonic region has great importance in the field of pharmacotherapy. Several colonic diseases such as inflammatory bowel disease (IBD), ulcerative colitis, Crohn’s disease can be treated more effectively by local delivery of antiinflammatory agents to the large intestine [15–18]. However, the systemic absorption of drugs from the upper part of the gastrointestinal tract of the human body may causes side effects. These can be eliminated or reduced by protecting the drug release prior to its entry in colonic region. An ideal colon specific drug delivery system should protect the release of drug from the acidic pH of the stomach. Simultaneously, it should release the drug rapidly into the proximal colon (i.e. in lower gastrointestinal tract). Thus, the pH-responsive
∗ Corresponding author. Tel.: +91 326 2235769; fax: +91 326 2296615. E-mail addresses: [email protected], [email protected] (S. Pal). http://dx.doi.org/10.1016/j.ijbiomac.2015.03.015 0141-8130/© 2015 Elsevier B.V. All rights reserved.
polymeric systems would be preferable for the colon targeted drug delivery [19–23]. 5-Amino salicylic acid (5-ASA) is also known as mesalamine, which belongs to the category of amino derivative of salicylic acid. It is an active component of azulfidine, a combination of a sulfa drug. 5-ASA is used as an anti-inflammatory drug. The immune system in our human body locates and destroys harmful substances, called antigens (such as bacteria, viruses, poisons). Inflammation is one of the basic tools of our immune system which can protect our bodies from bacteria, viruses, microbes and other foreign substances. Immune system (specifically white blood cells) produces certain disease-fighting chemicals and sends them to the areas of the body affected by the antigens. The chemicals fight the antigens, but at the same time also cause the redness, swelling, and pain which we recognize as symptoms of inflammation. This medication (5-ASA) is effectively used to treat ulcerative colitis, helps to reduce rectal bleeding, stomach pain and also mild to moderate Crohn’s disease. 5-ASA works to diminish the overgrowth of bacteria in the body, particularly in the colonic region that causes inflammation, tissue damage and diarrhea. As a derivative of salicylic acid, mesalamine is also considered as antioxidant that traps free radicals, which potentially damaged the by-products of metabolism. From last few decades, cellulose derivatives [24,25] are extensively used in controlled drug release applications. Hydroxypropyl methyl cellulose (HPMC), one of the most important cellulose derivatives are used frequently as a carrier for controlled release of drugs in tablet formulations [26–29]. However, the use of
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unmodified polysaccharides has certain limitations in drug delivery applications such as faster rate of drug release, higher rate of erosion and so on. To overcome these limitations and modify the polysaccharides, several methods have been developed. Grafting is one of the most important methods for the synthesis of modified biopolymer/natural polymers for controlled drug delivery applications. Recently in authors’ laboratory, various modified polysaccharides have been developed and used as matrices for controlled release of model drugs [30–33]. More recently, we have designed a novel pH sensitive graft copolymer derived from HPMC and poly (acrylamide) in presence of microwave irradiation [30]. Out of various techniques, microwave irradiation based grafting process improves the reaction rate and % grafting efficiency (% GE). The electromagnetic irradiation selectively excites the polar bonds compared to the non-polar bonds of polysaccharides which results in the cleavage/breakage of only polar bonds. This results free radical sites for grafting on polysaccharide surface without cleavage of C C bond. Subsequently, the product selectivity was enhanced in compared to conventional chemical grafting method. It was also explained before that higher the % GE, better would be the efficacy as matrix for controlled release of drugs [33]. Thus in one hand, HPMC because of its natural abundance, presence of hydroxyl groups, inexpensive and biocompatible nature, and on the other hand polyacrylamide can play important role for stimulus responsive behaviour, the developed copolymer i.e. g-HPMC (M) probably be a suitable candidate for colon specific drug carrier. Herein, we report the application of polyacrylamide modified HPMC developed by microwave irradiation [g-HPMC (M)] for controlled release of colonic drug – 5-ASA. The synthesized hydrogel seems to be a potential candidate for 5-ASA carrier as it demonstrates the supplementary requirements such as excellent compatibility with the drug (as evidenced from UV–vis–NIR, FTIR and FESEM analyses), better swelling characteristics [30], pH-responsive behaviour, non-cytotoxic and biodegradable nature [30]. The details of drug release mechanism and kinetics has also been explored. The in vitro release profiles suggest that g-HPMC (M) releases 5-ASA in a more sustained way than that of neat HPMC.
g-HPMC 6 (M) has been further characterized and used it as matrix for in vitro controlled release of 5-ASA. 2.3. Characterization FTIR spectra of g-HPMC (M), 5-ASA and tablet formulations were recorded in solid state using FTIR spectrometer (IR-Perkin Elmer, Spectrum 2000, USA). Solid state UV–vis–NIR study was performed using Cary series UV–vis–NIR Spectrophotometer (Cary–5000). The TGA and DTG analyses of g-HPMC (M) were executed using a thermogravimetric analyser (Shimadzu DTG–60) with a heating rate of 10 ◦ C/min under nitrogen atmosphere. The surface morphologies of the copolymer, 5-ASA and the tablet formulation were carried out in dry state using field emission scanning electron microscopy (FESEM Supra 55, Make – Zeiss, Germany). 2.4. Swelling characteristics in various salt solutions The extracellular fluids of the human body contain various ions including sodium, potassium, calcium, chloride, hydrogen carbonate. Whereas, the plasma contains mineral ions like Na+ , K+ , Mg2+ , HCO3 − , Cl− . Thus it is essential to observe the effect of various salts on swelling behaviour of the hydrogels for drug delivery applications. Because of the interactions between hydrogel and salt cations, it may affect the rate of swelling of the hydrogel. Besides it was also observed that the drug release is directly proportional to the swelling behaviour of the hydrogel. For this purpose, the equilibrium swelling characteristic of gHPMC (M) was carried out in aqueous media and different salt solutions (LiCl, NaCl, KCl, MgCl2 , CaCl2 , BaCl2 , AlCl3 ) through gravimetric method. A known weight of dried polymer [g-HPMC (M)] was taken and immersed into 100 mL of water or in various salt solutions for 24 h at a constant temperature (37 ◦ C). After a certain time interval (every 3 h) swollen polymer was withdrawn, wiped with tissue paper to remove excess of solvent, and then reweighed. The equilibrium swelling was attained at ∼21 h. The % swelling (Ps) of g-HPMC (M) was calculated using Eq. (1) [30,31]. Ps =
Weight of swollen gel − Weight of dried gel × 100 Weight of dried gel
(1)
2. Materials and methods 2.5. Determination of % erosion 2.1. Materials HPMC (Lancaster, UK), acrylamide (E. Merck, Mumbai, India), potassium persulphate (Qualigens Fine chemicals, Mumbai, India), 5-ASA (AR Grade, Spectrochem Pvt. Ltd. Mumbai, India), acetone (S. D. Fine chemicals, Mumbai, India), hydroquinone (S. D. Fine chemicals, Mumbai, India) were used as received, without further purification. 2.2. Preparation of g-HPMC (M) in presence of microwave irradiation The graft copolymer [g-HPMC (M)] was developed by free radical polymerization using microwave irradiation. The reaction was performed at a temperature of 70 ◦ C in presence of 900 W microwave irradiation and potassium persulphate initiator. The details of reaction conditions and procedure have been described in our previous report [30]. The homopolymer (i.e. polyacrylamide), which was formed during the copolymerization reaction was separated through solvent extraction method (using 1:1 formamide/acetic acid) [30]. By variation of reaction parameters, series of graft copolymers [g-HPMC (M)] were synthesized and optimized the best one with respect to higher % GE and lower % equilibrium swelling ratio [30]. Here the optimized copolymer i.e.
Rate of drug release from polymer matrix also depends on the erosion of matrix. It is presumed that erosion of the polymer matrix starts once ‘critical gel concentration’ attained [32]. The % erosion (% ER) was determined using Eq. (2) [32]. %ER =
Wi − Wd (t) − Wdrug (1 − Mt /M∞ ) Wi
× 100
(2)
where, Wi is the initial weight of the dried tablet, Wd is the weight of the dried tablet at time t, Wdrug is the initial weight of the drug, Mt /M∞ is the fraction of drug release at time t. 2.6. In vitro 5-amino salicylic acid (5-ASA) release study 2.6.1. Preparation of tablet 450 mg of g-HPMC (M) as matrix, 50 mg of guar gum as binder and 500 mg of 5-ASA was used for the tablet preparation. The tablet was prepared in the same method as reported previously [30,32]. 2.6.2. 5-Amino salicylic acid release study The in vitro release of loaded 5-ASA drug from neat HPMC and gHPMC (M) was investigated using dissolution apparatus (Lab India, Model: DS 8000) with constant rotation of 60 rpm at 37 ± 0.5 ◦ C using 900 mL various buffer solutions related to simulated gastric
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Fig. 1. Proposed scheme and probable structure of g-HPMC (M).
fluid (pH 1.2) and intestinal fluid (pH 7.4). After every 1 h, 10 mL aliquot was withdrawn from the release media and replaced by an equal volume of buffers at each sampling time. The amount of drug release was measured with the help of absorbance (max : 303 nm at pH – 1.2, and max : 331 nm at pH – 7.4) in UV–visible spectrophotometer (Model UV-1800, Shimadzu, Japan). The rate of drug release was graphically represented in form of drug release profile (% cumulative drug release vs. time). 2.6.3. Drug release kinetics and mechanism The drug release kinetics was investigated using zero order [34] and first order [35] kinetics models. To investigate the release mechanism, the release data were fitted in Korsmeyer–Peppas [36] and Kopcha models [37]. 3. Results and discussions 3.1. Synthesis of g-HPMC (M) copolymers Polyacrylamide functionalized HPMC [g-HPMC (M)] was prepared in presence of microwave irradiation and potassium persulphate (KPS) initiator [30]. With the variation of reaction parameters, different grades of g-HPMC (M) were synthesized to optimize the best copolymer [30]. It was assumed that initially in presence of microwave irradiation, KPS generates free radical sites on HPMC backbone. Besides, acrylamide (monomer) polymerized to form polyacrylamide chains into the reaction media. After that, the generated free radical of HPMC react with polyacrylamide chains to form graft copolymer i.e. g-HPMC (M) [30]. The polymerization reaction was terminated using hydroquinol solution. The reaction mixture was dispersed in acetone for the removal of homopolymer (i.e. polyacrylamide) and unreacted monomer. The proposed mechanism for the development of g-HPMC (M) has been shown in our previous report [30]. The probable formation of gHPMC (M) is shown in Fig. 1.
Fig. 2. Probable interactions between g-HPMC (M) and 5-ASA.
characteristic peak of 5-ASA (332.3 nm) shifted to lower value (326.4 nm) in tablet formulation, which signifies a blue shift. This confirmed the physical interaction between the drug and the copolymer as specified in Fig. 2.
3.2. Physical characterization FTIR spectra of HPMC [31], g-HPMC (M) [30], 5-ASA and tablet formulations are reported in Table 1. From FTIR spectra of tablet formulation (Table 1), it is apparent that all the peaks of 5-ASA are present but the frequency of amide-I and amide-II of g-HPMC (M) shifted toward lower value (in case of amide-I: 1660–1626 cm−1 , for amide-II: 1588–1548 cm−1 ). The O H stretching vibrations shifted from 3433 cm−1 to 3420 cm−1 . This observation indicates the good compatibility between drug and matrix along with physical interactions between them as shown in Fig. 2. Fig. 3 demonstrates the UV–vis–NIR spectra of g-HPMC (M), 5-ASA and tablet formulation. It is obvious from the spectra that
Fig. 3. UV–vis–NIR study of the drug, g-HPMC (M) and triturated form of tablet.
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Table 1 FTIR values of HPMC, g-HPMC (M), pure 5-ASA, and 5-ASA tablets. Substrate
OH str.
NH Str.
CH str.
C O str.
Amide-I, amide-II str.
CH2 scissoring
NH bending
OH bending
C N str.
HPMC [31]
3485
2936
–
–
1458
–
1378
–
g-HPMC (M) [30]
3433
2912
–
1451
–
1349
1397
5-ASA 5-ASA tablet (initial)
3455 3420
2922 2929
1648 –
1660 1588 – 1626 1548
– 1451
1441 –
– 1349
1355 1380
3100 3108
C O C str. 1063 943 1086 1024 – 1045 987
is covered with 5-ASA, which confirmed the physical interaction between 5-ASA and g-HPMC (M) copolymer. 3.3. Swelling characteristics of g-HPMC (M) in various salt solutions
Fig. 4. TGA-DTG curve of g-HPMC (M).
Fig. 4 shows the TGA thermogram of g-HPMC (M). It was reported that HPMC has two distinct zones of weight loss, which are responsible for the presence of moisture and the degradation of polysaccharide backbone [31]. Compared to HPMC, graft copolymer [g-HPMC (M)] exhibits one additional weight loss region (350–475 ◦ C) which is due to the degradation of polyacrylamide chains present on HPMC backbone. Fig. 5 exhibits the FE-SEM images of g-HPMC (M), 5-ASA and tablet formulation. It was found that HPMC has granular surface [30], while the copolymer [g-HPMC (M)] showed fibrillar morphology with rough surface. Conversely, the morphological changes took place on tablet formulation. The fibrillar surface of copolymer
When a material is immersed in a solvent, the solvent enters into it and results in an increase in the total volume of the material, which is known as swelling. The presence of relative amount of water in hydrogels can be defined as the swelling ratio at equilibrium, which is the weight of the swollen gel divided by the weight of dried polymer. The equilibrium swelling ratio (ESR) of the hydrogels was measured in aqueous media and various salt solutions by gravimetric analysis as described in Section 2.4. The swelling of hydrogels depends on various factors like crosslinking density, pH, ionic strength of the solution i.e. on salt concentration [38]. From Fig. 6, it has been observed that the ESR of g-HPMC (M) is less in salt solutions than that of aqueous media. This is because of the fact that with increase in the charge of cations, the charge density (charge/radius ratio) of cation of the salt increases. Consequently, stronger would be the interaction between the hydrophilic groups of the copolymer matrix and cationic species which resist the diffusion of water molecules into the copolymer. This results the lower % ESR in salt solution which contain higher charge cations than that of lower charge cations. Thus the order follows: monovalent > divalent > trivalent cations [39,40]. Besides, it was also reported that the rate of drug release depends on the rate of swelling [32]. As extracellular fluids and plasma contain various ions, thus the swelling rate of hydrogel should be affected by the ions present in the human body. Besides, the ions present in the human body can form salts with water insoluble drugs or sparingly soluble drugs. Thus the solubility of drug increases, which maintained the drug concentration in the plasma. Consequently, it is imperative to observe the effect of salt on swelling of hydrogels which can be used as drug delivery matrix. 3.4. In vitro drug release study Fig. 7 represents the % cumulative release of 5-ASA from HPMC and g-HPMC (M) as a function of time. From the release profile
Fig. 5. FE-SEM images of (a) g-HPMC (M), (b) 5-ASA and (c) tablet (triturated form).
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Fig. 6. (a) % swelling and (b) % equilibrium swelling of g-HPMC (M) at various salt solutions; (c) % swelling and (d) % equilibrium swelling of g-HPMC (M) at different NaCl concentrations. Results represented here are ±SD (n = 3).
(Fig. 7), it is obvious that HPMC released the entire drug within 7 h, while g-HPMC 6(M) released ∼50% drug in 12 h. This confirms the sustained release behaviour of g-HPMC (M). This is attributed to the minimum % erosion (see Table 2) and controlled swelling nature of g-HPMC (M) [30]. In addition, it was also observed that rate of drug release is higher at pH 7.4 in compared to pH 1.2. In pH 1.2 all the hydrophilic groups remain in protonated state, which makes the rate of swelling slower. While in pH 7.4, the hydrophilic groups remain free. This leads to the rate of swelling higher. As a consequence, rate of 5-ASA release is higher in pH 7.4 than that of pH 1.2. This feature confirms the application of g-HPMC (M) as an excellent matrix for colon specific release of 5-ASA.
3.4.1. Effects of salts on 5-ASA release from g-HPMC (M) hydrogel Fig. 8 depicts the 5-ASA release profile of g-HPMC (M) hydrogel at various salt solutions. It was observed that the rate of 5-ASA release was declined with increase in charge density on the cations of salt solutions. This is because of the fact that the % ESR of the hydrogels decreased with increase of the charge density of the cations of various salt solutions. Besides, the rate of drug release also depends on the rate of swelling. Thus the release rate of 5-ASA decreased in various salt solutions compared to buffer solutions (pH 1.2 and 7.4). The release order follows according to dissolution medium as: buffer solution> 0.1 M NaCl > 0.1 M CaCl2 > 0.1 M AlCl3
Table 2 Rate of erosion and release kinetics parameters of 5-ASA tablets at pH 7.4. Polymer matrix
Rate of erosion (%) (±SD, n = 3)
Zero order (R2 )
First order (R2 )
Release kinetics of 5-ASA tablets at pH 7.4 (without any salt concentration) 95.4 0.9124 0.9875 HPMC 17.8 ± 3.5 0.9045 0.9974 g-HPMC (M) Release kinetics of 5-ASA tablet of g-HPMC (M) matrix at different salt solution of pH 7.4 15.7 ± 2.5 0.9047 0.9971 0.1 M NaCl 13.7 ± 1.9 0.9102 0.9923 0.1 M CaCl2 12.4 ± 2.7 0.9017 0.9954 0.1 M AlCl3
Korsmeyer–Peppas model
Kopcha model
R2
n
R2
A
B
0.9976 0.9974
0.55 0.60
0.9970 0.9925
3.40 1.34
5.11 1.42
0.9943 0.9921 0.9962
0.55 0.60 0.51
0.9963 0.9919 0.9879
1.23 1.37 1.18
1.35 1.48 1.39
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3.4.3. Mechanism of drug release The release mechanism of 5-ASA from g-HPMC (M) matrix was investigated using Korsmeyer–Peppas model [36]. It is obvious from Table 2 that the diffusion exponent ‘n’ is in the range of 0.45 < n < 0.89, suggesting the non-Fickian diffusion mechanism follows, where the diffusion and relaxation rates are comparable [32]. Additionally in order to investigate the relative contributions of diffusion and polymer relaxation to drug release quantitatively, the release mechanism was analysed using Kopcha model (Eq. (3)) [37]. Qt = At 1/2 + Bt
(3)
where, ‘A’ is diffusional exponent and ‘B’ is erosional exponent. If ‘A’ is much greater than ‘B’ then the ratio of the exponents A/B will be very high, suggesting that the drug release from matrix is primarily controlled by Fickian diffusion process. It was found that the value of ‘A’ and ‘B’ (Table 2) obtained from Kopcha model are comparable, which signifies that the drug release is controlled by both diffusion as well as polymer relaxation for gHPMC (M). From release data of Table 2, it is obvious that A and B values of HPMC are 3.4 and 5.11 while for g-HPMC (M) are 1.34 and 1.42. Since the value of B (5.11) is significantly higher than that of A (3.4) during the release of 5-ASA from HPMC, thus polymer relaxation plays more significant role rather than diffusion. This further confirmed from the higher % erosion of HPMC, resulting faster release of 5-ASA (Table 2). Fig. 7. % Cumulative release of 5-ASA with time from HPMC and g-HPMC (M) matrices. Results represented here are ±SD (n = 3).
4. Conclusion From the above experimental observations and discussions, it is apparent that g-HPMC (M) can be used as an efficient matrix for controlled release of 5-ASA. Physico-chemical characterizations indicate that the drug (5-ASA) remains in the hydrogel matrix [g-HPMC (M)] by physical interaction. In vitro release study demonstrates that g-HPMC (M) can potentially deliver the 5-ASA in the colonic region more controlled way than that of neat HPMC. It has been observed that the rate of swelling and drug release were declined with increase of salt concentration. The drug release follows first order kinetics and non-Fickian diffusion mechanism, which indicates that diffusion as well as relaxation of polymer matrix are responsible for the controlled release of 5-ASA. Acknowledgement Authors earnestly acknowledge the financial support from Department of Science and Technology, New Delhi, India in form of a research grant (No: SR/FT/CS-094/2009) to carry out the reported investigation. References
Fig. 8. % Cumulative release of 5-ASA with time from g-HPMC (M) in presence and in absence of various salt solutions. Results represented here are ±SD (n = 3).
3.4.2. Release kinetics To understand the release kinetics of 5-ASA from g-HPMC (M), in vitro release data were fitted with zero order [34] and first order [35] kinetics models. The results suggest that 5-ASA release from both HPMC and g-HPMC (M) followed first order kinetics model than that of zero order kinetics model (based on higher R2 value, Table 2).
[1] R. Langer, N.A. Peppas, AIChE J. 49 (2003) 2990–3006. [2] E.M. Mart´n del Valle, M.A. Galán, R.G. Carbonell, Ind. Eng. Chem. Res. 48 (2009) 2475–2486. [3] N. Larson, H. Ghandehari, Chem. Mater. 24 (2012) 840–853. [4] P.R. Ninawe, S.J. Parulekar, Ind. Eng. Chem. Res. 51 (2012) 1741–1755. [5] H. Tian, Z. Tang, X. Zhuang, X. Chen, X. Jing, Prog. Polym. Sci. 37 (2012) 237–280. [6] L.S. Nair, C.T. Laurencin, Prog. Polym. Sci. 32 (2007) 762–798. [7] V. Pillay, R. Fassihi, J. Control. Release 59 (1999) 229–242. [8] G. Unsoy, R. Khodadust, S. Yalcin, P. Mutlu, G. Gunduz, Eur. J. Pharm. Sci. 62 (2014) 243–250. [9] X. Pi, H. Liu, K. Wei, Y. Lin, X. Zheng, Z. Wen, Int. J. Pharm. 382 (2009) 160–164. [10] D.R. Friend, Adv. Drug Deliv. Rev. 57 (2005) 247–265. [11] X. Huang, Y. Xiao, M. Lang, Carbohydr. Polym. 87 (2012) 790–798. [12] A. Rieux, V. Fievez, M. Garinot, Y.J. Schneider, V. Préat, J. Control. Release 116 (2006) 1–27. [13] G. Gaucher, P. Satturwar, M.C. Jones, A. Furtos, J.C. Leroux, Eur. J. Pharm. Biopharm. 76 (2010) 147–158. [14] S. Jana, N. Maji, A.K. Nayak, K.K. Sen, S.K. Basu, Carbohydr. Polym. 98 (2013) 870–876.
R. Das, S. Pal / International Journal of Biological Macromolecules 77 (2015) 207–213 [15] W.S. Omwancha, R. Mallipeddi, B.L. Valle, S.H. Neau, Int. J. Pharm. 441 (2013) 343–351. [16] S. Davaran, J. Hanaee, A. Khosravi, J. Control. Release 58 (1999) 279–287. [17] J.F. Pinto, Int. J. Pharm. 395 (2010) 44–52. [18] V.R. Sinha, R. Kumria, Int. J. Pharm. 224 (2001) 19–38. ´ J. Control. Release 58 (1999) 215–222. [19] M.Z.I. Khan, Zˇ . Prebeg, N. Kurjakovic, [20] A. Islam, T. Yasin, Carbohydr. Polym. 88 (2012) 1055–1060. [21] R. Das, S. Pal, Colloids Surf. B: Biointerfaces 110 (2013) 236–241. [22] G.U. Rani, A.K. Konreddy, S. Mishra, G. Sen, Int. J. Biol. Macromol. 65 (2014) 375–382. [23] G. Sen, S. Mishra, U. Jha, S. Pal, Int. J. Biol. Macromol. 47 (2010) 164–170. [24] B. Saˇsa, P. Odon, S. Stane, K. Julijana, Eur. J. Pharm. Sci. 27 (2006) 375–383. [25] S.C. Angadi, L.S. Manjeshwar, T.M. Aminabhavi, Int. J. Biol. Macromol. 47 (2010) 171–179. [26] A. Viridén, B. Wittgren, A. Larsson, Eur. J. Pharm. Biopharm. 77 (2011) 99–110. [27] K. Asare-Addo, B.R. Conway, H. Larhrib, M. Levina, A.R.R. Siahboomi, J. Tetteh, J. Boateng, A. Nokhodchi, Colloids Surf. B: Biointerfaces 111 (2013) 384–391. [28] J. Siepmann, N.A. Peppas, Adv. Drug Deliv. Rev. 64 (2012) 163–174.
213
[29] A.A. Barba, M. d’Amore, S. Chirico, G. Lamberti, G. Titomanlio, Carbohydr. Polym. 78 (2009) 469–474. [30] R. Das, D. Das, P. Ghosh, A. Ghosh, S. Dhara, A.B. Panda, S. Pal, Cellulose 22 (2015) 313–327. [31] R. Das, A.B. Panda, S. Pal, Cellulose 19 (2012) 933–945. [32] D. Das, R. Das, P. Ghosh, S. Dhara, A.B. Panda, S. Pal, RSC Adv. 3 (2013) 25340–25350. [33] G. Sen, S. Pal, Int. J. Biol. Macromol. 45 (2009) 45–48. [34] M. Donbrow, Y. Samuelov, J. Pharm. Pharmacol. 32 (1980) 463–470. [35] M. Gibaldi, S. Feldman, J. Pharm. Sci. 56 (1967) 1238–1242. [36] R.W. Korsemeyer, R. Gurny, E. Doelker, P. Buri, N.A. Peppas, Int. J. Pharm. 15 (1983) 25–35. [37] M. Kopcha, N.G. Lordi, K.J. Toja, J. Pharm. Pharmacol. 43 (1991) 382–387. [38] V.B. Bueno, R. Bentini, L.H. Catalani, D.F.S. Petri, Carbohydr. Polym. 92 (2013) 1091–1099. [39] Q. Li, Z. Ma, Q. Yue, B. Gao, W. Li, X. Xu, Bioresour. Technol. 118 (2012) 204–209. [40] Y. Bao, J. Ma, N. Li, Carbohydr. Polym. 84 (2011) 76–82.
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International Journal of Biological Macromolecules journal homepage: www.elsevier.com/locate/ijbiomac
Modified hydroxypropyl methyl cellulose: Efficient matrix for controlled release of 5-amino salicylic acid Raghunath Das, Sagar Pal ∗ Polymer Chemistry Laboratory, Department of Applied Chemistry, Indian School of Mines, Dhanbad 826004, India
a r t i c l e
i n f o
Article history: Received 30 November 2014 Received in revised form 20 February 2015 Accepted 7 March 2015 Available online 19 March 2015 Keywords: 5-Amino salicylic acid Controlled drug release HPMC
a b s t r a c t Hydroxypropyl methyl cellulose has been modified by grafting synthetic polyacrylamide chains [g-HPMC (M)] in presence of microwave irradiation, which has used as carrier for controlled release of 5-amino salicylic acid (5-ASA). The FTIR and UV–vis–NIR studies reveal the excellent compatibility between g-HPMC (M) and 5-ASA. Field emission scanning electron microscopy (FESEM) and UV–vis–NIR analyses suggest that physical interaction predominates between the drug and matrix. % equilibrium swelling ratio (% ESR) of g-HPMC (M) decreased with addition of salt solutions and follow the order: Na+ > K+ > Mg2+ > Ca2+ > Al3+ . The in vitro 5-ASA release studies indicate that g-HPMC (M) delivers the drug preferentially in colonic region in more sustained way than that of HPMC. The 5-ASA release follows first order kinetics and nonFickian diffusion mechanism. These favorable features make the graft copolymer a potential matrix for colon specific delivery of 5-ASA. © 2015 Elsevier B.V. All rights reserved.
1. Introduction In recent years, polymeric materials have gained significant attention for the delivery of various therapeutic agents. Biodegradable polymers are widely used for encapsulating drugs and their subsequent release behaviour [1–6]. Recently, targeted or sitespecific drug delivery [7–9] is one of the major challenge in disease therapy. Among the various modes of drug delivery, oral mode is the most suitable and commonly employed route owing to its ease of administration, cost effectiveness, high patient compliance, and flexibility in the design of dosage form [10–14]. Site-specific drug delivery to the colonic region has great importance in the field of pharmacotherapy. Several colonic diseases such as inflammatory bowel disease (IBD), ulcerative colitis, Crohn’s disease can be treated more effectively by local delivery of antiinflammatory agents to the large intestine [15–18]. However, the systemic absorption of drugs from the upper part of the gastrointestinal tract of the human body may causes side effects. These can be eliminated or reduced by protecting the drug release prior to its entry in colonic region. An ideal colon specific drug delivery system should protect the release of drug from the acidic pH of the stomach. Simultaneously, it should release the drug rapidly into the proximal colon (i.e. in lower gastrointestinal tract). Thus, the pH-responsive
∗ Corresponding author. Tel.: +91 326 2235769; fax: +91 326 2296615. E-mail addresses: [email protected], [email protected] (S. Pal). http://dx.doi.org/10.1016/j.ijbiomac.2015.03.015 0141-8130/© 2015 Elsevier B.V. All rights reserved.
polymeric systems would be preferable for the colon targeted drug delivery [19–23]. 5-Amino salicylic acid (5-ASA) is also known as mesalamine, which belongs to the category of amino derivative of salicylic acid. It is an active component of azulfidine, a combination of a sulfa drug. 5-ASA is used as an anti-inflammatory drug. The immune system in our human body locates and destroys harmful substances, called antigens (such as bacteria, viruses, poisons). Inflammation is one of the basic tools of our immune system which can protect our bodies from bacteria, viruses, microbes and other foreign substances. Immune system (specifically white blood cells) produces certain disease-fighting chemicals and sends them to the areas of the body affected by the antigens. The chemicals fight the antigens, but at the same time also cause the redness, swelling, and pain which we recognize as symptoms of inflammation. This medication (5-ASA) is effectively used to treat ulcerative colitis, helps to reduce rectal bleeding, stomach pain and also mild to moderate Crohn’s disease. 5-ASA works to diminish the overgrowth of bacteria in the body, particularly in the colonic region that causes inflammation, tissue damage and diarrhea. As a derivative of salicylic acid, mesalamine is also considered as antioxidant that traps free radicals, which potentially damaged the by-products of metabolism. From last few decades, cellulose derivatives [24,25] are extensively used in controlled drug release applications. Hydroxypropyl methyl cellulose (HPMC), one of the most important cellulose derivatives are used frequently as a carrier for controlled release of drugs in tablet formulations [26–29]. However, the use of
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unmodified polysaccharides has certain limitations in drug delivery applications such as faster rate of drug release, higher rate of erosion and so on. To overcome these limitations and modify the polysaccharides, several methods have been developed. Grafting is one of the most important methods for the synthesis of modified biopolymer/natural polymers for controlled drug delivery applications. Recently in authors’ laboratory, various modified polysaccharides have been developed and used as matrices for controlled release of model drugs [30–33]. More recently, we have designed a novel pH sensitive graft copolymer derived from HPMC and poly (acrylamide) in presence of microwave irradiation [30]. Out of various techniques, microwave irradiation based grafting process improves the reaction rate and % grafting efficiency (% GE). The electromagnetic irradiation selectively excites the polar bonds compared to the non-polar bonds of polysaccharides which results in the cleavage/breakage of only polar bonds. This results free radical sites for grafting on polysaccharide surface without cleavage of C C bond. Subsequently, the product selectivity was enhanced in compared to conventional chemical grafting method. It was also explained before that higher the % GE, better would be the efficacy as matrix for controlled release of drugs [33]. Thus in one hand, HPMC because of its natural abundance, presence of hydroxyl groups, inexpensive and biocompatible nature, and on the other hand polyacrylamide can play important role for stimulus responsive behaviour, the developed copolymer i.e. g-HPMC (M) probably be a suitable candidate for colon specific drug carrier. Herein, we report the application of polyacrylamide modified HPMC developed by microwave irradiation [g-HPMC (M)] for controlled release of colonic drug – 5-ASA. The synthesized hydrogel seems to be a potential candidate for 5-ASA carrier as it demonstrates the supplementary requirements such as excellent compatibility with the drug (as evidenced from UV–vis–NIR, FTIR and FESEM analyses), better swelling characteristics [30], pH-responsive behaviour, non-cytotoxic and biodegradable nature [30]. The details of drug release mechanism and kinetics has also been explored. The in vitro release profiles suggest that g-HPMC (M) releases 5-ASA in a more sustained way than that of neat HPMC.
g-HPMC 6 (M) has been further characterized and used it as matrix for in vitro controlled release of 5-ASA. 2.3. Characterization FTIR spectra of g-HPMC (M), 5-ASA and tablet formulations were recorded in solid state using FTIR spectrometer (IR-Perkin Elmer, Spectrum 2000, USA). Solid state UV–vis–NIR study was performed using Cary series UV–vis–NIR Spectrophotometer (Cary–5000). The TGA and DTG analyses of g-HPMC (M) were executed using a thermogravimetric analyser (Shimadzu DTG–60) with a heating rate of 10 ◦ C/min under nitrogen atmosphere. The surface morphologies of the copolymer, 5-ASA and the tablet formulation were carried out in dry state using field emission scanning electron microscopy (FESEM Supra 55, Make – Zeiss, Germany). 2.4. Swelling characteristics in various salt solutions The extracellular fluids of the human body contain various ions including sodium, potassium, calcium, chloride, hydrogen carbonate. Whereas, the plasma contains mineral ions like Na+ , K+ , Mg2+ , HCO3 − , Cl− . Thus it is essential to observe the effect of various salts on swelling behaviour of the hydrogels for drug delivery applications. Because of the interactions between hydrogel and salt cations, it may affect the rate of swelling of the hydrogel. Besides it was also observed that the drug release is directly proportional to the swelling behaviour of the hydrogel. For this purpose, the equilibrium swelling characteristic of gHPMC (M) was carried out in aqueous media and different salt solutions (LiCl, NaCl, KCl, MgCl2 , CaCl2 , BaCl2 , AlCl3 ) through gravimetric method. A known weight of dried polymer [g-HPMC (M)] was taken and immersed into 100 mL of water or in various salt solutions for 24 h at a constant temperature (37 ◦ C). After a certain time interval (every 3 h) swollen polymer was withdrawn, wiped with tissue paper to remove excess of solvent, and then reweighed. The equilibrium swelling was attained at ∼21 h. The % swelling (Ps) of g-HPMC (M) was calculated using Eq. (1) [30,31]. Ps =
Weight of swollen gel − Weight of dried gel × 100 Weight of dried gel
(1)
2. Materials and methods 2.5. Determination of % erosion 2.1. Materials HPMC (Lancaster, UK), acrylamide (E. Merck, Mumbai, India), potassium persulphate (Qualigens Fine chemicals, Mumbai, India), 5-ASA (AR Grade, Spectrochem Pvt. Ltd. Mumbai, India), acetone (S. D. Fine chemicals, Mumbai, India), hydroquinone (S. D. Fine chemicals, Mumbai, India) were used as received, without further purification. 2.2. Preparation of g-HPMC (M) in presence of microwave irradiation The graft copolymer [g-HPMC (M)] was developed by free radical polymerization using microwave irradiation. The reaction was performed at a temperature of 70 ◦ C in presence of 900 W microwave irradiation and potassium persulphate initiator. The details of reaction conditions and procedure have been described in our previous report [30]. The homopolymer (i.e. polyacrylamide), which was formed during the copolymerization reaction was separated through solvent extraction method (using 1:1 formamide/acetic acid) [30]. By variation of reaction parameters, series of graft copolymers [g-HPMC (M)] were synthesized and optimized the best one with respect to higher % GE and lower % equilibrium swelling ratio [30]. Here the optimized copolymer i.e.
Rate of drug release from polymer matrix also depends on the erosion of matrix. It is presumed that erosion of the polymer matrix starts once ‘critical gel concentration’ attained [32]. The % erosion (% ER) was determined using Eq. (2) [32]. %ER =
Wi − Wd (t) − Wdrug (1 − Mt /M∞ ) Wi
× 100
(2)
where, Wi is the initial weight of the dried tablet, Wd is the weight of the dried tablet at time t, Wdrug is the initial weight of the drug, Mt /M∞ is the fraction of drug release at time t. 2.6. In vitro 5-amino salicylic acid (5-ASA) release study 2.6.1. Preparation of tablet 450 mg of g-HPMC (M) as matrix, 50 mg of guar gum as binder and 500 mg of 5-ASA was used for the tablet preparation. The tablet was prepared in the same method as reported previously [30,32]. 2.6.2. 5-Amino salicylic acid release study The in vitro release of loaded 5-ASA drug from neat HPMC and gHPMC (M) was investigated using dissolution apparatus (Lab India, Model: DS 8000) with constant rotation of 60 rpm at 37 ± 0.5 ◦ C using 900 mL various buffer solutions related to simulated gastric
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Fig. 1. Proposed scheme and probable structure of g-HPMC (M).
fluid (pH 1.2) and intestinal fluid (pH 7.4). After every 1 h, 10 mL aliquot was withdrawn from the release media and replaced by an equal volume of buffers at each sampling time. The amount of drug release was measured with the help of absorbance (max : 303 nm at pH – 1.2, and max : 331 nm at pH – 7.4) in UV–visible spectrophotometer (Model UV-1800, Shimadzu, Japan). The rate of drug release was graphically represented in form of drug release profile (% cumulative drug release vs. time). 2.6.3. Drug release kinetics and mechanism The drug release kinetics was investigated using zero order [34] and first order [35] kinetics models. To investigate the release mechanism, the release data were fitted in Korsmeyer–Peppas [36] and Kopcha models [37]. 3. Results and discussions 3.1. Synthesis of g-HPMC (M) copolymers Polyacrylamide functionalized HPMC [g-HPMC (M)] was prepared in presence of microwave irradiation and potassium persulphate (KPS) initiator [30]. With the variation of reaction parameters, different grades of g-HPMC (M) were synthesized to optimize the best copolymer [30]. It was assumed that initially in presence of microwave irradiation, KPS generates free radical sites on HPMC backbone. Besides, acrylamide (monomer) polymerized to form polyacrylamide chains into the reaction media. After that, the generated free radical of HPMC react with polyacrylamide chains to form graft copolymer i.e. g-HPMC (M) [30]. The polymerization reaction was terminated using hydroquinol solution. The reaction mixture was dispersed in acetone for the removal of homopolymer (i.e. polyacrylamide) and unreacted monomer. The proposed mechanism for the development of g-HPMC (M) has been shown in our previous report [30]. The probable formation of gHPMC (M) is shown in Fig. 1.
Fig. 2. Probable interactions between g-HPMC (M) and 5-ASA.
characteristic peak of 5-ASA (332.3 nm) shifted to lower value (326.4 nm) in tablet formulation, which signifies a blue shift. This confirmed the physical interaction between the drug and the copolymer as specified in Fig. 2.
3.2. Physical characterization FTIR spectra of HPMC [31], g-HPMC (M) [30], 5-ASA and tablet formulations are reported in Table 1. From FTIR spectra of tablet formulation (Table 1), it is apparent that all the peaks of 5-ASA are present but the frequency of amide-I and amide-II of g-HPMC (M) shifted toward lower value (in case of amide-I: 1660–1626 cm−1 , for amide-II: 1588–1548 cm−1 ). The O H stretching vibrations shifted from 3433 cm−1 to 3420 cm−1 . This observation indicates the good compatibility between drug and matrix along with physical interactions between them as shown in Fig. 2. Fig. 3 demonstrates the UV–vis–NIR spectra of g-HPMC (M), 5-ASA and tablet formulation. It is obvious from the spectra that
Fig. 3. UV–vis–NIR study of the drug, g-HPMC (M) and triturated form of tablet.
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Table 1 FTIR values of HPMC, g-HPMC (M), pure 5-ASA, and 5-ASA tablets. Substrate
OH str.
NH Str.
CH str.
C O str.
Amide-I, amide-II str.
CH2 scissoring
NH bending
OH bending
C N str.
HPMC [31]
3485
2936
–
–
1458
–
1378
–
g-HPMC (M) [30]
3433
2912
–
1451
–
1349
1397
5-ASA 5-ASA tablet (initial)
3455 3420
2922 2929
1648 –
1660 1588 – 1626 1548
– 1451
1441 –
– 1349
1355 1380
3100 3108
C O C str. 1063 943 1086 1024 – 1045 987
is covered with 5-ASA, which confirmed the physical interaction between 5-ASA and g-HPMC (M) copolymer. 3.3. Swelling characteristics of g-HPMC (M) in various salt solutions
Fig. 4. TGA-DTG curve of g-HPMC (M).
Fig. 4 shows the TGA thermogram of g-HPMC (M). It was reported that HPMC has two distinct zones of weight loss, which are responsible for the presence of moisture and the degradation of polysaccharide backbone [31]. Compared to HPMC, graft copolymer [g-HPMC (M)] exhibits one additional weight loss region (350–475 ◦ C) which is due to the degradation of polyacrylamide chains present on HPMC backbone. Fig. 5 exhibits the FE-SEM images of g-HPMC (M), 5-ASA and tablet formulation. It was found that HPMC has granular surface [30], while the copolymer [g-HPMC (M)] showed fibrillar morphology with rough surface. Conversely, the morphological changes took place on tablet formulation. The fibrillar surface of copolymer
When a material is immersed in a solvent, the solvent enters into it and results in an increase in the total volume of the material, which is known as swelling. The presence of relative amount of water in hydrogels can be defined as the swelling ratio at equilibrium, which is the weight of the swollen gel divided by the weight of dried polymer. The equilibrium swelling ratio (ESR) of the hydrogels was measured in aqueous media and various salt solutions by gravimetric analysis as described in Section 2.4. The swelling of hydrogels depends on various factors like crosslinking density, pH, ionic strength of the solution i.e. on salt concentration [38]. From Fig. 6, it has been observed that the ESR of g-HPMC (M) is less in salt solutions than that of aqueous media. This is because of the fact that with increase in the charge of cations, the charge density (charge/radius ratio) of cation of the salt increases. Consequently, stronger would be the interaction between the hydrophilic groups of the copolymer matrix and cationic species which resist the diffusion of water molecules into the copolymer. This results the lower % ESR in salt solution which contain higher charge cations than that of lower charge cations. Thus the order follows: monovalent > divalent > trivalent cations [39,40]. Besides, it was also reported that the rate of drug release depends on the rate of swelling [32]. As extracellular fluids and plasma contain various ions, thus the swelling rate of hydrogel should be affected by the ions present in the human body. Besides, the ions present in the human body can form salts with water insoluble drugs or sparingly soluble drugs. Thus the solubility of drug increases, which maintained the drug concentration in the plasma. Consequently, it is imperative to observe the effect of salt on swelling of hydrogels which can be used as drug delivery matrix. 3.4. In vitro drug release study Fig. 7 represents the % cumulative release of 5-ASA from HPMC and g-HPMC (M) as a function of time. From the release profile
Fig. 5. FE-SEM images of (a) g-HPMC (M), (b) 5-ASA and (c) tablet (triturated form).
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Fig. 6. (a) % swelling and (b) % equilibrium swelling of g-HPMC (M) at various salt solutions; (c) % swelling and (d) % equilibrium swelling of g-HPMC (M) at different NaCl concentrations. Results represented here are ±SD (n = 3).
(Fig. 7), it is obvious that HPMC released the entire drug within 7 h, while g-HPMC 6(M) released ∼50% drug in 12 h. This confirms the sustained release behaviour of g-HPMC (M). This is attributed to the minimum % erosion (see Table 2) and controlled swelling nature of g-HPMC (M) [30]. In addition, it was also observed that rate of drug release is higher at pH 7.4 in compared to pH 1.2. In pH 1.2 all the hydrophilic groups remain in protonated state, which makes the rate of swelling slower. While in pH 7.4, the hydrophilic groups remain free. This leads to the rate of swelling higher. As a consequence, rate of 5-ASA release is higher in pH 7.4 than that of pH 1.2. This feature confirms the application of g-HPMC (M) as an excellent matrix for colon specific release of 5-ASA.
3.4.1. Effects of salts on 5-ASA release from g-HPMC (M) hydrogel Fig. 8 depicts the 5-ASA release profile of g-HPMC (M) hydrogel at various salt solutions. It was observed that the rate of 5-ASA release was declined with increase in charge density on the cations of salt solutions. This is because of the fact that the % ESR of the hydrogels decreased with increase of the charge density of the cations of various salt solutions. Besides, the rate of drug release also depends on the rate of swelling. Thus the release rate of 5-ASA decreased in various salt solutions compared to buffer solutions (pH 1.2 and 7.4). The release order follows according to dissolution medium as: buffer solution> 0.1 M NaCl > 0.1 M CaCl2 > 0.1 M AlCl3
Table 2 Rate of erosion and release kinetics parameters of 5-ASA tablets at pH 7.4. Polymer matrix
Rate of erosion (%) (±SD, n = 3)
Zero order (R2 )
First order (R2 )
Release kinetics of 5-ASA tablets at pH 7.4 (without any salt concentration) 95.4 0.9124 0.9875 HPMC 17.8 ± 3.5 0.9045 0.9974 g-HPMC (M) Release kinetics of 5-ASA tablet of g-HPMC (M) matrix at different salt solution of pH 7.4 15.7 ± 2.5 0.9047 0.9971 0.1 M NaCl 13.7 ± 1.9 0.9102 0.9923 0.1 M CaCl2 12.4 ± 2.7 0.9017 0.9954 0.1 M AlCl3
Korsmeyer–Peppas model
Kopcha model
R2
n
R2
A
B
0.9976 0.9974
0.55 0.60
0.9970 0.9925
3.40 1.34
5.11 1.42
0.9943 0.9921 0.9962
0.55 0.60 0.51
0.9963 0.9919 0.9879
1.23 1.37 1.18
1.35 1.48 1.39
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3.4.3. Mechanism of drug release The release mechanism of 5-ASA from g-HPMC (M) matrix was investigated using Korsmeyer–Peppas model [36]. It is obvious from Table 2 that the diffusion exponent ‘n’ is in the range of 0.45 < n < 0.89, suggesting the non-Fickian diffusion mechanism follows, where the diffusion and relaxation rates are comparable [32]. Additionally in order to investigate the relative contributions of diffusion and polymer relaxation to drug release quantitatively, the release mechanism was analysed using Kopcha model (Eq. (3)) [37]. Qt = At 1/2 + Bt
(3)
where, ‘A’ is diffusional exponent and ‘B’ is erosional exponent. If ‘A’ is much greater than ‘B’ then the ratio of the exponents A/B will be very high, suggesting that the drug release from matrix is primarily controlled by Fickian diffusion process. It was found that the value of ‘A’ and ‘B’ (Table 2) obtained from Kopcha model are comparable, which signifies that the drug release is controlled by both diffusion as well as polymer relaxation for gHPMC (M). From release data of Table 2, it is obvious that A and B values of HPMC are 3.4 and 5.11 while for g-HPMC (M) are 1.34 and 1.42. Since the value of B (5.11) is significantly higher than that of A (3.4) during the release of 5-ASA from HPMC, thus polymer relaxation plays more significant role rather than diffusion. This further confirmed from the higher % erosion of HPMC, resulting faster release of 5-ASA (Table 2). Fig. 7. % Cumulative release of 5-ASA with time from HPMC and g-HPMC (M) matrices. Results represented here are ±SD (n = 3).
4. Conclusion From the above experimental observations and discussions, it is apparent that g-HPMC (M) can be used as an efficient matrix for controlled release of 5-ASA. Physico-chemical characterizations indicate that the drug (5-ASA) remains in the hydrogel matrix [g-HPMC (M)] by physical interaction. In vitro release study demonstrates that g-HPMC (M) can potentially deliver the 5-ASA in the colonic region more controlled way than that of neat HPMC. It has been observed that the rate of swelling and drug release were declined with increase of salt concentration. The drug release follows first order kinetics and non-Fickian diffusion mechanism, which indicates that diffusion as well as relaxation of polymer matrix are responsible for the controlled release of 5-ASA. Acknowledgement Authors earnestly acknowledge the financial support from Department of Science and Technology, New Delhi, India in form of a research grant (No: SR/FT/CS-094/2009) to carry out the reported investigation. References
Fig. 8. % Cumulative release of 5-ASA with time from g-HPMC (M) in presence and in absence of various salt solutions. Results represented here are ±SD (n = 3).
3.4.2. Release kinetics To understand the release kinetics of 5-ASA from g-HPMC (M), in vitro release data were fitted with zero order [34] and first order [35] kinetics models. The results suggest that 5-ASA release from both HPMC and g-HPMC (M) followed first order kinetics model than that of zero order kinetics model (based on higher R2 value, Table 2).
[1] R. Langer, N.A. Peppas, AIChE J. 49 (2003) 2990–3006. [2] E.M. Mart´n del Valle, M.A. Galán, R.G. Carbonell, Ind. Eng. Chem. Res. 48 (2009) 2475–2486. [3] N. Larson, H. Ghandehari, Chem. Mater. 24 (2012) 840–853. [4] P.R. Ninawe, S.J. Parulekar, Ind. Eng. Chem. Res. 51 (2012) 1741–1755. [5] H. Tian, Z. Tang, X. Zhuang, X. Chen, X. Jing, Prog. Polym. Sci. 37 (2012) 237–280. [6] L.S. Nair, C.T. Laurencin, Prog. Polym. Sci. 32 (2007) 762–798. [7] V. Pillay, R. Fassihi, J. Control. Release 59 (1999) 229–242. [8] G. Unsoy, R. Khodadust, S. Yalcin, P. Mutlu, G. Gunduz, Eur. J. Pharm. Sci. 62 (2014) 243–250. [9] X. Pi, H. Liu, K. Wei, Y. Lin, X. Zheng, Z. Wen, Int. J. Pharm. 382 (2009) 160–164. [10] D.R. Friend, Adv. Drug Deliv. Rev. 57 (2005) 247–265. [11] X. Huang, Y. Xiao, M. Lang, Carbohydr. Polym. 87 (2012) 790–798. [12] A. Rieux, V. Fievez, M. Garinot, Y.J. Schneider, V. Préat, J. Control. Release 116 (2006) 1–27. [13] G. Gaucher, P. Satturwar, M.C. Jones, A. Furtos, J.C. Leroux, Eur. J. Pharm. Biopharm. 76 (2010) 147–158. [14] S. Jana, N. Maji, A.K. Nayak, K.K. Sen, S.K. Basu, Carbohydr. Polym. 98 (2013) 870–876.
R. Das, S. Pal / International Journal of Biological Macromolecules 77 (2015) 207–213 [15] W.S. Omwancha, R. Mallipeddi, B.L. Valle, S.H. Neau, Int. J. Pharm. 441 (2013) 343–351. [16] S. Davaran, J. Hanaee, A. Khosravi, J. Control. Release 58 (1999) 279–287. [17] J.F. Pinto, Int. J. Pharm. 395 (2010) 44–52. [18] V.R. Sinha, R. Kumria, Int. J. Pharm. 224 (2001) 19–38. ´ J. Control. Release 58 (1999) 215–222. [19] M.Z.I. Khan, Zˇ . Prebeg, N. Kurjakovic, [20] A. Islam, T. Yasin, Carbohydr. Polym. 88 (2012) 1055–1060. [21] R. Das, S. Pal, Colloids Surf. B: Biointerfaces 110 (2013) 236–241. [22] G.U. Rani, A.K. Konreddy, S. Mishra, G. Sen, Int. J. Biol. Macromol. 65 (2014) 375–382. [23] G. Sen, S. Mishra, U. Jha, S. Pal, Int. J. Biol. Macromol. 47 (2010) 164–170. [24] B. Saˇsa, P. Odon, S. Stane, K. Julijana, Eur. J. Pharm. Sci. 27 (2006) 375–383. [25] S.C. Angadi, L.S. Manjeshwar, T.M. Aminabhavi, Int. J. Biol. Macromol. 47 (2010) 171–179. [26] A. Viridén, B. Wittgren, A. Larsson, Eur. J. Pharm. Biopharm. 77 (2011) 99–110. [27] K. Asare-Addo, B.R. Conway, H. Larhrib, M. Levina, A.R.R. Siahboomi, J. Tetteh, J. Boateng, A. Nokhodchi, Colloids Surf. B: Biointerfaces 111 (2013) 384–391. [28] J. Siepmann, N.A. Peppas, Adv. Drug Deliv. Rev. 64 (2012) 163–174.
213
[29] A.A. Barba, M. d’Amore, S. Chirico, G. Lamberti, G. Titomanlio, Carbohydr. Polym. 78 (2009) 469–474. [30] R. Das, D. Das, P. Ghosh, A. Ghosh, S. Dhara, A.B. Panda, S. Pal, Cellulose 22 (2015) 313–327. [31] R. Das, A.B. Panda, S. Pal, Cellulose 19 (2012) 933–945. [32] D. Das, R. Das, P. Ghosh, S. Dhara, A.B. Panda, S. Pal, RSC Adv. 3 (2013) 25340–25350. [33] G. Sen, S. Pal, Int. J. Biol. Macromol. 45 (2009) 45–48. [34] M. Donbrow, Y. Samuelov, J. Pharm. Pharmacol. 32 (1980) 463–470. [35] M. Gibaldi, S. Feldman, J. Pharm. Sci. 56 (1967) 1238–1242. [36] R.W. Korsemeyer, R. Gurny, E. Doelker, P. Buri, N.A. Peppas, Int. J. Pharm. 15 (1983) 25–35. [37] M. Kopcha, N.G. Lordi, K.J. Toja, J. Pharm. Pharmacol. 43 (1991) 382–387. [38] V.B. Bueno, R. Bentini, L.H. Catalani, D.F.S. Petri, Carbohydr. Polym. 92 (2013) 1091–1099. [39] Q. Li, Z. Ma, Q. Yue, B. Gao, W. Li, X. Xu, Bioresour. Technol. 118 (2012) 204–209. [40] Y. Bao, J. Ma, N. Li, Carbohydr. Polym. 84 (2011) 76–82.
