INTRODUCTION:
Fast dissolving films or rapidly dissolving dosage forms have great importance in thepharmaceutical industry due to their unique properties and advantages.[1-3] Fast dissolving films a type of oral drug delivery system for the oral delivery of the drug, was developed based on the technology of the transdermal patch.[4-7] This delivery system consists of a thin film, which is simply placed on the patient’s tongue or mucosal tissue, instantly wet by saliva; the film rapidly dissolves. Then it rapidly disintegrates and dissolves to release the medication for oral mucosal absorption. They undergo rapid disintegration in the salivary fluids of the oral cavity in less than a minute, where they release the drug.
Most of the drug is swallowed orally with the saliva and the absorption of drug takes place in the gastro-intestinal tract. The dosage forms were first introduced in 1970's as an alternative to theconventional immediate release tablet and capsule whichrequire swallowing of thedosage form. Fast disintegration dosage forms are available in the market for a variety of drugs.[7-10] Orally disintegrating films were introduced in the market as breath fresheners and personal care products such as dental care strips and soap strips. It is also useful whether local action desired such as local anesthetic for toothaches, oral ulcers, cold sores or teething. However these dosage forms are introduced inthe United States and European pharmaceutical markets for better therapeutic benefits.[11] The oral disintegrating films are prepared using water soluble and/or water swellable film formingpolymer due to which the film dissolves rapidly when placed on the tongue in the oral cavity. Hydroxy propyl methyl cellulose is the water soluble swellable polymer which was used as afilm forming agents at low viscosity. The most preferred grades of HPMC film formers.[12-14]
Risperidone (C23H27N4O2) is a benzisoxazole derivative, is a second-generation atypical antipsychotic agent indicated for the treatment of schizophrenia with reduced side effects especially extra-pyramidal symptoms.[15-16] It is a dopamine antagonist possessing anti-serotonergic, anti-adrenergic and anti-histaminergic properties. It is used primarily in the management of schizophrenia, inappropriate behaviour in severe dementia and manic episodes associated with bipolar I disorder.[17 ]Risperidone is effective for treating the positive and negative symptoms of schizophrenia compared to first generation antipsychotics.[18-19] Risperidone was approved by the United States Food and Drug Administration (FDA) in 1994 for the treatment of schizophrenia. Physicochemical properties and long half-life of Risperidone make it suitable candidate for oral fast dissolving drug delivery system. [20]
MATERIALS AND METHOD:
Chemicals Used:
Risperidone, HPMC K15and Citric acid, Propylene glycol, Sorbital and Potassium Dihydrogen Phosphate used were of pharmaceutical grade.
Equipment Used:
Glass petriplate, dissolution apparatus, disintegration apparatus, UV Spectrophotometer.
Preparation of buffer solution:
6.8pH phosphate buffer was prepared by mixing 250ml of 0.2M potassium dihydrogen phosphate along with 100ml of 0.2M NaOH, distilled water was added to adjust the volume and make up the volume to 1000ml.
Preparation of standard stock solution:
Standard drug solution of risperidone was prepared by dissolving 50.00mg pure drug in 50.00ml 6.8pH phosphate buffer. A concentration of 1000μg/ml was obtained, from which desired concentration solutions were prepared.
Determination of λmax:
10μg/ml solution of risperidone was prepared and scanned in UV range 200-400nm and spectrum was obtained. The λmax was found to be 205nm.
Preparation of calibration curve:
From the stock solution of risperidone, a series of dilutions ranging from 2-10 μg/ml were prepared. Absorbance of these solutions was measured at 205nm wavelength (Table 1). And calibration curve was plotted between concentration and absorbance (Fig. 1).
Table 1.Standard calibration curve of risperidone
|
Concentration (μg/ml) |
Absorbance (nm) |
|
2 |
0.16 |
|
4 |
0.198 |
|
6 |
0.233 |
|
8 |
0.277 |
|
10 |
0.311 |
Fig. 1.Calibration curve of risperidone was prepared in 6.8pH phosphate buffer. In 6.8 phosphate buffer the slope of the graph was found to be 0.019 and intercept with -0.121 with regression coefficient R2 = 0.998.
Formulation and Development of mouth dissolving film:
Mouth dissolving film of Risperidonewas prepared by solvent casting techniqueusing the formula given in Table 2.
Aqueous solution ‘A’ was prepared by dissolving HPMCk15 polymer in 15 ml cool water with stirring to produce solution and kept for 24 hrs. to remove all the air bubbles and form clear solution
Aqueous solution ‘B’ was prepared by dissolving Risperidone, sorbital, citric acid and propylene glycol in specific proportion in 5 ml of distilled water. The aqueous solutions ‘A’ and ‘B’ were mixed and stirred for 1 hr. The solutions were cast on to glasspetri plate of 9 cm diameter and were dried in the oven at 45° C till a peelable film was formed. Then driedfilms were cut into rectangular shape pieces, with 3.0 cm2 (2.0 cm × 1.5 cm) total surface area. Desired quantityof Risperidone was 0.5 mg (dose of drug) per 3.0 cm2 films.
Table 2: Composition of mouth dissolving films of Risperidone
|
Ingredients |
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
|
Risperidone |
0.5 |
0.5 |
0.5 |
0.5 |
0.5 |
0.5 |
|
HPMC K15 |
0.150 |
0.160 |
0.170 |
0.185 |
0.200 |
0.250 |
|
PG |
0.09 |
0.12 |
0.15 |
0.18 |
0.21 |
0.21 |
|
Citric acid |
0.25 |
0.25 |
0.25 |
0.25 |
0.25 |
0.25 |
|
sorbital |
0.15 |
0.15 |
0.15 |
0.15 |
0.15 |
0.15 |
Evaluation of mouth dissolving films:
Physical appearance:
Films of each formulation were randomly selected and inspected visually as well as by feel or touch fortexture.
Weight variation test:
The cast film was cut at different places and the weight of each film was checked with the help of an electronic balance and the average weight was calculated.
Folding Endurance:
Folding endurance was determined by repeatedly folding the film at the same position until it breaks. The number of times the films can be folded without breaking is termed as the folding endurance value.
Thickness of Films:
The thickness of film is determined by screw gauge or micrometer at different points of the films. This is essential to determine uniformity in the thickness of the film as this is directly related to the accuracy of dose in the strip.
Surface pH of films:
Film was left to swell for 2hrs on the surface of an agar plate. Agar plate was prepared by dissolving 2 % (w/v) agar in warm isotonic phosphate buffer (pH 6.8) with stirring and then pouring the solution into a petridish and allowing it to gel at room temperature. The surface pH was measured by means of a pH paper placed on the surface of the swollen film.
Percentage moisture loss (PML):
Percentage moisture loss was calculated to check the integrity of films at dry condition. Three 1cm square films wascut out and weighed accurately and kept in desiccators containing fused anhydrous calcium chloride. After 72 hoursthe films were removed and weighed. The percentage moisture loss was calculated by using this formula.
Drug content uniformity:
Content uniformity is determined by estimating the API content in individual strip. Three films fromeach formulation were took and individually dissolved in 50 ml of 6.8 pH phosphate buffer to give solutions of10μg/ml concentration. These solutions were filtered and absorbance of each solution was recorded at 276 nm(λ max of Risperidone) using the placebo patch (patch without drug) solution as a blank. The percentage drugcontent was determined. Mean of the percentage drug content and standard deviations were calculated. TheLimit of content uniformity is 85-115%.
Disintegration time:
This test is carried out using the disintegration apparatus. Three films from each formulation were takenand performed disintegration test by placing the films in the cylindrical glass tube of disintegration apparatuscontaining 6.8 pH phosphate buffer. The time at which film disintegrated is noted. Mean and standard deviationwere calculated. Normally disintegration time for fast dissolving oral films is 5-30 seconds.
Dissolution test:
Dissolution testing performed in pH 6.8 phosphate buffer (dissolution media) using the standard basketapparatus at 37 ± 0.5° C and 50 rpm. A single film was placed in 500 ml dissolution media. 5 ml of sampleswere withdrawn at suitable time intervals and replaced with fresh dissolution medium. Then samples weredetermined using UV visible spectrophotometer at 276 nm and cumulative drug release was calculated.
Accelerated stability studies:
The stability studies were conducted according to ICH guidelines to investigate the effect of -
temperature, relative humidity on drug in formulation. Final optimized formulation was subjected to aggravatedconditions of temperature and relative humidity by wrapping it in aluminium foil and packaging it in glasscontainer. The films were kept in stability chamber, at 40 ± 20 C temperature and 75 ± 5% RH for 3 months.
After 1, 2 and 3 months, films were tested for:
1 Change in the appearance.
2 Change in the disintegration time.
3 Change in the surface pH.
4 Change in the folding endurance
RESULT AND DISCUSSION:
Evalution of mouth dissolving film of risperidone
Table 3.Evaluation of Weight uniformity, Thickness and Moisture content loss
|
Formulation code |
Weight uniformity (mg) |
Thickness |
Moisture content loss(%) |
|
F1 |
25.7 |
0.12 |
9.05 |
|
F2 |
27.0 |
0.12 |
6.11 |
|
F3 |
29.1 |
0.14 |
8.95 |
|
F4 |
31.5 |
0.16 |
4.05 |
|
F5 |
34.9 |
0.18 |
5.69 |
|
F6 |
38.4 |
0.19 |
7.87 |
Table 4. Evaluation of Folding endurance, Disintegration and time Drug content uniformity
|
Formulation Code |
Folding endurance |
Disintegrationtime (sec) |
Drug content uniformity(mg) |
|
F1 |
105 |
10 |
0.40 |
|
F2 |
95 |
15 |
0.47 |
|
F3 |
115 |
18 |
0.50 |
|
F4 |
130 |
21 |
0.42 |
|
F5 |
144 |
25 |
0.44 |
|
F6 |
160 |
30 |
0.46 |
Table 5.Percent drug release of risperidone film
|
Time (min) |
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
|
2 |
0 |
0 |
0 |
41.23 |
38.46 |
38.22 |
|
4 |
46.9 |
55.11 |
50.0 |
48.90 |
48.61 |
47.04 |
|
6 |
50.34 |
60.02 |
59.4 |
56.78 |
59.13 |
49.88 |
|
8 |
67.52 |
78.38 |
63.26 |
70.10 |
78.89 |
65.22 |
|
9 |
73.16 |
82.61 |
74.52 |
83.17 |
80.60 |
76.46 |
|
10 |
81.75 |
86.05 |
79.66 |
85.33 |
82.49 |
80.11 |
Evaluation of various parameters is mentioned in Tables 3-5. Mouth dissolving film of risperidone were prepared by the method of solvent casting technique. The prepared risperidone mouth dissolving film were evaluated or characterised based upon their physic-chemical characteristic their mouth dissolving time, surface PH, percentage moisture loss, thickness, weight variation, folding endurance, & drug content uniformity, dissolution, disintergration. The film thickness were observed using digital vernier callipers & found to be in the range of 0.15 to 0.19. The weight of film was found in the range of 25.8 to 30.5 mg the mouth dissolving time of film was found in the range of 10 to 50 second.Formulation of F2 was considered as the best oral film containing HPMC k15 & drug ratio of (3011) the drug release from formulation F2was 85% which showed maximum absorption from saliva, it also show a better disintegrating i.ewithin 10 second.
CONCLUSION:
Successful formulation of Risperidone mouth dissolving films may prevent firstpass metabolism to a large possible extent. From the present study it can be concluded that HPMCk15 based mouth dissolving films of Risperidone can be successfully prepared with considerable good stability and improved bioavailability.The results have shown that the HPMCk15 is good film former and shows bioadhesion property. In combination with PG, it has shown promising fast drug release within 10 min. And good folding endurance. Hence, a semi-synthetic cellulose derivative which is affordable and abundantly available can be used as a potential drug release modifier and also used to improve flexibility and processability in the mouth dissolving films. Successful formulation of Risperidone mouth dissolving films may prevent first.
ACKNOWLEDGMENT:
Authors want to acknowledge the facilities provided by the Rungta College of Pharmaceutical Sciences and Research, Kohka, Kurud Road, Bhilai, Chhattisgarh, India. The authors also wants to acknowledge Chhattisgarh Council of Science and Technology (CGCOST) for providing financial assistance under mini research project (MRP) vide letter no. 1124/CCOST/MRP/2015; Dated: September 4, 2015 and 1115/CCOST/MRP/2015; Dated: September 4, 2015.
REFERENCES:
1. Liang AC, Chen LH, 2001, Fast Dissolving Intraoral Drug Delivery Systems, Exp. OpinTheir. Patents., 11,981
2. Kumar SV, Gavaskar B, Sharan G, Rao YM. Overview on Fast Dissolving Films, InternationalJournal of Pharmacy and Pharmaceutical Sciences, 2010, 2 (3), 29-33.
3. Kaur M, Rana C, Seth N. Fast dissolving films: An innovative drug delivery system, International Journal of Pharmaceutical Research & Allied Sciences, 2013, 2, 14-24 4.
4. Kumar KR, Mercy SM. Fast dissolving films: A unique strategy for drug delivery, Asian J. Pharm. Res., 2014, 4, 7-9
5. Smart JD.Drug delivery using buccal-adhesive systems, Advanced Drug Delivery Reviews, 1993, 11,253-270.
6. Saini P, Kumar A, Sharma P, Visht S. Fast Disintegrating Oral Films: A Recent Trend of Drug Delivery. International Journal of Drug Development & Research, October-December, 2012, 4 (4), 80-94.
7. Patel K., Soni S, Patel R, Pandya V, Bharadia P, Mouth Dissolving Film: A Review, InternationalJournal for Pharmaceutical Research Scholars, 2012, 1 (3), 154-163.
8. Alexander A, Ajazuddin, Khan J, Saraf S, Saraf S. Polyethylene glycol (PEG)–Poly(N-isopropylacrylamide) (PNIPAAm) based thermosensitive injectable hydrogels for biomedical applications. European Journal of Pharmaceutics and Biopharmaceutics 2014; 88 (3): 575-85.
9. Ashawat MS, Saraf S, Saraf S. Preparation and characterization of herbal creams for improvement of skin viscoelastic properties. International Journal of Cosmetic Science 2008; 30 (3): 183-93.
10. Vyas A, Saraf S, Saraf S, Encapsulation of cyclodextrincomplexed simvastatin in chitosan nanocarriers: A novel technique for oral delivery. J InclPhenomMacrocyclChem 2010; 66 (3-4): 251-59. English.
11. Singh D, Singh M, Saraf S, Dixit VK, Saraf S, Optimization and Characterization of Gentamicin Loaded Chitosan Microspheres for Effective Wound Healing. Indian J Pharm Educ Res 2010; 44 (2): 171-182
12. Alexander A, Ajazuddin, Patel RJ, Saraf S, Saraf S. Recent expansion of pharmaceutical nanotechnologies and targeting strategies in the field of phytopharmaceuticals for the delivery of herbal extracts and bioactives. Journal of Controlled Release 2016; 241:110-124.
13. Alexander A, Saraf S, Saraf S. Understanding the role of poloxamer 407 based thermoreversible in situ gelling hydrogel for delivery of PEGylated melphalan conjugate. Current Drug Delivery 2016; 13 (4): 621-630
14. Jeswani G, Alexander A, Saraf S, Saraf S, Qureshi A, Ajazuddin. Recent approaches for reducing hemolytic activity of chemotherapeutic agents. Journal of Controlled Release 2015; 211:10-21.
15. Alexander A, Saraf S, Saraf S. A comparative study of chitosan and poloxamer based thermosensitive hydrogel for the delivery of PEGylated melphalan conjugates. Drug Development and Industrial Pharmacy 2015;41(12):1954-61
16. Alexander A, Ajazuddin, Khan J, Saraf S, Saraf S. Poly(ethylene glycol)–poly(lactic-co-glycolic acid) based thermosensitive injectable hydrogels for biomedical applications. Journal of Controlled Release 2013; 172 (3): 715-29
17. Sahu S, Saraf S, Kaur SD, Saraf S. Biocompatible Nanoparticles for Sustained Topical Delivery of Anticancer Phytoconstituent Quercetin. Pakistan Journal of Biological Sciences 2013; 16: 601-09.
18. Ajazuddin, Alexander A, Khan J, Giri TK, Tripathi DK, Saraf S. Advancement in stimuli triggered in situ gelling delivery for local and systemic route. Expert Opinion on Drug Delivery 2012; 9 (12): 1573-92.
19. Alexander A, Dwivedi S, Ajazuddin, Giri TK, Saraf S, Saraf S, Tripathi DK. Approaches for breaking the barriers of drug permeation through transdermal drug delivery. Journal of Controlled Release 2012; 164 (1): 26-40.
20. Ajazuddin, Saraf S, Applications of novel drug delivery system for herbal formulations. Fitoterapia 2010; 81 (7): 680-89.
Received on 15.08.2017 Modified on 13.09.2017
Accepted on 19.10.2017 © RJPT All right reserved
Research J. Pharm. and Tech 2018; 11(7): 2922-2925.
DOI: 10.5958/0974-360X.2018.00539.5