International Journal of Biological Macromolecules 64 (2014) 347–352
Contents lists available at ScienceDirect
International Journal of Biological Macromolecules journal homepage: www.elsevier.com/locate/ijbiomac
Unfolding type gastroretentive film of Cinnarizine based on ethyl cellulose and hydroxypropylmethyl cellulose Shakuntla Verma a , Kalpana Nagpal b,∗ , S.K. Singh c , D.N. Mishra c a b c
Jan Nayak Ch. Devilal Memorial College of Pharmacy, Sirsa 125055, Haryana, India School of Pharmacy, Lovely Faculty of Applied Medical Sciences, Lovely Professional University, Phagwara 144411, Punjab, India Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science and Technology, Hisar 125001, Haryana, India
a r t i c l e
i n f o
Article history: Received 3 October 2013 Received in revised form 17 December 2013 Accepted 18 December 2013 Available online 24 December 2013 Keywords: Gastroretentive dosage form Hydroxypropyl cellulose, Ethyl cellulose
a b s t r a c t The present work was based on the development and characterization of unfolding type gastro retentive dosage form appropriate for controlled release of Cinnarizine (CNZ), a drug with narrow therapeutic window. The drug loaded polymer film of biological macromolecules, i.e., ethyl cellulose (EC) and hydroxypropylmethyl cellulose (HPMC K15) was folded into hard gelatin capsules. The film was folded in different patterns for characterizing their unfolding behavior. The polymeric film revealed a fast release during the first hour followed by a more gradual drug release during a 12-h period following a non-Fickian diffusion process. Tensile strength of polymeric film was optimized using different amount (0.2–0.7 ml) of polyethylene glycol (PEG 400). Various physical parameters were studied for evaluating their performance as a gastroretentive dosage form. Drug and polymers were found to be compatible as revealed by differential scanning calorimetry (DSC) study and scanning electron micrograph (SEM) study revealed uniform dispersion of CNZ in polymeric matrices. The results indicate that unfolding type gastro retentive drug delivery system holds lots of potential for drug having stability problems in alkaline pH or are which mainly absorbed in acidic pH. © 2013 Elsevier B.V. All rights reserved.
1. Introduction The development of an oral controlled release formulation has an incredible impact on the drug delivery area especially for the drugs with a narrow absorption window but the limitation of this approach is insufficient retention of drug in the stomach [1–3]. In order to overcome this limitation, a number of strategies including, floating drug delivery system, mucoadhesives, co-administration of agents that alter the gastric motility have been developed [4,5]. Other approaches and drug carriers have been designed which unfold or expand in the stomach to form a complex geometric shape to obstruct its escape through the pyloric sphincter [6–8]. Combination of floating with the ability to expand by unfolding and swelling using blend of biodegradable polymers (hydrophilic and hydrophobic) is an alternative strategy to increase gastric residence time [9–11]. The present work is an effort to design a compressed device containing drug loaded polymeric film folded using different patterns into hard gelatin capsule. The capsule dissolves after ingestion and the compressed device release the film which then
∗ Corresponding author at: Pharmaceutics Domain, Lovely Professional University, Phagwara, Punjab, India. Tel.: +91 9416729190. E-mail address: [email protected] (K. Nagpal). 0141-8130/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ijbiomac.2013.12.030
unfolds and the swelling usually results by osmotic absorption of gastric fluid [12]. Convenience of hard gelatin capsule is the major advantage of such type of dosage forms. In order to modify drug release through polymeric film design, there remain a number of issues including; selection of a polymer with the desired ability to unfold and expand in the stomach and complexity in formulating a drug loaded polymeric film [9]. CNZ, 1-(Diphenylmethyl)-4-(3-phenyl-2-propenyl)-piperazine, is a Histamine H1 receptor antagonist; antihistamines are widely used in treating nausea and vomiting associated with disorders of the inner ear such as Meniere’s disease and motion sickness. It works by blocking histamine receptors which are found in various sites in the body, including an area in the brain known as the vomiting center. CNZ is a Biopharmaceutical Classification System (BCS) Class II drug with poor aqueous solubility and permeability. It is mainly absorbed in the upper gastrointestinal tract and has a short half-life of 4 h [13,14]. The present work is an based on practical aspects of designing floating and unfolding type polymeric films which deliver immediate release (IR) to achieve the therapeutic drug concentration in a short period of time and controlled release to maintain the concentration for the desired period of time and provide optimal drug release in upper gastrointestinal tract [15,16].
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Table 1 Composition of drug loaded polymeric films containing different amount of stearic acid. Batch Code
Wt. of CNZ (mg)
Wt. of HPMC-K15 (mg)
Wt. of EC (mg)
Wt. of stearic acid (mg)
Amount of PEG 400 (ml)
S0 S10 S20 S30 S40 S50
40 40 40 40 40 40
90 90 90 90 90 90
90 90 90 90 90 90
0 10 20 30 40 50
0.2 0.2 0.2 0.2 0.2 0.2
2. Materials and methods 2.1. Materials CNZ was generously gifted by Montaik Biopharma, India. HPMC K15M. EC was obtained from Central Drug House (P) Ltd. India. All other reagents and chemicals were of suitable analytical grade and were used as received. 2.2. Preparation of polymer film The polymer film was made by solvent casting method. A polymeric dispersion of HPMC K15 and EC was prepared by dissolving in optimum amount of methanol and chloroform, respectively. In previous polymeric dispersion, amount of stearic acid was increased in batch S10 (0.1%) followed by S20 (0.2%), S30 (0.3%), S40 (0.4%), and S50 (0.5%), respectively, with addition of CNZ by vigorous stirring as stated in Table 1. The resulting solution was casted on Teflon plates (4 × 2 cm2 ) and were allowed to dry for 24 h at room temperature and were carefully removed [17,18]. 2.3. In vitro unfolding study The prepared polymeric film was folded in two different patterns (rolling and accordion pattern) and inserted into 00 size capsules (Fig. 1). In vitro unfolding study was carried out in 900 ml of 0.1 N HCl (pH 1.2) using USP type I apparatus (TDT-08 L, Electrolab, Mumbai, India) at constant temperature of 37 ± 0.5 ◦ C at 50 rpm. To examine their unfolding behavior baskets were removed after interval of 5, 10, 20, 40, 80, 160, 320, 640 and 1280 min. 2.4. Characterization of polymeric films 2.4.1. SEM SEM (268D, Fei-Philips Morgagni) of polymeric film from batch S0 and S30 was performed at an acceleration voltage of 15 kV at different magnifications. 2.4.2. Differential scanning calorimetry The DSC thermogram of CNZ, physical mixture (HPMC + EC + Stearic acid + CNZ), stearic acid, polymeric films
S-0 and S-30, HPMC and EC was estimated in terms of their melting endotherms using differential scanning calorimeter (Q10, TA System, USA). The samples were heated in temperature range from 40 to 250 ◦ C at a heating rate of 10 ◦ C per minute under nitrogen atmosphere. 2.5. Evaluation of polymeric films 2.5.1. Thickness Digital micrometer screw gauge (Aerospace, China) was used to measure thickness of polymer film at different strategic locations which is essential to ascertain uniformity of the film thickness. 2.5.2. Folding endurance Folding endurance was determined by repeatedly folding the film at the same place until it breaks. The number of times the film could be folded at the same place without breaking was taken as the folding endurance value. It is an indirect assessment of toughness of film where lower value of folding endurance indicates brittleness of the film [19]. 2.5.3. Tensile strength Tensile strength is the maximum load that a strip specimen can support without fracture when being stretched, divided by the original cross-sectional area of the material. The weight was gradually increased so as to increase the pulley force till the film breaks. The percent elongation before the film breaks was noted with the help of a magnifying glass on graph paper and tensile strength was calculated as kg/cm2 [20]. 2.5.4. Mechanical strength Mechanical strength is the force applied manually. Mechanical strength is measured in kg/cm2 using paper bursting machine. This machine applies mechanical force on a ball which passes through the film after rupturing it when fixed horizontally in a frame (Fig. 2) [21,22]. 2.5.5. Water vapour transmission Polymeric films were fixed on the brim of the pre-weighed glass vials (5 ml) containing fused calcium chloride (1 g) with an adhesive, in a humidity chamber at different humidities.
Fig. 1. (a) Cinnarizine polymeric film. (b) Optimized accordion folding pattern polymeric film. (c) Film compressed into capsule shell.
S. Verma et al. / International Journal of Biological Macromolecules 64 (2014) 347–352
Fig. 2. Paper bursting machine.
2.5.6. Percent moisture absorbed The presence of moisture may not affect the hardness of the film in normal environmental conditions but may be affected in exaggerated conditions. Pre-weighed polymeric films were placed in humidity chamber maintained at 68% RH for 72 h [18]. The percent moisture absorbed was calculated using formula: % moisture absorbed =
initial weight − final weight × 100 initial weight
2.5.7. In vitro drug release study In vitro drug release study of various batches were conducted in simulated gastric fluid medium (900 ml) using USP apparatus I (TDT-08 L, Electrolab, Mumbai, India) with constant temperature maintained at 37 ± 0.5 ◦ C and 50 rpm till 13 h. An aliquot of 5 ml was withdrawn and replaced with another 5 ml of fresh simulated gastric fluid medium at various time intervals. The contents of CNZ in sample were analyzed by double beam UV spectrophotometer (Cary 5000, Varian Australia) at max 254 nm. Then the corresponding concentrations were determined from the standard curve of CNZ prepared in simulated gastric fluid medium (pH 1.2) at max 254 nm [19]. 2.5.8. Modeling and release kinetics To explore the kinetic behavior, results of in vitro release of CNZ from polymeric film was fitted to zero order, first order, Higuchi square root equation and Koresmeyer–Peppas equation and the value of k was determined for different models [23]. However, the drug release mechanism from polymeric system with swelling and/or erosion during dissolution was explained only by fitting in vitro release data in Koresmeyer–Peppas equation: Log
Mt = log k + n log t Mx
where Mt = the fraction of drug released at time t; Mx = amount of drug released after infinite time; k = release rate constant; and n = release exponent. The log value of percentage drug dissolved was plotted against log time for each batch for the determination of release exponent, ‘n’ for different batches of the polymeric films and only the initial portion of release curve (Mt /Mf < 0.6) was used, according to above equation. A value of n = 0.45 indicates Fickian diffusion (Case I) release; the release of drug is primarily by diffusion through the matrix. A value of n (0.45 < n < 0.89) indicates non-Fickian (anomalous) release, the release mechanism of drug was found to be the combination of drug diffusion and polymer erosion. The value of n > 0.89 indicates super
349
Fig. 3. DSC curve of Cinnarizine, physical mixture, stearic acid, polymeric film of batch S0, polymeric film of batch S50, HPMC and EC.
Case II type of release. The value of n = 1.0 indicates Case II which generally refers to the erosion mechanism of drug release fromS the polymeric matrix [23]. 2.5.9. Stability studies Stability studies for polymeric films were carried out in triplicate for three months at 45 ± 2 ◦ C and 75% RH. At the end of the period physical parameters and release profiles were determined [24].
3. Results and discussion 3.1. Unfolding behavior of polymeric film Reduction in mechanical shape after prolonged stress applied is the major difficulty in unfolding type of polymeric films. Polymeric material with glass transition temperatures close to ambient temperature with its resiliency to restore its original shape are therefore useful in polymeric formulation since they undergo less plastic deformation and retain their elasticity even when they were folded [12]. The unfolding behavior of both the foldings (roll and accordion) of polymeric film was not satisfactory because they were found to stick to each other. Accordion folding unfolds enthusiastically in comparison with roll folding after coating it with talcum powder and with a property of very high glass transition temperature of HPMC K15 polymer. 3.2. Characterization of polymeric films 3.2.1. DSC studies DSC was performed to find the physical state of CNZ in the polymeric film. In the present study, DSC thermogram of CNZ, physical mixture, stearic acid, polymeric films S0 and S50, HPMC and EC is shown in Fig. 3. DSC of CNZ exhibits a sharp endothermic peak at 121.19 ◦ C corresponding to its melting point which indicates the crystalline nature of incorporated CNZ. Stearic acid exhibited endotherm peaks at 57.47 ◦ C. EC and HPMC elicit broad endotherm, suggesting the amorphous nature of the polymers. Physical mixture showed separate characteristic peaks of CNZ and stearic acid which indicates their compatibility. The broadening endotherm of CNZ and stearic acid in DSC curve of formulation S0 and S50 revealed amorphous nature of both and there were no polymorphic changes in drug as well as excipients during the formulation of polymer film.
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and that was increased due to increase in PEG 400 concentration up to 0.7 ml. After that polymer film could not dry and it was difficult to peel off from the plate. It was observed that PEG 400 was necessary for the success of dosage form which shall otherwise be brittle. 3.3.3. Tensile strength There was not much difference in tensile strength of various batches but it was increased as the concentration of PEG 400 was increased, because of the presence of PEG 400 which may be acting as plasticizer. The results showed that PEG with higher concentration provides a better plasticizing effect for the polymeric film but increases the water vapour permeability of the film. Batch S50 was found to have maximum (up to 320 g) tensile strength as described in Table 3. 3.3.4. Mechanical strength Mechanical strength is the force applied tangentially through round ball on a uniform area of film. The bursting machine used was calibrated in terms of kg/cm2 and the results indicated that S50 film possessed sufficient mechanical strength which may be due to more PEG 400 concentration which acted as plastisizer (Table 2).
Fig. 4. Scanning electron micrograph of (a) polymeric film of batch S0; (b) polymeric film of batch S50.
3.2.2. SEM studies The surface morphology of polymeric films was shown in Fig. 4. Batch S0 at 727x showed fibrous structure (Fig. 4a). The surface morphology of polymer film of batch S50 at the magnification of 398x shows particulate material scattered on the surface with polyhedral depressions which is due to the stearic acid surrounded by the drug, form a channel for leaching out of the drug and which may be responsible for the maximum drug release at first hour (Fig. 4b). 3.3. Evaluation of formulated polymeric films 3.3.1. Thickness The thickness of prepared film varied from 70–110 m. Maximum thickness was observed with S50 batch whereas the minimum thickness was of S0 batch which may be due increase in concentration of stearic acid in S0, S10, S20, S30, S40, S50, respectively, as shown in Table 2. 3.3.2. Folding endurance of polymer films Folding endurance was determined by repeatedly folding the film at the same place until it breaks. The number of times the film could be folded at the same place without breaking was the folding endurance value. The minimum folding endurance was of S0 batch Table 2 Physical characteristics of polymeric films. Batch
Thickness (m)
S0 S10 S20 S30 S40 S50
70 76 80.3 84 88.4 93.1
± ± ± ± ± ±
0.02 0.01 0.03 0.01 0.01 0.02
Mechanical strength (kg/cm2 ) 0.6 1.5 1.8 1.8 1.9 1.9
± ± ± ± ± ±
0.03 0.02 0.02 0.01 0.02 0.01
Moisture absorbed (%) 14.12 9.07 7.66 6.08 6.99 6.01
± ± ± ± ± ±
0.15 0.10 0.22 0.34 0.24 0.27
3.3.5. Water vapour transmission Water vapour transmission test was done at four different humidities (32%, 75%, 80%, 90%). As the humidity was increased, the weight gain by fused CaCl2 also increased. The maximum weight gain was at 90% relative humidity. Batch S50 showed minimum weight gain by fused CaCl2. Based on the observation, it may be concluded that the membrane possessed negligible permeability indicating the success of method of formulation (casting) to yield film of sufficient thickness without pores/thin areas. It may be due to the presence of more stearic acid, a hydrophilic polymer which may act as a moisture barrier from outside as depicted in Table 4. 3.3.6. Percent moisture absorbed The maximum moisture was absorbed by S0 formulation and the least by S50 formulation. This may be due to the presence of stearic acid in S50 formulation which may act as a moisture barrier (Table 2). 3.3.7. In vitro dissolution studies The in vitro drug release study from all six set of formulation (S0, S10, S20, S30, S40, and S50) was performed. The result revealed that formulation S50 showed a minimum percentage drug release of 63.39% followed by the formulation S40, S30, S20, S10, and S0 of 66.10%, 78.78%, 80.30%, 81.93% and 8.70% in 13-h, respectively, which indicates a fast release during the first hour followed by a more steady drug release during a 12-h period as the concentration of stearic acid was increased. Stearic acid, a hydrophobic polymer, used as sustained drug delivery, reduces the drug release from the formulation, as it surrounds the drug, EC and HPMC and make channels from which the drug leaches out more initially and later release slowly by diffusion from HPMC and ethyl cellulose. During the hydration of HPMC, there is formation of gel layer around the dry core of HPMC and swelling of polymer takes place which attributes to be used as an oral controlled drug delivery system because of its high swellability (Fig. 5a). 3.3.8. Drug release kinetics The data obtained from dissolution studies of different batches was analyzed using different mathematical models for the determination of release kinetics. Most of the batches followed Higuchi model. However, the release mechanism is not well known or more than one type of release phenomenon be involved. The value of R2 is 0.9847, 0.935, 0.9581, 0.9849, 0.9863 and 0.94 for S0, S10, S20, S30, S40, and S50 batches, respectively, was found to be maximum for
S. Verma et al. / International Journal of Biological Macromolecules 64 (2014) 347–352
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Table 3 Tensile strength of polymeric films. Weight suspended (g)
30 60 90 120 150 180 210 240 270 300 320
Increase in length (cm) S0 + PEG 400 (0.2 ml)
S10 + PEG 400 (0.3 ml)
S20 + PEG 400 (0.4 ml)
S30 + PEG 400 (0.5 ml)
S40 + PEG 400 (0.6 ml)
S50 + PEG 400 (0.7 ml)
8.3 ± 0.32 8.8 ± 0.32 9.3 ± 0.36 9.8 ± 0.43 10.4 ± 0.54 10.7 ± 0.33 Break Break Break Break Break
8.3 ± 0.23 8.5 ± 0.12 8.5 ± 0.43 8.5 ± 0.39 8.6 ± 0.29 8.7 ± 0.23 90 ± 0.43 9.1 ± 0.23 9.1 ± 0.22 Break Break
8.1 ± 0.13 8.2 ± 0.22 8.5 ± 0.17 8.7 ± 0.18 8.7 ± 0.33 8.8 ± 0.14 8.9 ± 0.33 9.1 ± 0.28 9.2 ± 0.10 Break Break
8.3 ± 0.11 8.5 ± 0.32 8.6 ± 0.21 9.0 ± 0.43 9.4 ± 0.26 9.9 ± 0.16 10.4 ± 0.12 10.5 ± 0.10 10.6 ± 0.12 Break Break
8.0 ± 0.2 8.3 ± 0.11 8.4 ± 0.21 8.5 ± 0.31 8.8 ± 0.27 9.4 ± 0.12 9.6 ± 0.16 10 ± 0.15 10.5 ± 0.22 10.9 ± 0.16 Break
8.1 8.2 8.3 8.7 8.9 9.3 9.5 10.6 10.8 11.0 11.9
± ± ± ± ± ± ± ± ± ± ±
0.1 0.2 0.11 0.21 0.33 0.22 0.32 0.11 0.43 0.11 0.31
Table 4 Water vapour transmission of polymeric films. Relative humidity
Weight gained (mg) by batch S0
32% 75% 80% 91%
0.48 0.72 0.79 0.89
S10 ± ± ± ±
0.21 0.33 0.34 0.28
0.44 0.72 0.80 0.88
S20 ± ± ± ±
0.18 0.34 0.32 0.35
0.47 0.74 0.79 0.89
S30 ± ± ± ±
0.20 0.30 0.26 0.21
0.46 0.75 0.80 0.84
S40 ± ± ± ±
0.11 0.31 0.23 0.39
0.47 0.74 0.78 0.90
S50 ± ± ± ±
0.17 0.28 0.20 0.35
0.45 0.73 0.77 0.88
± ± ± ±
0.23 0.19 0.26 0.29
3.3.9. Stability studies The results of stability studies of CNZ loaded polymeric films shows more sustained effect as compared to previous drug release studies. When the polymeric films were stored at 45 ± 2 ◦ C and 75% RH for 3 months, it was observed that polymers and stearic acid mixture formed a transparent hard film like insoluble substance which may be due to their mutual interaction that may have reduced the porosity of the polymeric film. This will reduce the ingress of the dissolution medium leading to slower dissolution (Fig. 5b). But there was a slight change in mechanical properties of the polymer film. 4. Conclusions
Fig. 5. Comparative in vitro release profile of Cinnarizine from various batches of polymeric films. (a) Before stability testing; (b) after stability testing.
Koresmeyer–Peppas model. Hence, all batches except S0 follow this model and the drug release mechanism was thus both by diffusion as well as erosion. The value of n was found to be 0.6049, 0.4779, 0.4606, 0.4117, 0.2923 and 0.29 for S0, S10, S20, S30, S40, and S50 batches respectively. The data indicates that with an increase in concentration of stearic acid, erosion of film was decreased. The result revealed that polymeric film of batch S50 had minimum erosion as compared to other batches.
The unfolding type gastroretentive compressed dosage form for controlled release of Cinnarizine, a drug with narrow absorption window, was successfully formulated. The formulated batches were characterized through various physicochemical parameters like, release characteristics, floating characteristics, stability study and integrity during their release period. It consists of drug loaded polymeric film of HPMC K15 and EC, folded in two different patterns inside a hard gelatin capsule. The result revealed that unfolding films (S10–S50) were appropriate in comparison with roll folding pattern in simulated gastric fluid. The presence of stearic acid in polymeric film was crucial to provide an immediate and sustained effect. The floating and mechanical performance of the film indicated the gastroretentive potential of the dosage form. We can certainly explore this drug delivery system for further development through its in vivo evaluation studies which may lead to an improved bioavailability and ensured therapy with other already existing drugs of such type. References [1] [2] [3] [4] [5]
P.G. Yeole, S. Khan, V.F. Patel, Indian J. Pharm. Sci. 67 (2005) 265–272. B.N. Singh, K.H. Kim, J. Control. Release 63 (2000) 235–259. A.J. Moes, Crit. Rev. Ther. Drug Carrier Syst. 10 (1993) 143–195. M. Oth, M. Franz, J. Timmermans, A. Moes, Pharm. Res. 9 (1992) 298–302. Y. Sato, Y. Kawashima, H. Takeuchi, H. Yamamoto, J. Control. Release 93 (2003) 39–47. [6] R. Cargill, K. Engle, C.R. Gardner, P.A. Porter, R.V. Sparer, J.A. Fix, Pharm. Res. 6 (1989) 506–509.
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[7] A. Hoffmana, E.A. Klausnera, E. Lavy, M. Friedmana, J. Control. Release 90 (2003) 143–162. [8] N. Washington, C. Washington, C.G. Wilson, Physiological Pharmaceutics, 2nd ed., Taylor & Francis, New York, 2001. [9] A. Rubinstein, V.H.K. Li, P. Gruber, J.R. Robinson, Gastrointestinal–physiological variables affecting the performance of oral sustained release dosage forms, in: A. Yacobi, E. Halperin-Walega (Eds.), Oral Sustained Release Formulation Design and Evaluation, Pergamon Press, New York, 1988, pp. 125–156. [10] H.J. Ehrlein, Am. J. Physiol. 254 (1988) 650–657. [11] K.W. Leong, R. Langer, Adv. Drug Deliv. Rev. 1 (1987) 199–233. [12] E.A. Klausner, E. Lavy, M. Friedman, A. Hoffman, Expandable gastroretentive dosage forms, J. Control. Rel. 90 (2003) 143–162. [13] M. Demirel, Y. Yajan, B.S. Kalava, Turk. J. Pharm. Sci. 2 (2005) 51–62. [14] R. Arieli, A. Shupak, B. Shachal, A. Shenedrey, O. Ertracht, G. Rashkovan, Undersea Hyperbar. Med. 26 (1999) 105–109.
[15] R.J. Barrett, B. Zolov, J. Maine Med. Assoc. 51 (1960) 454–457. [16] G. Towse, J. Laryngol. Otol. 94 (1980) 1009–1015. [17] F. Cilureo, I. Cupone, P. Minghtti, F. Selmin, L. Montanari, Eur. J. Pharma. Biopharm. (2008) 1–17. [18] A. Mundada, P. Satturwar, S. Fulzele, S. Joshi, A. Dorle, Iran. J. Pharm. Res. 10 (2011) 35–42. [19] R.P. Dixit, S.P. Puthli, J. Control. Release 139 (2009) 94–107. [20] P. Arora, M. Biswajit, J. Pharm. Sci. 91 (2002) 2076–2089. [21] M.V.S. Udhumansha Reddy, R. Kumaresan, F.J. Ahmad, R.K. Khar, AAPS PharmSciTech. 8 (2007) 1–8. [22] A. Mittal, U.S. Sara, A. Ali, Pharm. Acta 59 (2009) 383–393. [23] P. Costa, J.M.S. Loba, Eur. J. Pharm. Sci. 13 (2001) 123–133. [24] D. Preechagoon, V. Sumyai, K. Tontisirin, S. Aumpon, T. Pongjanyakul, J. Pharm. Sci. 8 (2005) 362–369.
Contents lists available at ScienceDirect
International Journal of Biological Macromolecules journal homepage: www.elsevier.com/locate/ijbiomac
Unfolding type gastroretentive film of Cinnarizine based on ethyl cellulose and hydroxypropylmethyl cellulose Shakuntla Verma a , Kalpana Nagpal b,∗ , S.K. Singh c , D.N. Mishra c a b c
Jan Nayak Ch. Devilal Memorial College of Pharmacy, Sirsa 125055, Haryana, India School of Pharmacy, Lovely Faculty of Applied Medical Sciences, Lovely Professional University, Phagwara 144411, Punjab, India Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science and Technology, Hisar 125001, Haryana, India
a r t i c l e
i n f o
Article history: Received 3 October 2013 Received in revised form 17 December 2013 Accepted 18 December 2013 Available online 24 December 2013 Keywords: Gastroretentive dosage form Hydroxypropyl cellulose, Ethyl cellulose
a b s t r a c t The present work was based on the development and characterization of unfolding type gastro retentive dosage form appropriate for controlled release of Cinnarizine (CNZ), a drug with narrow therapeutic window. The drug loaded polymer film of biological macromolecules, i.e., ethyl cellulose (EC) and hydroxypropylmethyl cellulose (HPMC K15) was folded into hard gelatin capsules. The film was folded in different patterns for characterizing their unfolding behavior. The polymeric film revealed a fast release during the first hour followed by a more gradual drug release during a 12-h period following a non-Fickian diffusion process. Tensile strength of polymeric film was optimized using different amount (0.2–0.7 ml) of polyethylene glycol (PEG 400). Various physical parameters were studied for evaluating their performance as a gastroretentive dosage form. Drug and polymers were found to be compatible as revealed by differential scanning calorimetry (DSC) study and scanning electron micrograph (SEM) study revealed uniform dispersion of CNZ in polymeric matrices. The results indicate that unfolding type gastro retentive drug delivery system holds lots of potential for drug having stability problems in alkaline pH or are which mainly absorbed in acidic pH. © 2013 Elsevier B.V. All rights reserved.
1. Introduction The development of an oral controlled release formulation has an incredible impact on the drug delivery area especially for the drugs with a narrow absorption window but the limitation of this approach is insufficient retention of drug in the stomach [1–3]. In order to overcome this limitation, a number of strategies including, floating drug delivery system, mucoadhesives, co-administration of agents that alter the gastric motility have been developed [4,5]. Other approaches and drug carriers have been designed which unfold or expand in the stomach to form a complex geometric shape to obstruct its escape through the pyloric sphincter [6–8]. Combination of floating with the ability to expand by unfolding and swelling using blend of biodegradable polymers (hydrophilic and hydrophobic) is an alternative strategy to increase gastric residence time [9–11]. The present work is an effort to design a compressed device containing drug loaded polymeric film folded using different patterns into hard gelatin capsule. The capsule dissolves after ingestion and the compressed device release the film which then
∗ Corresponding author at: Pharmaceutics Domain, Lovely Professional University, Phagwara, Punjab, India. Tel.: +91 9416729190. E-mail address: [email protected] (K. Nagpal). 0141-8130/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ijbiomac.2013.12.030
unfolds and the swelling usually results by osmotic absorption of gastric fluid [12]. Convenience of hard gelatin capsule is the major advantage of such type of dosage forms. In order to modify drug release through polymeric film design, there remain a number of issues including; selection of a polymer with the desired ability to unfold and expand in the stomach and complexity in formulating a drug loaded polymeric film [9]. CNZ, 1-(Diphenylmethyl)-4-(3-phenyl-2-propenyl)-piperazine, is a Histamine H1 receptor antagonist; antihistamines are widely used in treating nausea and vomiting associated with disorders of the inner ear such as Meniere’s disease and motion sickness. It works by blocking histamine receptors which are found in various sites in the body, including an area in the brain known as the vomiting center. CNZ is a Biopharmaceutical Classification System (BCS) Class II drug with poor aqueous solubility and permeability. It is mainly absorbed in the upper gastrointestinal tract and has a short half-life of 4 h [13,14]. The present work is an based on practical aspects of designing floating and unfolding type polymeric films which deliver immediate release (IR) to achieve the therapeutic drug concentration in a short period of time and controlled release to maintain the concentration for the desired period of time and provide optimal drug release in upper gastrointestinal tract [15,16].
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Table 1 Composition of drug loaded polymeric films containing different amount of stearic acid. Batch Code
Wt. of CNZ (mg)
Wt. of HPMC-K15 (mg)
Wt. of EC (mg)
Wt. of stearic acid (mg)
Amount of PEG 400 (ml)
S0 S10 S20 S30 S40 S50
40 40 40 40 40 40
90 90 90 90 90 90
90 90 90 90 90 90
0 10 20 30 40 50
0.2 0.2 0.2 0.2 0.2 0.2
2. Materials and methods 2.1. Materials CNZ was generously gifted by Montaik Biopharma, India. HPMC K15M. EC was obtained from Central Drug House (P) Ltd. India. All other reagents and chemicals were of suitable analytical grade and were used as received. 2.2. Preparation of polymer film The polymer film was made by solvent casting method. A polymeric dispersion of HPMC K15 and EC was prepared by dissolving in optimum amount of methanol and chloroform, respectively. In previous polymeric dispersion, amount of stearic acid was increased in batch S10 (0.1%) followed by S20 (0.2%), S30 (0.3%), S40 (0.4%), and S50 (0.5%), respectively, with addition of CNZ by vigorous stirring as stated in Table 1. The resulting solution was casted on Teflon plates (4 × 2 cm2 ) and were allowed to dry for 24 h at room temperature and were carefully removed [17,18]. 2.3. In vitro unfolding study The prepared polymeric film was folded in two different patterns (rolling and accordion pattern) and inserted into 00 size capsules (Fig. 1). In vitro unfolding study was carried out in 900 ml of 0.1 N HCl (pH 1.2) using USP type I apparatus (TDT-08 L, Electrolab, Mumbai, India) at constant temperature of 37 ± 0.5 ◦ C at 50 rpm. To examine their unfolding behavior baskets were removed after interval of 5, 10, 20, 40, 80, 160, 320, 640 and 1280 min. 2.4. Characterization of polymeric films 2.4.1. SEM SEM (268D, Fei-Philips Morgagni) of polymeric film from batch S0 and S30 was performed at an acceleration voltage of 15 kV at different magnifications. 2.4.2. Differential scanning calorimetry The DSC thermogram of CNZ, physical mixture (HPMC + EC + Stearic acid + CNZ), stearic acid, polymeric films
S-0 and S-30, HPMC and EC was estimated in terms of their melting endotherms using differential scanning calorimeter (Q10, TA System, USA). The samples were heated in temperature range from 40 to 250 ◦ C at a heating rate of 10 ◦ C per minute under nitrogen atmosphere. 2.5. Evaluation of polymeric films 2.5.1. Thickness Digital micrometer screw gauge (Aerospace, China) was used to measure thickness of polymer film at different strategic locations which is essential to ascertain uniformity of the film thickness. 2.5.2. Folding endurance Folding endurance was determined by repeatedly folding the film at the same place until it breaks. The number of times the film could be folded at the same place without breaking was taken as the folding endurance value. It is an indirect assessment of toughness of film where lower value of folding endurance indicates brittleness of the film [19]. 2.5.3. Tensile strength Tensile strength is the maximum load that a strip specimen can support without fracture when being stretched, divided by the original cross-sectional area of the material. The weight was gradually increased so as to increase the pulley force till the film breaks. The percent elongation before the film breaks was noted with the help of a magnifying glass on graph paper and tensile strength was calculated as kg/cm2 [20]. 2.5.4. Mechanical strength Mechanical strength is the force applied manually. Mechanical strength is measured in kg/cm2 using paper bursting machine. This machine applies mechanical force on a ball which passes through the film after rupturing it when fixed horizontally in a frame (Fig. 2) [21,22]. 2.5.5. Water vapour transmission Polymeric films were fixed on the brim of the pre-weighed glass vials (5 ml) containing fused calcium chloride (1 g) with an adhesive, in a humidity chamber at different humidities.
Fig. 1. (a) Cinnarizine polymeric film. (b) Optimized accordion folding pattern polymeric film. (c) Film compressed into capsule shell.
S. Verma et al. / International Journal of Biological Macromolecules 64 (2014) 347–352
Fig. 2. Paper bursting machine.
2.5.6. Percent moisture absorbed The presence of moisture may not affect the hardness of the film in normal environmental conditions but may be affected in exaggerated conditions. Pre-weighed polymeric films were placed in humidity chamber maintained at 68% RH for 72 h [18]. The percent moisture absorbed was calculated using formula: % moisture absorbed =
initial weight − final weight × 100 initial weight
2.5.7. In vitro drug release study In vitro drug release study of various batches were conducted in simulated gastric fluid medium (900 ml) using USP apparatus I (TDT-08 L, Electrolab, Mumbai, India) with constant temperature maintained at 37 ± 0.5 ◦ C and 50 rpm till 13 h. An aliquot of 5 ml was withdrawn and replaced with another 5 ml of fresh simulated gastric fluid medium at various time intervals. The contents of CNZ in sample were analyzed by double beam UV spectrophotometer (Cary 5000, Varian Australia) at max 254 nm. Then the corresponding concentrations were determined from the standard curve of CNZ prepared in simulated gastric fluid medium (pH 1.2) at max 254 nm [19]. 2.5.8. Modeling and release kinetics To explore the kinetic behavior, results of in vitro release of CNZ from polymeric film was fitted to zero order, first order, Higuchi square root equation and Koresmeyer–Peppas equation and the value of k was determined for different models [23]. However, the drug release mechanism from polymeric system with swelling and/or erosion during dissolution was explained only by fitting in vitro release data in Koresmeyer–Peppas equation: Log
Mt = log k + n log t Mx
where Mt = the fraction of drug released at time t; Mx = amount of drug released after infinite time; k = release rate constant; and n = release exponent. The log value of percentage drug dissolved was plotted against log time for each batch for the determination of release exponent, ‘n’ for different batches of the polymeric films and only the initial portion of release curve (Mt /Mf < 0.6) was used, according to above equation. A value of n = 0.45 indicates Fickian diffusion (Case I) release; the release of drug is primarily by diffusion through the matrix. A value of n (0.45 < n < 0.89) indicates non-Fickian (anomalous) release, the release mechanism of drug was found to be the combination of drug diffusion and polymer erosion. The value of n > 0.89 indicates super
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Fig. 3. DSC curve of Cinnarizine, physical mixture, stearic acid, polymeric film of batch S0, polymeric film of batch S50, HPMC and EC.
Case II type of release. The value of n = 1.0 indicates Case II which generally refers to the erosion mechanism of drug release fromS the polymeric matrix [23]. 2.5.9. Stability studies Stability studies for polymeric films were carried out in triplicate for three months at 45 ± 2 ◦ C and 75% RH. At the end of the period physical parameters and release profiles were determined [24].
3. Results and discussion 3.1. Unfolding behavior of polymeric film Reduction in mechanical shape after prolonged stress applied is the major difficulty in unfolding type of polymeric films. Polymeric material with glass transition temperatures close to ambient temperature with its resiliency to restore its original shape are therefore useful in polymeric formulation since they undergo less plastic deformation and retain their elasticity even when they were folded [12]. The unfolding behavior of both the foldings (roll and accordion) of polymeric film was not satisfactory because they were found to stick to each other. Accordion folding unfolds enthusiastically in comparison with roll folding after coating it with talcum powder and with a property of very high glass transition temperature of HPMC K15 polymer. 3.2. Characterization of polymeric films 3.2.1. DSC studies DSC was performed to find the physical state of CNZ in the polymeric film. In the present study, DSC thermogram of CNZ, physical mixture, stearic acid, polymeric films S0 and S50, HPMC and EC is shown in Fig. 3. DSC of CNZ exhibits a sharp endothermic peak at 121.19 ◦ C corresponding to its melting point which indicates the crystalline nature of incorporated CNZ. Stearic acid exhibited endotherm peaks at 57.47 ◦ C. EC and HPMC elicit broad endotherm, suggesting the amorphous nature of the polymers. Physical mixture showed separate characteristic peaks of CNZ and stearic acid which indicates their compatibility. The broadening endotherm of CNZ and stearic acid in DSC curve of formulation S0 and S50 revealed amorphous nature of both and there were no polymorphic changes in drug as well as excipients during the formulation of polymer film.
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and that was increased due to increase in PEG 400 concentration up to 0.7 ml. After that polymer film could not dry and it was difficult to peel off from the plate. It was observed that PEG 400 was necessary for the success of dosage form which shall otherwise be brittle. 3.3.3. Tensile strength There was not much difference in tensile strength of various batches but it was increased as the concentration of PEG 400 was increased, because of the presence of PEG 400 which may be acting as plasticizer. The results showed that PEG with higher concentration provides a better plasticizing effect for the polymeric film but increases the water vapour permeability of the film. Batch S50 was found to have maximum (up to 320 g) tensile strength as described in Table 3. 3.3.4. Mechanical strength Mechanical strength is the force applied tangentially through round ball on a uniform area of film. The bursting machine used was calibrated in terms of kg/cm2 and the results indicated that S50 film possessed sufficient mechanical strength which may be due to more PEG 400 concentration which acted as plastisizer (Table 2).
Fig. 4. Scanning electron micrograph of (a) polymeric film of batch S0; (b) polymeric film of batch S50.
3.2.2. SEM studies The surface morphology of polymeric films was shown in Fig. 4. Batch S0 at 727x showed fibrous structure (Fig. 4a). The surface morphology of polymer film of batch S50 at the magnification of 398x shows particulate material scattered on the surface with polyhedral depressions which is due to the stearic acid surrounded by the drug, form a channel for leaching out of the drug and which may be responsible for the maximum drug release at first hour (Fig. 4b). 3.3. Evaluation of formulated polymeric films 3.3.1. Thickness The thickness of prepared film varied from 70–110 m. Maximum thickness was observed with S50 batch whereas the minimum thickness was of S0 batch which may be due increase in concentration of stearic acid in S0, S10, S20, S30, S40, S50, respectively, as shown in Table 2. 3.3.2. Folding endurance of polymer films Folding endurance was determined by repeatedly folding the film at the same place until it breaks. The number of times the film could be folded at the same place without breaking was the folding endurance value. The minimum folding endurance was of S0 batch Table 2 Physical characteristics of polymeric films. Batch
Thickness (m)
S0 S10 S20 S30 S40 S50
70 76 80.3 84 88.4 93.1
± ± ± ± ± ±
0.02 0.01 0.03 0.01 0.01 0.02
Mechanical strength (kg/cm2 ) 0.6 1.5 1.8 1.8 1.9 1.9
± ± ± ± ± ±
0.03 0.02 0.02 0.01 0.02 0.01
Moisture absorbed (%) 14.12 9.07 7.66 6.08 6.99 6.01
± ± ± ± ± ±
0.15 0.10 0.22 0.34 0.24 0.27
3.3.5. Water vapour transmission Water vapour transmission test was done at four different humidities (32%, 75%, 80%, 90%). As the humidity was increased, the weight gain by fused CaCl2 also increased. The maximum weight gain was at 90% relative humidity. Batch S50 showed minimum weight gain by fused CaCl2. Based on the observation, it may be concluded that the membrane possessed negligible permeability indicating the success of method of formulation (casting) to yield film of sufficient thickness without pores/thin areas. It may be due to the presence of more stearic acid, a hydrophilic polymer which may act as a moisture barrier from outside as depicted in Table 4. 3.3.6. Percent moisture absorbed The maximum moisture was absorbed by S0 formulation and the least by S50 formulation. This may be due to the presence of stearic acid in S50 formulation which may act as a moisture barrier (Table 2). 3.3.7. In vitro dissolution studies The in vitro drug release study from all six set of formulation (S0, S10, S20, S30, S40, and S50) was performed. The result revealed that formulation S50 showed a minimum percentage drug release of 63.39% followed by the formulation S40, S30, S20, S10, and S0 of 66.10%, 78.78%, 80.30%, 81.93% and 8.70% in 13-h, respectively, which indicates a fast release during the first hour followed by a more steady drug release during a 12-h period as the concentration of stearic acid was increased. Stearic acid, a hydrophobic polymer, used as sustained drug delivery, reduces the drug release from the formulation, as it surrounds the drug, EC and HPMC and make channels from which the drug leaches out more initially and later release slowly by diffusion from HPMC and ethyl cellulose. During the hydration of HPMC, there is formation of gel layer around the dry core of HPMC and swelling of polymer takes place which attributes to be used as an oral controlled drug delivery system because of its high swellability (Fig. 5a). 3.3.8. Drug release kinetics The data obtained from dissolution studies of different batches was analyzed using different mathematical models for the determination of release kinetics. Most of the batches followed Higuchi model. However, the release mechanism is not well known or more than one type of release phenomenon be involved. The value of R2 is 0.9847, 0.935, 0.9581, 0.9849, 0.9863 and 0.94 for S0, S10, S20, S30, S40, and S50 batches, respectively, was found to be maximum for
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Table 3 Tensile strength of polymeric films. Weight suspended (g)
30 60 90 120 150 180 210 240 270 300 320
Increase in length (cm) S0 + PEG 400 (0.2 ml)
S10 + PEG 400 (0.3 ml)
S20 + PEG 400 (0.4 ml)
S30 + PEG 400 (0.5 ml)
S40 + PEG 400 (0.6 ml)
S50 + PEG 400 (0.7 ml)
8.3 ± 0.32 8.8 ± 0.32 9.3 ± 0.36 9.8 ± 0.43 10.4 ± 0.54 10.7 ± 0.33 Break Break Break Break Break
8.3 ± 0.23 8.5 ± 0.12 8.5 ± 0.43 8.5 ± 0.39 8.6 ± 0.29 8.7 ± 0.23 90 ± 0.43 9.1 ± 0.23 9.1 ± 0.22 Break Break
8.1 ± 0.13 8.2 ± 0.22 8.5 ± 0.17 8.7 ± 0.18 8.7 ± 0.33 8.8 ± 0.14 8.9 ± 0.33 9.1 ± 0.28 9.2 ± 0.10 Break Break
8.3 ± 0.11 8.5 ± 0.32 8.6 ± 0.21 9.0 ± 0.43 9.4 ± 0.26 9.9 ± 0.16 10.4 ± 0.12 10.5 ± 0.10 10.6 ± 0.12 Break Break
8.0 ± 0.2 8.3 ± 0.11 8.4 ± 0.21 8.5 ± 0.31 8.8 ± 0.27 9.4 ± 0.12 9.6 ± 0.16 10 ± 0.15 10.5 ± 0.22 10.9 ± 0.16 Break
8.1 8.2 8.3 8.7 8.9 9.3 9.5 10.6 10.8 11.0 11.9
± ± ± ± ± ± ± ± ± ± ±
0.1 0.2 0.11 0.21 0.33 0.22 0.32 0.11 0.43 0.11 0.31
Table 4 Water vapour transmission of polymeric films. Relative humidity
Weight gained (mg) by batch S0
32% 75% 80% 91%
0.48 0.72 0.79 0.89
S10 ± ± ± ±
0.21 0.33 0.34 0.28
0.44 0.72 0.80 0.88
S20 ± ± ± ±
0.18 0.34 0.32 0.35
0.47 0.74 0.79 0.89
S30 ± ± ± ±
0.20 0.30 0.26 0.21
0.46 0.75 0.80 0.84
S40 ± ± ± ±
0.11 0.31 0.23 0.39
0.47 0.74 0.78 0.90
S50 ± ± ± ±
0.17 0.28 0.20 0.35
0.45 0.73 0.77 0.88
± ± ± ±
0.23 0.19 0.26 0.29
3.3.9. Stability studies The results of stability studies of CNZ loaded polymeric films shows more sustained effect as compared to previous drug release studies. When the polymeric films were stored at 45 ± 2 ◦ C and 75% RH for 3 months, it was observed that polymers and stearic acid mixture formed a transparent hard film like insoluble substance which may be due to their mutual interaction that may have reduced the porosity of the polymeric film. This will reduce the ingress of the dissolution medium leading to slower dissolution (Fig. 5b). But there was a slight change in mechanical properties of the polymer film. 4. Conclusions
Fig. 5. Comparative in vitro release profile of Cinnarizine from various batches of polymeric films. (a) Before stability testing; (b) after stability testing.
Koresmeyer–Peppas model. Hence, all batches except S0 follow this model and the drug release mechanism was thus both by diffusion as well as erosion. The value of n was found to be 0.6049, 0.4779, 0.4606, 0.4117, 0.2923 and 0.29 for S0, S10, S20, S30, S40, and S50 batches respectively. The data indicates that with an increase in concentration of stearic acid, erosion of film was decreased. The result revealed that polymeric film of batch S50 had minimum erosion as compared to other batches.
The unfolding type gastroretentive compressed dosage form for controlled release of Cinnarizine, a drug with narrow absorption window, was successfully formulated. The formulated batches were characterized through various physicochemical parameters like, release characteristics, floating characteristics, stability study and integrity during their release period. It consists of drug loaded polymeric film of HPMC K15 and EC, folded in two different patterns inside a hard gelatin capsule. The result revealed that unfolding films (S10–S50) were appropriate in comparison with roll folding pattern in simulated gastric fluid. The presence of stearic acid in polymeric film was crucial to provide an immediate and sustained effect. The floating and mechanical performance of the film indicated the gastroretentive potential of the dosage form. We can certainly explore this drug delivery system for further development through its in vivo evaluation studies which may lead to an improved bioavailability and ensured therapy with other already existing drugs of such type. References [1] [2] [3] [4] [5]
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