Research Article Formulation and evaluation of polymeric thin films of zolmitriptan Garima Bansal 1,2 *, Vipin Kumar Garg 1, K. K. Jha 2 ABSTRACT Background: A lot of work had been done in recent years in the development of oral thin films (OTFs) for drug delivery. Triptans, which are highly selective serotonin agonist used for migraine therapy, were used as a model drug for developing novel thin film drug delivery platform. Aim of the present work was to exploit the combination of hydrophilic polymer and β-cyclodextrin to formulated fast dissolving OTF of Zolmitriptan. Method: A total of nine batches of the thin films with different concentration of hydrophilic Methocel E5(HPMC E5) and β-cyclodextrin reportedly having taste-masking and bioenhancing effect were prepared using glycerin as plasticizer. The mechanical properties such as folding endurance, elongation, and tensile strength along with disintegration time were evaluated. Result and conclusion: In vitro dissolution studies carried out in simulated saliva and gastric fluid indicated that more than 80% of the drug was released in <10 min. A compromise was reached between moderate tensile strength and minimum disintegration time as both in vitro disintegration time and tensile strength of film increased with increase in the concentration of polymer. Thus, it was concluded that the one can successfully formulate novel thin film drug delivery system for triptans using a combination of Methocel E5 and β cyclodextrin. KEY WORDS: β-cyclodextrin, Methocel E5, Thin films, Triptans INTRODUCTION According to the classification of headaches published by the International Headache Society in 2004, triptans are therapeutically effective for the treatment of migraine with or without aura. Migraine is one of ten most debilitating pain in the world which can last for the duration of hours to days and is often associated with nausea, vomiting, etc. Triptans were proved to be highly selective agonist, especially at the serotonin 5-HT1B and 5-HT1D receptor subtypes. Both zolmitriptan and rizatriptan benzoate are available in the market as swallowable tablets, orally disintegrating tablets, and nasal spray. [1,2] Although effective, some drawbacks are associated with triptan therapy like faster onset and longer duration of action was needed for migraine therapy than provided by triptans. Zolmitriptan has short biological half-life and only 40% bioavailability. [3] Furthermore, the swallowing of tablets can stimulate gastric reflex of gastrointestinal tract, worsening the Access this article online Website: jprsolutions.info ISSN: 0974-6943 nausea, and vomiting condition associated with a migraine. Thin films have become an attractive alternative to deliver medicines that are usually available as liquids, tablets, or capsules. Furthermore, oral thin films (OTFs) offer faster onset of action, better bioavailability and patient compliance than conventional drug delivery systems. Thus, we can exploit the feature of thin film drug delivery system for overcoming the drawbacks associated with the conventional triptan therapy of migraine. In the present work, fast dissolving thin films of zolmitriptan were developed using a hydrophilic polymer and cyclodextrin. MATERIAL AND METHOD Zolmitriptan was purchased from Jubilant life sciences Ltd. (Noida, India), hydroxypropyl methylcellulose (HPMC 5 cps) Methocel E5 PREM LV was obtained from Dow Chemicals (Mumbai, India), Himedia laboratory Pvt. Ltd (Mumbai), glycerol and sodium saccharin from CDH Laboratories (New Delhi, India). All other chemicals and solvents used were of pharmaceutical and analytical grade. 1 Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, Meerut, Uttar Pradesh, India, 2 College of Pharmacy, Teerthankar Mahaveer University, Moradabad, Uttar Pradesh, India *Corresponding author: Garima Bansal, Teerthanker Mahaveer College of Pharmacy, Teerthanker Mahaveer University, Moradabad, Uttar Pradesh, India. +91-9927034240. E-mail: garimagarg2000@hotmail.com Received on: 26-09-2017; Revised on: 18-10-2017; Accepted on: 27-11-2017 168 Journal of Pharmacy Research Vol 12 Issue 2 2018
Formulation Design and Procedure On the basis of literature review, preliminary studies were carried out using different hydrophilic polymers for thin film casting, [4,5] and HPMC E5 was selected as the most suitable film former in combination with cyclodextrin. [6] The composition of the film was given in Table 1. Evaluation of the Drug-loaded Thin Films The physical appearance was observed visually, and the thickness was measured using digital micrometer (Mitutoyo, Japan). Weight uniformity For determining the weight uniformity, five different sections of (2 2) cm 2 films from each batch were cut and weighed individually using electronic balance, and standard deviation (SD) for each batch was determined. Drug content For determination of drug content, 2 2 cm 2 film from each batch was kept in 10 ml phosphate buffer ph 6.8 for 24 h. Then, the solution was filtered, and drug content was determined using (Pharmaspec-1700S, Shimadzu, Japan) ultraviolet spectrophotometer. Three readings from each batch were taken. Average and SD for each batch were calculated. Surface ph Agar plates were prepared by dissolving 2% w/v of agar in a warm isotonic PBS (ph6.2) and then allowed to solidify in a Petri dish. The oral films were cut into smaller pieces (2 2 cm 2 ) kept over the surface of the prepared plate to swell. The surface ph was measured by means of a ph meter (Systronic, India) placed in contact with the swollen film. The average value and SD of three readings were calculated. Determination of percentage moisture absorption [7] The percentage moisture absorption test was carried out to ascertain the physical stability of the oral films during highly humid conditions. In the present study, the moisture absorption capacity of the films was determined as follows. Three 2 2 cm 2 films were cut out and weighed accurately, then the films were placed in desiccator containing saturated solution of aluminum chloride, keeping the humidity inside the desiccators at 80% RH after 3 days, the films were removed and weighed, and percentage moisture absorption was calculated. Average percentage moisture absorption of three films was calculated. Percentage moisture absorption = final weight initial weight 100 Initial weight Determination of percentage moisture loss (PML)[7] Impact of dry conditions on the integrity of the hydrophilic polymeric films can be studied by PML studies. The three films (2 2 cm 2 ) were weighed initially and then placed in a desiccators having fused anhydrous CaCl 2 in the chamber for 3 days. Then, the films were removed from the desiccator and weighed again to calculate the PML by the films using the following formula: Percentage moisture loss = Initial weight-final weight 100 Initial weight Folding endurance The number of times a thin film can be folded at the same plane at 180 without being broken indicates its folding endurance. An average of three observations was taken. Tensile strength The tensile strength of the film was calculated by determining the maximum force applied at the point of rupture of the film divided by its cross-sectional area. Tensile strength = Force at break/initial cross-sectional area of film Percent elongation When stress was exerted on a polymeric film, it tends to stretch out which is called as strain. It can be computed by determining the change in the length of the specimen of the film and dividing it by initial length of the film without any externally applied stress. It was determined by the following formula: Percent elongation = (change in length/initial length) 100 Table 1: Composition of fast dissolving OTFs of zolmitriptan Ingredients (mg) Z1 Z2 Z3 Z4 Z5 Z6 Z7 Z8 Z9 HPMC 400 400 400 600 600 600 800 800 800 Zolmitriptan 105 105 105 105 105 105 105 105 105 β cyclodextrin 105 150 200 105 150 200 105 150 200 Glycerin 100 100 100 150 150 150 200 200 200 Saccharine sodium 1 1 1 1 1 1 1 1 1 Tween 80 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Citric acid 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Distilled water q.s 20 20 20 20 20 20 20 20 20 HPMC: Hydroxypropyl methylcellulose, Journal of Pharmacy Research Vol 12 Issue 2 2018 169
Both the abovementioned mechanical properties of polymeric fast dissolving OTFs were evaluated by microtensile tester (Instron Microtensile Tester 5848, Singapore) with a 5 kg load cell. A film of 6 2 cm 2 dimension without any visible imperfections was held between two clamps in a vertical position with a distance of 3 cm in between. The cutting of the films due to metallic clamps was avoided fixing a piece of cardboard on the surface with the help of a tape. The film strip was pulled at the rate of 2 mm/s toward upper side till it breaks. In vitro disintegration test [8] In vitro disintegration test was conducted to ascertain the disintegration of OTF. The samples of film were placed in the tubes of the test apparatus (Electrolab, India) and disks were kept over it. The test was carried out in the simulated saliva maintained at 37 C, till the film completely disintegrates. from the dissolution flasks at various time intervals which were replaced with an equivalent volume of dissolution media. Zolmitriptan in the samples was determined by spectrophotometric analysis at appropriate λ max nm. RESULT AND DISCUSSION As reported in Table 2 the thickness of formulated films varied from 0.111 mm to 0.132 mm that increased with the concentration of the polymer and total solid content. The acidic or alkaline ph may cause irritation of oral mucosa and can also influence hydration of polymer Disintegration time by Petri Dish method [6] The film containing dose equivalent of drug (zolmitriptan) was placed on a stainless steel wire mesh kept in a Petri dish containing 10 ml of phosphate buffer (ph 6.8) at 37±0.5 C. The time required for the film to break was noted as in vitro disintegration time. All studies were performed in triplicate for each batch. In vitro dissolution study The in vitro dissolution studies were carried out using USP paddle Type 2 dissolution apparatus (Electrolab, Mumbai). The dissolution media was simulated saliva (ph 6.8) and simulated gastric fluid maintained at 37 ± 0.5 C at 50 rpm. 5 ml of the samples were withdrawn Figure 1: In vitro dissolution studies of zolmitriptan films in phosphate buffer (ph6.8) Figure 2: In vitro dissolution profile of fast dissolving oral thin film of zolmitriptan at ph 1.2 Table 2: Evaluation parameters of zolmitriptan fast dissolving OTF Batch Thickness (mm) Weight (mg) Drug content (%) Surface ph PMA PML Z1 0.111±0.08 56±0.4 100.05±0.85 6.67±0.05 3.23±0.011 5.54±0.23 Z2 0.109±0.004 58.8±0.70 101.58±0.52 6.76±0.08 4.21±0.016 5.97±0.33 Z3 0.112±0.014 62±0.34 100.85±0.88 6.81±0.05 4.65±0.031 6.59±0.54 Z4 0.119±0.004 65.2±0.31 99.11±1.18 6.82±0.05 3.81±0.04 5.12±0.21 Z5 0.120±0.004 68.3±0.48 98.59±1.43 6.74±0.06 4.53±0.033 5.34±0.65 Z6 0.124±0.014 70±0.36 98.51±1.28 6.90±0.04 6.11±0.052 6.43±0.01 Z7 0.129±0.02 74.5±0.08 100±1.68 6.82±0.03 6.23±0.049 4.35±0.04 Z8 0.130±0.004 78.3±0.04 100.71±2.47 6.93±0.03 6.36±0.014 7.65±0.05 Z9 0.132±0.003 73.4±0.30 100.58±2.32 6.90±0.02 6.18±0.022 7.18±0.01 Table 3: Evaluation of mechanical property and disintegration time of zolmitriptan loaded OTFs Formulation Folding endurance Tensile strength (N/cm 2 ) Elongation (%) In vitro disintegration time (s) Disintegration time (Petri dish) (s) Z1 50±2 0.912±0.172 25.32±2 45±1.73 47±1.52 Z2 59±5 1.231±0.145 20.45±1 48±2 52±1.15 Z3 62±1 1.962±0.058 21.7±2 50±1.08 50±1.52 Z4 77±2 1.834±0.065 25.6±1 60±1.1 70±1 Z5 82±4 1.661±0.048 23.1±1 69±1.73 80±1 Z6 74±3 2.143±0.060 20.9±1 67.33±1.53 75±1.5 Z7 80±2 2.252±0.107 31.4±1 70±2.08 90±1.73 Z8 74±2 2.350±0.134 33.7±2 75±1.52 92±2.52 Z9 64±3 2.640±0.112 18.1±1 72.21±1.81 85±1.53 170 Journal of Pharmacy Research Vol 12 Issue 2 2018
as well as the stability of drug β-cyclodextrin complex, and thus, surface ph of all the formulated batches was determined. It was found to be within the range of 6.5 7. As the ph was approximately similar to ph of oral cavity, there were no chances of irritation of oral mucosa. The film flexibility was found to increase with increase in ratio of cyclodextrin w.r.t drug from 1:1 to 1:2 (D: β-cyclodextrin may be due to increase in the solubility of zolmitriptan in presence of β-cyclodextrin, but it decreases at higher concentration of HPMC E5 due to increase in thickness of the film). In vitro disintegration time mentioned in Table 3 was found to increase with an increase in the concentration of polymer used. All the batches of fast dissolving strips for each formulation disintegrated in <2 min in vitro. Thickness and tensile strength of film also increased with increase in the concentration of polymer. Thus, a compromise was reached between moderate tensile strength and minimum disintegration time. In vitro Drug Release Studies The in vitro drug release for the fast dissolving OTFs of the antimigraine drug was carried out in both phosphate buffer (ph 6.8) and 0.1 N HCl dissolution media reported in Tables 4 and 5 respectively. After 10 min, more than 80% of zolmitriptan was released from batches at ph 6.8, while more than 99% of the drug released after 10 min interval from all the films in dissolution media of 0.1 N HCl. The difference in the amount of drug released in different media might be due to the formation of complex with β-cyclodextrin from which drug released more rapidly at the acidic ph than at ph 6.8. The SEM of drug loaded film (Figures 3 and 4) clearly show uniform distribution of zomitriptan within polymeric film. Fourier transform infrared (FTIR) spectra of the physical mixture of components (Figure 5) indicate that there were no major changes in the FTIR spectra indicating Figure 3: Scanning electron microscopy of zolmitriptan fast dissolving oral thin film at 100 Table 4: In vitro dissolution release data profile of fast dissolving OTF of zolmitriptan at ph 6.8 Time (min) Cumulative drug release (%) Z1 Z2 Z3 Z4 Z5 Z6 Z7 Z8 Z9 0 0 0 0 0 0 0 0 0 0 2 27.5±1.21 28.2±0.99 26.70±0.45 26.93±0.53 33.98±0.74 30.78±0.70 28.80±0.40 31.16±0.61 33.11±0.09 4 38.2±0.07 35.9±1.10 47.51±0.63 37.09±0.62 38.56±0.28 38.84±0.36 41.32±0.32 44.38±1.33 49.21±1.10 6 50.1±0.13 52.51±1.30 57.59±1.05 50.49±0.25 56.18±0.50 57.85±1.21 48.88±0.65 58.62±0.95 57.14±1.13 8 62.3±1.05 64.73±0.05 70.14±0.99 61.52±0.67 68.45±0.36 71.52±1.11 57.49±1.07 64.27±0.54 70.37±0.92 10 80±0.96 78.95±0.14 82.48±0.78 83.09±0.12 79.25±0.91 80.47±0.53 71.61±0.68 78.67±0.42 83.02±0.65 15 89.9±0.12 91.82±0.53 86.62±0.50 88.46±1.03 95.19±0.45 96.69±0.32 86.67±0.66 81.61±0.41 87.92±0.52 Table 5: In vitro dissolution data of fast dissolving OTF of zolmitriptan at ph 1.2 Time (min) Cumulative drug release (%) Z1 Z2 Z3 Z4 Z5 Z6 Z7 Z8 Z9 0 0 0 0 0 0 0 0 0 2 69.5±1.21 68.2±0.56 66.70±1.01 66.93±0.07 63.98±0.56 65.78±0.32 68.80±1.01 67.16±0.87 68.11±0.51 4 78.2±0.93 77.85±0.61 79.08±0.08 76.25±1.21 78.67±0.91 78.84±0.31 74.32±1.20 74.38±0.82 76.21±0.90 6 89.9±0.24 86.62±0.32 88.46±0.57 82.48±1.32 83.09±0.56 84.45±0.44 81.90±0.47 82.71±0.90 83.37±0.62 8 95.3±1.09 94.73±0.45 95.14±0.60 96.52±0.65 96.45±0.64 94.52±1.32 87.49±0.98 88.27±0.06 87.37±0.31 10 98±0.53 98.95±0.15 99.48±0.31 99.09±0.89 99.25±0.43 98.47±1.21 97.61±0.60 98.67±0.50 99.02±0.67 Table 6: Stability study of zolmitriptan fast dissolving OTF Time Physical appearance % Drug content Disintegration time (s) Tensile strength (N/cm 2 ) Initial Translucent thin film 99.71±0.92 46.74±1.52 1.015 1 month Translucent thin film 99.3±1.04 47.24±1.15 1.015 3 months Translucent thin film 99.34±1.41 49.56±2.86 0.995 6 months Opaque thin film 98.85±0.78 49±1.04 0.981 Journal of Pharmacy Research Vol 12 Issue 2 2018 171
no chemical interaction between the components. However, changes observed in the FTIR spectra of optimized fast dissolving OTF i.e (Figure 6) might be due to the complexation between antimigraine triptan and β-cyclodextrin. Optimized film was analyzed by differential scanning calorimetry (DSC) spectra (Figure 8) and compared with DSC spectra of pure drug i.e (Figure 7). Zolmitriptan completely losts its crystalline structure, and thus, no visible peak was seen at the corresponding melting point of the pure drug. The disappearance of the peak of crystalline molecule on inclusion complex formation had been reported in many research works. Figure 4: Scanning electron microscopy of zolmitriptan fast dissolving oral thin film at 500 Stability Studies of Optimized Batch As per the ICH Q1A (R2) guidelines, the stability of each drug-loaded fast dissolving OTF was investigated. Optimized batches of films were studied Figure 5: Fourier transforms infrared of a physical mixture of major components of optimized fast dissolving oral thin film Figure 6: Fourier transforms infrared of optimized fast dissolving oral thin film of zolmitriptan 172 Journal of Pharmacy Research Vol 12 Issue 2 2018
CONCLUSION Figure 7: Differential scanning calorimetry thermogram of pure zolmitriptan Zolmitriptan fast dissolving OTFs were successfully formulated by exploiting the features of HPMC E5 as film-forming polymer as well as a stabilizer of cyclodextrin complexes while the β-cyclodextrin formed inclusion complex with the drug and as reported in not only mask the bitterness of triptans but also enhance its permeation. The thin film formulations are more convenient for the migraine patients experiencing associated nausea and difficulty in swallowing tablets or liquids. REFERENCES Figure 8: Differential scanning calorimetry thermogram of optimized zolmitriptan film for stability parameters at 40 ± 2 C/75% RH ± 5% RH for six months, observations were summerized in Table 6. The formulations showed satisfactory tensile strength, disintegration time, and drug content without any alteration in the physical characteristics, thus confirming their stability. 1. Adelman JU, Lewit EJ. Comparative aspects of triptans in treating migraine. Clin Cornerstone 2001;4:53-64. 2. Diener H. Novel approaches in migraine treatment. Nov Approaches Migraine Treat 2013;2-4. DOI: 10.2217/ ebo.12.457. 3. Gladstone JP, Gawel M. Newer formulations of the triptans: Advances in migraine management. Drugs 2003;63:2285-305. 4. Stella VJ, Rajewski RA. Cyclodextrins: Their future in drug formulation and delivery. Pharm Res 1997;14:556. 5. Bansal G, Vipin G. Ternary complexation approach for the development of oral thin films of Rizatriptan benzoate. JPR BioMedRx Int J 2013;1:810-6. 6. Garsuch V, Breitkreutz J. Comparative investigations on different polymers for the preparation of fast-dissolving oral films. J Pharm Pharmacol 2010;62:539-45. 7. Alagusundaram M, Chetty CM, Dhachinamoorthi D. Development and evaluation of novel-trans-buccoadhesive films of famotidine. J Adv Pharm Technol Res 2011;2:17-23. 8. Kunte S, Tandale P. Fast dissolving strips: A novel approach for the delivery of verapamil. J Pharm Bioallied Sci 2010;2:325-8. Journal of Pharmacy Research Vol 12 Issue 2 2018 173