|Year : 2013 | Volume
| Issue : 4 | Page : 246-255
Levocetirizine dihydrochloride and ambroxol hydrochloride oral soluble films: Design, optimization, and patient compliance study on healthy volunteers
V Senthil1, Rizwan Basha Khatwal2, Varun Rathi1, Siddhartha T Venkata1
1 Department of Pharmaceutics, Jagadguru Sri Shivarathreeshwara College of Pharmacy, Rocklands, Ootacamund, Tamil Nadu, India
2 Department of Pharmaceutics; Department of Pharmaceutical Biotechnology, Jagadguru Sri Shivarathreeshwara College of Pharmacy, Rocklands, Ootacamund, Tamil Nadu, India
|Date of Web Publication||7-Feb-2014|
Rizwan Basha Khatwal
JSS College of Pharmacy, Rocklands, Ootacamund - 643 001, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Clinical trial registration JSSCP/DPP/IRB/007/2010-11
Objective: The aim of this study was to develop taste masked oral soluble films (OSFs) for levocetirizine dihydrochloride (LCT) and ambroxol hydrochloride (AMB) using different combination of polymers such as polyvinyl pyrrolidone (PVP) K30, propylene glycol (PG), gelatin, sodium alginate (SA), pectin, gaur gum (GG), and hydroxypropyl methylcellulose (HPMC) K15M and super disintegrants like carboxymethyl cellulose (CMC) and sodium starch glycolate (SSG). Materials and Methods: The different basic formulations were developed using solvent casting method for with and without drugs loading and prepared films were evaluated different morphological and mechanical parameters facilitated the screening of a formulation with best characteristics. Results: The films made from HPMC K15M (42.2% w/w) and pectin (35.2% w/w) and considered as an optimized batch among the other formulations. The addition of (titanium dioxide) (TiO 2 ) films was shown opaque nature. The optimized films were subjected to further of drugs content, drugs release profile, stability, and organoleptic properties by human volunteers. The percentage release at end of 90 th s found 73.11 ± 5.2% in pH 6.0 and 81.07 ± 5.6% in water for LCT and 89.2 ± 4.5% in pH 6.0 and 86.22 ± 4.2% in water for AMB, respectively and there were insignificant changes showed at stability study. The organoleptic properties revealed that by complexing drugs with hydroxypropyl β-cyclodextrin (HPβ-CD) in 1:1.5 ratios masked the bitter taste of drugs. Conclusion: Developed OSFs can be considered as one of the promising formulation to administer bitter drugs such as LCT and AMB especially for pediatric, geriatric, and non-cooperative patients.
Keywords: Ambroxol hydrochloride, hydroxypropyl β-cyclodextrin, levocetirizine dihydrochloride, oral soluble films, taste masking
|How to cite this article:|
Senthil V, Khatwal RB, Rathi V, Venkata ST. Levocetirizine dihydrochloride and ambroxol hydrochloride oral soluble films: Design, optimization, and patient compliance study on healthy volunteers. Int J Health Allied Sci 2013;2:246-55
|How to cite this URL:|
Senthil V, Khatwal RB, Rathi V, Venkata ST. Levocetirizine dihydrochloride and ambroxol hydrochloride oral soluble films: Design, optimization, and patient compliance study on healthy volunteers. Int J Health Allied Sci [serial online] 2013 [cited 2020 Feb 21];2:246-55. Available from: http://www.ijhas.in/text.asp?2013/2/4/246/126713
| Introduction|| |
Among the various routes, the oral route is the most convenient and acceptable for the patients.  Drug delivery through the oral cavity offers many advantages. The oral mucosa is conveniently and easily accessible and therefore allows uncomplicated application of dosage forms. Furthermore, the oral mucosa is robust against local stress or damage and shows fast cellular recovery after such incidents.  A systemic action can be achieved via drug permeation through the mucosal endothelium. For systemic drug absorption, various dosage forms and devices, e.g., buccal patches, buccoadhesive discs, and mechatronic delivery devices have recently been developed. ,,,
Developing formulations for pediatrics has been a challenging task. Amongst other factors, palatability of formulations of pediatric oral medications is one of the most significant factors influencing compliance to therapeutic regimens. , Although solid dosage forms are widely accepted by elders and adolescents, younger children tend to prefer liquid formulations that are easier to swallow.  From last several decades, scientists have developed numerous oral disintegration (OD) dosage forms for ease of administration and swallowing such as tablets taken with water being the most widely utilized. OD tablets absorb saliva and immediately disintegrate in the oral cavity. After disintegration, the drug and the insoluble components such as the disintegrated material incorporated in the OD tablet remain on or around the tongue. However, this dosage form may not be easy to swallow, so the development of new forms for patients who have difficulty swallowing regular tablets is desirable.
Recently, fast dissolving drug delivery systems have started gaining popularity and acceptance as new drug delivery systems due to easy administration and lead to better patient compliance. These delivery systems either dissolve in the mouth rapidly, without requiring any water to aid in swallowing. They also impart unique product differentiation, thus enabling use as line extensions for existing commercial products. This novel drug delivery system can also be beneficial for meeting the current needs of the industry are improved solubility/stability, biological half-life, and bioavailability enhancement of drugs and also improved the patient compliance to overcome swallowing (dysphasia) conventional dosage forms. ,
Among other fast dissolving drug delivery systems, fast dissolving films are gaining interest as an alternative of fast dissolving tablets. These films are designed to dissolve upon contact with a wet surface, such as the tongue, within a few seconds, meaning the consumer can take the product without need for additional liquid. This convenience provides both a marketing advantage and increased patient compliance. A fast dissolving oral film has been successfully used to deliver medicines to patients having difficulty in swallowing, those with oral pain due to mucositis or after oral surgery, or those with nausea. Several film preparations have been developed for analgesics such as ketrolac  or fentanyl, , the antiemetic agent prochlorperazine  and Ca 2+ channel antagonist verapamil.  Our attempt was to develop taste masked oral soluble films (OSFs) for bitter tasting drugs and investigate the patient compliance study on healthy volunteers.
Levocetirizine dihydrochloride (LCT) and ambroxol hydrochloride (AMB) were chosen as model drugs in design and development of OSFs. These drugs are highly bitter in taste and are more frequently used for cough and cold are targeting to especially pediatric and geriatric population. These both drugs are also highly bitter in taste which is hard to mask by any sweetening agents both of natural and synthetic origin. Hence, hydroxypropyl β-cyclodextrin (HPβ-CD) was taken into consideration to complex the taste of drugs by grinding process. This idea of dosage form was development imparts many novelties into delivery system such as they are considered to be most of time pills and syrup, possess more flexibility, and shows rapid dissolution in oral cavity due to large surface area. They are also nicknamed as give and go which is self-explainable itself.
| Materials and Methods|| |
LCT were kindly supplied from Arbro Pharmaceuticals Ltd, Delhi. AMB and hydroxypropyl methylcellulose (HPMC) K15M were sponsored by Oryx Pharmaceuticals, Haryana. Polyvinyl pyrrolidone (PVP) K30, propylene glycol (PG), isopropyl alcohol (IPA), gelatin, sodium alginate (SA), pectin, gaur gum (GG), carboxymethyl cellulose (CMC), sodium starch glycolate (SSG), citric acid (CA), glycerol, and sodium saccharin (SS) was purchased from S.D. Fine Chemicals, Mumbai. Aspartame and coloring agents was obtained from Abbyss Pharmaceuticals, Delhi. All other materials and solvents used are of reagent or analytical grade and they were used without further purification.
PVP K30, PG, gelatin, SA, pectin, GG, and HPMC K15M and super disintegrants like CMC and SSG.
Development of oral soluble films for levocetirizine dihydrochloride and ambroxol hydrochloride
Based on scientific literatures  and patent,  a basic formulation was developed on the basis of main components such as film former, plasticizer, saliva stimulant, super-disintegrants, preservatives, and mouth feel improvers. The materials were used LCT and AMB as an active pharmaceutical ingredient (API), pectin, and HPMC K15M was used as film former, glycerol as a plasticizer, citric acid as a saliva stimulant, CMC and SSG as super disintegrants, titanium dioxide (TiO 2 ) as an opacifying agent, SS and aspartame were used as sweetening agents, and HPβ-CD were used as a complexing agent for taste masking.
The different basic formulations were developed using solvent casting method for with and without drugs loading. All batches of films were developed as shown in [Table 1]. The film casting solution was prepared containing different ratios of various polymers by successively measured amounts as per formulation codes. The solution was stirred until completely mixed and thick viscous solution was degassed for ultrasonication (Mark, Mumbai) to remove air entraps. Measured quantity of solution was casted on a 30 × 45 cm 2 glass plate and dried in an oven at 60°C for 2 h. The film was carefully removed from the glass plate, checked for any imperfections and cut to the required size to deliver the dose equivalent of AMB and LCT to 35 and 2.5 mg, respectively (2 × 2 cm 2 ) per film. The films were stored in airtight plastic containers for further studies. The film samples were also stored for long-term stability studies as per International Conference on Harmonisation (ICH) guidelines.
|Table 1: Composition (% w/w) of investigated film solutions with different ratios of different polymers|
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Fourier transform infrared analysis (FTIR)
The FTIR spectral measurements of pure drugs and physical mixture of drugs and polymers were taken at ambient temperature using a FTIR spectrophotometer (Perkin Elmer, Japan). About 5 mg of samples were mixed with suitable quantity of KBr and vacuum-packed to obtain pellets of the material. All the spectra acquired scans between 400 and 4,000 cm−1 at a resolution of 4 cm−1 .
| Evaluations|| |
Visual observation was evaluated for appearance of films such as color, homogeneity, transparency, and the feel of touch. ,, These films were assessed in 1 month time intervals over a period of 3 months by allowing the films to expose to normal conditions without any packaging stored at room temperature.
About eight stages of film drying process have been identified such as set-to-touch, dust-free, tack-free (surface dry), dry-to-touch, dry-hard, dry-through (dry-to-handle), dry-to-recoat, and dry print free. Although these tests were primarily used for paint films, most of the studies can be adapted intricately to evaluate pharmaceutical oral film as well. 
Microscopic and image analysis
Visual comparison of films made from different forms was observed by microscopically and the images of the films were captured by using motic microscope ((Motic Ba310, Harmony LifeCare, India).
Film thickness was determined using a micrometer screw (Mitutoyo, Neuss, Germany). Each film was measured at five positions (central and the four corners) and the mean value was calculated. ,
It was measured manually for prepared each film. A strip was repeatedly folded at the same place till the film breaks.  The number of times the film is folded without breaking is computed as the folding endurance value.
Loss on drying
Loss on drying was used as a comparative method to Karl-Fischer-titration. The loss on drying is the loss of mass expressed as percent (mass/mass). It was determined to obtain moisture content and hygroscopicity of dry powder drugs. The test was performed by accurately drugs weighed for 1 g and placed in an oven at 105 C for 3 h at atmospheric pressure.
The surface pH of fast dissolving strip was determined in order to investigate the possibility of any side effects in vivo. As an acidic or alkaline pH may cause irritation to the oral mucosa, it was determined to keep the surface pH as close to neutral as possible. The pH value was determined by using a combined pH electrode. Film was slightly wet with the help of distilled water. The pH was measured by bringing the electrode in contact with the surface of the OSFs. Differences were expected because due to various polymers and APIs were used. The experiments were performed in triplicate, and average values were reported. 
There was no disintegration official test for OSFs. This test was performed as per Mahesh et al., 2010 described.  Two milliliter of phosphate buffer (pH 6.6) was placed in a Petridish and one film was placed on the surface of the buffer. The time taken for the oral film to dissolve completely was measured. This whole disintegration process was carried out in non-agitation method.
To compare the results, a second method was also carried out in agitation method. This test was carried out in a water shaker bath which is maintained in a controlled temperature. The films were taken into the phosphate buffer (pH 6.6) containing conical flask and maintained agitation at 25 rpm to indicate the mulching action. The time required to completely disintegrate in conical flask was noted. All measurements were performed five times for each batch in both methods.
This was determined by standard assay method as per described in the standard pharmacopoeia for these particular APIs. APIs loaded OSFs was dissolved into 50 ml of volumetric flask containing 20 ml of phosphate buffer (pH 6.6), shake well to dissolve and sonicated (Mark, Mumbai) for 20 min, and makeup to 50 ml using pH 6.6. Solution was filtered through Whatman filter paper no. 1 and diluted 5 ml of filtrate to 25 ml using mobile phase. The content of APIs in the films was assayed by reverse phase high-performance liquid chromatography (HPLC; Shimadzu UFLC LC20AD) with chromatographic conditions as acetonitrile and water (70:30) as mobile phase and phenomenex Gemini C18 (250 × 4.6 mm, i.d. 5 μ) as a stationary phase. The flow rate of mobile phase was set at 1 ml/min and the samples were detected by LC solutions.
Limit of content uniformity is 85-115%. This work was carried out at Indian Pharmacopoeia Commission, Ghaziabad.
The drugs content was calculated using equation (1) and expressed as percentage.
Drug release profile
The in vitro drug release of the films was determined using the USP 24 apparatus type 2 at 50 rpm (Sotax AT6, Sotax GmbH, Lorrach, Germany) in pH 6.0 and water with volume of 250 mL. The temperature of the media was maintained at 37 ± 0.5 C throughout the process.
At known time interval the samples were withdrawn manually for analysis (HPLC, Shimadzu-LC 20AD) and replaced with equal quantity of the media to maintain the sink condition (USP-NF24, 2006). One film was placed into each vessel. The measurement was replicated three times with the standard deviation as a measure of variation. ,,
The films were stored under controlled conditions of 25 C/60% RH and 40 C/75% RH for 12 months, according to the ICH guideline Q1A (R2) 'Stability testing of new drug substances and products'. Films were clamped into slide frames for storage to prevent contact. The physical appearance, thickness, and disintegration were determined after 0, 3, 6, 9, and 12 months. 
Oral film assessment by human volunteers
The optimized OSFs are intended to disintegrate rapidly or reside for more duration of time in the oral cavity, the product needs to have acceptable organoleptic palatable characteristics. The product should possess the desired features of sweeteners and flavors which is acceptable to a large mass of population. A special controlled human taste panels were used for psychophysical characteristics evaluation.
The human volunteers of the study were subjected to the randomized single blind trial study after getting approval from Ethics Committee of JSS College of Pharmacy, Ooty (JSSCP/DPP/IRB/007/2010-11). Currently used method involves six human volunteers (four males and two females) who are screened prior to the test for assigning a fitness certificate indicating that they were healthy volunteers. A specimen of 2 × 2 cm 2 was placed in the oral cavity by the volunteer, directly on the tongue. These human volunteers were well-trained for taste evaluation by using reference solutions ranging in taste from tasteless to very bitter. Numerical values are then assigned to these levels of bitterness (e, g., 0-5) in the case of the taste; subsequently, test solution is tasted and rated on the same scale to assess its bitterness and further the test also involves scaling in the levels of bitter acceptability with color, odor, after mouth feel, and texture. 
| Results and Discussion|| |
Fourier transform infrared analysis
[Figure 1] and [Table 2] shows the FTIR spectra and peaks of of pure drugs and physical mixture of drugs and polymers. All the spectra acquired scans between 400 and 4,000 cm−1 at a resolution of 4 cm−1 . Results of FTIR studies revealed no evidence of chemical or physical interaction of drugs and excipients.
|Figure 1: Transmission Fourier transform infrared (FTIR) spectra of (a) pure levocetirizine dihydrochloride (LCT), (b) pure ambroxol hydrochloride (AMB), and (c) physical mixture of active pharmaceutical ingredients (APIs) with polymers|
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|Table 2: Assignment of FTIR spectrum of LCT, AMB, and physical mixture of LCT and AMB with HPMC K15M and pectin|
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The visual inspection was done on all batches of films made from different combination of polymers with different ratios like PVP K30 and PG, gelatin and SA, gelatin and pectin, HPMC K15M and pectin, and observed characteristics was shown in [Table 1]. The films made from the combination from HPMC K15M and pectin batches like LA06-LA14 showed good appearance of stable remaining without any change in their properties. But films made from guar gum showed no film formation. The addition of opacifying agent of TiO 2 to last optimized batch showed opaque in nature [Figure 2]b and confirmed that without addition of TiO 2 showed some degree of transparency [Figure 2]a. The addition of 30 mg (4.2% w/w) of Aspartame improved palatability of films. From visual inspection confirms that, films made from HPMC K15M (42.2% w/w) and pectin (35.2% w/w) with and without addition of opacifying agent was considered for further characterization and compare with films made from other combinations of polymers batches like LA1, LA2, and LA3. Results of visual inspection showed in [Table 3].
|Figure 2: Drugs loaded oral soluble films (OSFs) of (a) LA13 batch and (b) LA14 batch|
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Similar to the visual inspection the dryness test was carried out which includes eight stages for 3 months and results shown in [Table 4]. All these stages indicate ability of the respective film to possess its properties of adequate moisture content throughout the storage period of 3 months. Further interpreting the results indicates that, films made from HPMC K15M (42.2% w/w) and pectin (35.2% w/w) showed best results than any other films and the obtained results suggested positively consistent for set to free and dust free test in the time period of 3 months, while the tests shows a bit of inconsistency at the end of 3 rd month.
Microscopic and image analysis
The visual microscopic inspection was done to understanding the surface texture visually on all batches made from all combination of films. The images of films made from all combination shown in [Figure 3]. From these microscopic examinations confirmed, films made from combination of HPMC K15M (42.2% w/w) and pectin (35.2% w/w) without addition of TiO 2 showed good transparency compared to other batches.
|Figure 3: Microscopic image analysis of different formulations: (a) LA1, (b) LA2, (c) LA3, (d) LA13, and (e) LA14|
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The thickness of film directly influences the mass of film and content of drugs loaded in it. The results for the different batches made with different combination of polymers are shown in [Figure 4]. All the prepared films were showed significant in thickness due to different combination of polymers were used. Films made from combination of HPMC K15M (42.2% w/w) and pectin (35.2% w/w) were showed less thickness batches like LA14 (0.37 ± 0.05 mm) and LA13 (0.47 ± 0.03 mm). Results suggested that addition of TiO 2 showed less thickness even considered addition HPβ-CD as best batch due its good transparency nature.
|Figure 4: Film thickness of different formulations. Bars show mean ± confidence interval (n = 5)|
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Folding endurance tests have been used to estimate the ability to withstand repeated bending, folding, and creasing without breaking. Folding endurance has also been useful for measuring the deterioration of film upon aging. The test was repeated five times and results implemented in [Figure 5]. The film made from combination of HPMC K15M (42.2% w/w) and pectin (35.2% w/w) without addition of TiO 2 were shown much more flexible with 163 ± 4.3 average folds, while the film formed of PVP K30 and pectin combination showed least number of folds with average of 41.3 ± 1.5.
|Figure 5: Folding endurance of different formulations. Bars show mean ± confidence interval (n = 5)|
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Loss on drying
Loss on drying test directly indicates that moisture content and the degree of hygroscopicity of films. The percentage of loss on drying shown in [Table 5] and results were showed similar loss on all batches. The loss on drying was found within the limits thus stating the films prepared static in their properties and do not absorb moisture on storage.
|Table 5: Average losses on drying and pH values of different formulation|
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The pH of films was determined in order to investigate the possibility of any side effects in vivo. The pH values of films made from different combination of polymers are given in [Table 5]. As an acidic or alkaline pH may cause irritation to the oral mucosa, it was determined to keep the surface pH to neutral as close as possible. The neutral pH shown for films assured that there will not be any kind of irritation to the mucosal lining of the oral cavity and LA13 batch films showed much closed to neutral with 7.5 ± 0.3, but addition of TiO 2 showed near to alkaline pH with 8.2 ± 0.2.
The results both agitation and non-agitation disintegration time shown in [Figure 6] and there was close results observed in both methods. The order of high disintegration time was observed like LA14 > LA13 > LA3 > LA2 > LA1. The all batches films showed less than 160 s to complete disintegration time. In both agitation methods a little more disintegration time was observed in case of films made from HPMC K15M (42.2% w/w) and pectin (35.2% w/w) with addition of TiO 2 ( 156.7 ± 6.2 and 143.2 ± 5.8 s) than without addition of TiO 2 ( 121.6 ± 5.2 and 120.6 ± 6.2 s). The disintegration time of other films made from other combination of polymers shown as PVP K30 and PG (57.4 ± 4.8 and 44.3 ± 3.5 s), gelatin and SA (111.3 ± 5.9 and 94.1 ± 5.4 s), and gelatin and pectin (144.3 ± 5.3 and 110.7 ± 3.9 s).
|Figure 6: Disintegration time of different formulations by both agitation and non-agitation method. Bars show mean ± confidence interval (n = 5)|
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With these evaluation characteristics confirmed that, the films made from HPMC K15M (42.2% w/w) and pectin (35.2% w/w) without addition of TiO 2 (LA13 batch) showed better characteristics among the other formulations and these batch films were considered for further studies such as varying content, drug release profile, organoleptic assessment, and stability studies.
The APIs content was done on six films of same batch of LA13. The APIs content in each film was calculated using equation (1). The average content of films was found 95.45 ± 2.2% for AMB and 101.75 ± 3.1% for LCT in the sample solutions. The content of both drugs in films was showed within the limits.
Drug release profile
The results of dissolution profile of drug-loaded LA13 batch films were shown in [Figure 7]. The samples were collected at 5, 10, 15, 30, 60, and 90 s. In both dissolution medium films completely dissolved within 120 s. The percentage release at end of 90 th s found 73.11 ± 5.2% in pH 6.0 and 81.07 ± 5.6% in water for LCT and 89.2 ± 4.5% in pH 6.0 and 86.22 ± 4.2% in water for AMB, respectively. Therefore, LCT was released more percentage in water than in pH 6.0 and AMB was released less amount in water than in pH 6.0.
|Figure 7: In vitro drug release profile in (a) buffer pH 6.0 and (b) in water (each point represents the mean ± standard deviation (SD) of six experiments)|
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The results of stability studies of optimized batch (LA13) were showed in [Table 6] and there was no much changes were observed in physical appearance, thickness, and drugs content and there was little change was observed in disintegration time. Thus, these films were taken for carried out organoleptic assessment in human volunteers.
Oral film assessment by human volunteers
The study was carried out by divided into two groups where first group (2 males and 1 female) indicates volunteers received plain drugs and second group (two males and one female) indicates volunteers received optimized batch films (LA13) made from HPβ-CD complexed drugs-loaded HPMC K15M (42.2% w/w) and pectin (35.2% w/w). The obtained score from human volunteers on taste, color, odor, and texture implemented in stem and leaf graph [Figure 8], revealed that HPβ-CD masked drug-loaded OSFs received less scale compared to the plain drugs indicated that, the form to be much acceptable compared to that of the film running alone with plain drugs.
|Figure 8: Stem and leaf graph of average point of all organoleptic parameters of (a) plain drug administered and (b) optimized batch films (LA13 batch) (each point represents the mean ± SD of six experiments)|
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| Conclusion|| |
With an objective to overcome all the limitations of conventional dosages form, the present OSFs were developed using various combination of polymers, super disintegrants, sweetening agents, and complexing agent for development of taste masked drugs-loaded OSFs. In process of optimization of film formation different combination of polymers such as PVP K30 and PG, gelatin and SA, gelatin and pectin, and HPMC K15M and pectin were used. Films made from combination of HPMC K15M (42.2% w/w) and pectin (35.2% w/w) showed good film formation than other combinations and without addition of TiO 2 films were showed better degree of transparency with good characteristics. Aspartame was shown better taste masking in drug-loaded OSFs than SS due to its fact of nature leaves certain extent of bitterness at the end. Further LA13 batch films showed within the limits of drugs loading property, immediate drug release nature and also found to be stable at under controlled conditions of 25 C/60% RH and 40 C/75% RH for 12 months. Organoleptic assessment by human volunteers scored less scale compared to the plain and suggested that by complexing drugs with HPβ-CD in 1:1.5 ratios masked the bitter taste of drugs. Thus, the designed OSFs can be considered as one of the promising formulation to administer bitter drugs such as LCT and AMB especially for pediatric and geriatric patients and non-cooperative patients due to its ease of administration as well as patient friendly dosage formulation.
| References|| |
|1.||Dixit RP, Puthli SP. Oral strip technology: Overview and future potential. J Control Release 2009;139:94-107. |
|2.||Rathbone MJ, Drummondb BK, Ian G. Tucker IG. The oral cavity as a site for systemic drug delivery. Adv Drug Deliv Rev 1994;13:1-22. |
|3.||El-Samaligy MS, Yahia SA, Basalious EB. Formulation and evaluation of diclofenac sodium buccoadhesive discs. Int J Pharm 2004;286:27-39. |
|4.||Chayed S, Winnik FM. In vitro evaluation of the mucoadhesive properties of polysaccharide-based nanoparticulate oral drug delivery systems. Eur J Pharm Biopharm 2007;65:363-70. |
|5.||Perioli L, Pagano C, Mazzitelli S, Rossi C, Nastruzzi C. Rheological and functional characterization of new anti-inflammatory delivery systems designed for buccal administration. Int J Pharm 2008;356:19-28. |
|6.||Scholz OA, Wolff A, Schumacher A, Giannola LI, Campisi G, Ciach T, et al. Drug delivery from the oral cavity: Focus on a novel mechatronic delivery device. Drug Discov Today 2008;13:247-53. |
|7.||Crama A, Breitkreutzb J, DessetèBrèthesc S, Nunn T, Tuleu C. European Paediatric Formulation Initiative (EuPFI). Challenges of developing palatable oral pediatric formulations. Int J Pharm 2009;365:1-3. |
|8.||Florence AT. Neglected diseases, neglected technologies, neglected patients? Int J Pharm 2008;350:1-2. |
|9.||Committee for Medicinal Products for Human Use, European Medicines Agency EMEA, Reflection paper: Formulation of choice for the pediatric population, Sep; 2006. |
|10.||Nishimura M, Matsuura K, Tsukioka T, Yamashita H, Inagaki N, Sugiyama T, et al. in vitro and in vivo characteristics of prochlorperazine oral disintegrating film. Int J Pharm 2009;368:98-102. |
|11.||Sakuda Y, Ito A, Sasatsu M, Machida Y. Preparation and evaluation of medical carbon oral films. Chem Pharm Bull (Tokyo) 2010;58:454-7. |
|12.||Mahesh A, Shastri N, Sadanandam M. Development of taste masked fast disintegrating films of levocetirizine dihydrochloride for oral use. Curr Drug Deliv 2010;7:21-7. |
|13.||Garsuch V, Breitkreutz J. Comparative investigations on different polymers for the preparation of fast-dissolving oral films. J Pharm Pharmcol 2010;62:539-45. |
|14.||Martínez-Camacho AP, Cortez-Rocha MO, Ezquerra-Brauer JM, Graciano-Verdugo AZ, Rodriguez-Félix, Castillo-Ortega MM, et al. Chitosan composite films: Thermal, structural, mechanical and antifungal properties. Carbohydr Polym 2010;82:305-15. |
|15.||Kunte S, Tandale P. Fast dissolving strips: A novel approach for the delivery of verapamil. J Pharm Bioallied Sci 2010;2:325-8. |
|16.||Patel R, Shardul N, Patel J, Baria A. Formulation development and evaluation of mouth melting films of ondensetron. Arch Pharm Sci Res 2009;1:213-7. |
|17.||Tingstad JE. Physical stability testing of pharmaceuticals. J Pharm Sci 1964;53:955-62. |
|18.||Sward G. Drying time. In: Sward G, editor. Paint Testing Manual-Physical and Chemical Examination of Paints Varnishes Lacquers, and Colors, 13 th ed. West Conshohocken: American Society for Testing and Materials 1972. p. 268. |
|19.||Zerbe HG, Serino AJ, Guo JH. Sofortige Benetzbarkeit aufweisende (r) wasserlöslicher Film oder wasserlösliche Schicht zur oralen Applikation. Eur Patent EP 2003;1:362,584. |
|20.||Shanmugasundaram S, Manjunatha N, Vijayan R, Khatwal RB, Samanta MK. Determination and estimation of pharmacokinetic profile of caffeine in form of extract of green tea leaves and its analogy with synthetic form. Indian J Pharm Sci 2011;73:649-55. |
|21.||Al-Hezaimi K, Al-Askar M, Selamhe Z, Fu JH, Alsarra IA, Wang HL. Evaluation of novel adhesive film containing ketorolac for post- post-surgery pain control: A safety and efficacy study. J Periodontol 2011;82:963-8. |
|22.||Vasisht N, Gever LN, Tagarro I, Finn AL. Single-dose pharmacokinetics of fentanyl buccal soluble film. Pain Med 2010;11:1017-23. |
|23.||Finn AL, Hill WC, Tagarro I, Gever LN. Absorption and tolerability of fentanyl buccal soluble film (FBSF) in patients with cancer in the presence of oral mucositis. J Pain Res 2011;4:245-51. |
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]