INTRODUCTION:
The film is an ideal intraoral fast-dissolving drug delivery system, which satisfies the unmet needs of the market, is easy to handle and administer, maintains a simple and convenient packaging, alleviates unpleasant taste, and is straightforward to manufacture. The film is placed on the top or the floor of the tongue. It is retained at the site of application and rapidly releases the active agent for local and/or systemic absorption. Oral fast dissolving film (FDF) is one such novel approach to increase consumer acceptance by virtue of rapid dissolution, self-administration without water or chewing. The need for non-invasive delivery systems continues due to patient’s poor acceptance and compliance with existing delivery regimes, limited market size for drug companies and drug uses, coupled with high cost of disease management.
These systems consist of the solid solid-dosage forms that disintegrate and dissolve quickly in the dosage forms that disintegrate and dissolve quickly in the oral cavity without the administration of water. Research and development in the oral drug delivery segment has led to transition of dosage forms from simple conventional tablets or capsules to modified release tablets or capsules to oral disintegrating tablet (ODT) towafer to the recent development of oral fast dissolving films (OFDFs). Amongst the plethora of avenues explored for the rapid drug releasing products, oral strip technology is gaining much attention.
Orally fast-dissolving film is new drug delivery system for the oral delivery of the drugs. It was developed on the basis of technology of the transdermal patch. The delivery system consists of a very thin oral strip, which is simply placed on the patient’s tongue or any oral mucosal tissue, instantly wet by saliva the film rapidly hydrates and adheres onto the site of application. It then rapidly disintegrates and dissolves to release the medication for oromucosal and intragastric absorption. Technology Catalysts forecasts the market for drug products in oral thin film formulations was valued of $500 million in 2007 and could reach $2 billion in 2012. Based on upward global growth trends of the past decade, the fast dissolving dosage market could produce revenues of $13 billion by 2015.
Definition:
The Center for Drug Evaluation and Research (CDER), US FDA defined Oral Disintegrating Tablets (ODT) as “A solid dosage form containing medicinal substances, which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue.”3FDTs disintegrate and/or dissolve instantaneously in the saliva without the use of water. Some tablets are designed to dissolve in saliva remarkably fast, within a few seconds, and are true fast-dissolving tablets. Others contain agents to enhance the rate of tablet disintegration in the oral cavity, and are more appropriately termed fast disintegrating tablets, as they may take up to a minute to completely disintegrate4. When placed on tongue, this tablet disintegrates rapidly, releasing the drug, which dissolves or disperses in the saliva. Some drugs are absorbed from the mouth, pharynx and esophagus as the saliva passes down into the stomach.
The Concept of Oral Dissolving Film:[3,4, 6,7,8]
This delivery system consists of a thin film.
· After placing it on the top of the tongue, the film dissolves within seconds, avoiding first pass metabolism and may increase the bioavailability of drug.
· Oral dissolving film is flexible so they are not as fragile and need not any kind of special package for protection during transportation and storage as compared to fast dissolving tablets.
· The drug should have good stability and solubility in water as well as in saliva.
· The large surface area available in the film dosage form allows rapid wetting by saliva then quickly disintegrates and dissolve and absorbed directly and can enter the systemic circulation without undergoing first-pass hepatic metabolism and on increase the bioavailability
· The first pass effect can be avoided, so a reduction in the dose which can lead to reduction in side effects associated with the molecule.
· Patients suffering from dysphagia, repeated emesis, hypertension, heart attack, asthma, motion sickness, paralysis and mental disorders prefer this dosage form as they are not capable to swallow large quantities of water.
Type of Mouth Dissolving Film:[6,7]
1. Medium disintegrating mucoadhesive film
2. Flash Dispersible film
3. Non-disintegrating film
4. Flash release film
Advantages:[3,9,10]
1. Rapid dissolution and absorption of drug, which may produce rapid onset of action.
2. Availability of larger surface area for drug absorption.
3. Drug enters systemic circulation with reduced hepatic first pass effect.
4. Good mouth feel property helps to change the perception of medication as bitter pill particularly in pediatric patient.
5. The risk of chocking or suffocation during oral administration of conventional formulation due to physical obstruction is avoided, thus providing improved safety.
6. Useful in cases where an rapid onset of action required such as in motion sickness, sudden episodes of allergic attack or coughing, bronchitis or asthma.
7. No need of water to swallow the dosage form, which is highly convenient feature for patients who are traveling.
8. Stability for longer duration of time, since the drug remains in solid dosage form till it is consumed. So, it combines advantage of solid dosage form in terms of stability and liquid dosage form in terms of bioavailability.
Disadvantages[2,10]
1. Drugs which are unstable at buccal pH cannot be administered.
2. Higher doses cannot be incorporated.
3. These dosage forms are moisture sensitive.
4. Special packaging- OFDFs are fragile and must be protected from water so it needs special packaging.
5. Taste masking- Most drugs have bitter taste, and need taste masking.
Limitations: [11]
Drugs with larger doses are difficult to formulate into FDT e.g. rifampin (600 mg), ethambutol(1000mg) etc. However, research has proven that the concentration level of active can be improved up to 50%per dose weight. Novartis Consumer Health's Gas-X® thin strip has a loading of 62.5 mg of sime thicone per strip.
Most bitter drugs should be avoided or taste masking is required proteinaceous drugs should be avoided if used then co-administration of enzyme inhibitors such as aprotinin, bestatin, puromicin and bile salts required for the inhibition of proteolytic enzymes present in saliva mainly cholesterol sulfate and glucosylceramides. Thenonkeratinized epithelia have been found to be considerably more permeable to water than keratinized epithelia.
Overview of Oral Mucosa:[2,12,13]
Fig.1 View of Oral Mucosa
Drug delivery via the oral mucosa is a promising route, when one wishes to achieve a rapid onset of action or improved bioavailability for drugs with high first-pass metabolism. Thus, there is a growing interest in developing alternative dosage forms, i.e. orally fast disintegrating strip, which allow a rapidly dissolving drug to absorb directly into the systemic circulation through the oral mucosa. These kinds of dosage forms are also convenient for children, elderly patients with swallowing difficulties, and in the absence of potable liquids. However, in addition to formulation considerations, the properties of the active compound have to be appropriate in order to achieve drug delivery into systemic circulation after intraoral administration. The oral mucosa is composed of an outermost layer of stratified squamous epithelium below this lies a basement membrane, a lamina propria followed by the submucosa as the innermost layer.
Methods of Preparation[14,15,16]
Following process can be used to manufacture the mouth dissolving films
1) Solvent casting
2) Semisolid casting
3) Hot melt extrusion
4) Rolling methods
1) Solvent Casting Method:
· Preparation of the casting solution,
· Deareation of the solution,
· Transfer of the appropriate volume of solution into a mold,
· Drying the casting solution,
· Cutting the final dosage form to contain the desired amount of drug,
· Packaging.
In solvent casting method excipients are dissolved in water, then water soluble polymers added in it and lastly drug is added and mixture is stirred to form homogeneous solution. Finally solution is casted in to the petri plate and dried.
2) Semisolid Casting:
· Water soluble polymers are dissolved in water
· Solution added to solution of acid insoluble polymer (CAP, CAB) which was prepared in NH4OH, NaOH.
· Plasticizer is added to obtain gel mass.
· The prepared gel mass is cast into films.
· Thickness : 0.015-0.05 inch
In this method, solution of water soluble film forming polymer is mixed to solution of acid insoluble polymer to form homogenous viscous solution (e.g. cellulose acetate phthalate and cellulose acetate butyrate). After sonication, it is coated on non-treated casting film. On drying the thickness of the film should be about 0.015-0.05 inches.. The ratio of the acid insoluble polymer to film forming polymer should be 1:4.
3) Hot Melt Extrusion:
· In the extrusion process the API and other ingredients are mixed in dry state, subjected to heating process and then extruded out in molten state.
· In this process, solvents are completely eliminated. The strips are further cooled and cut to the desired size.
· The high temperature used in this process may degrade thermolabile APIs.
· In hot melt extrusion method, firstly the drug is mixed with carriers in solid form. Then the extruder having heaters melts the mixture and finally the melt is shaped in to films by the dies. There are certain benefits of hot melt extrusion which includes
§ Fewer operation units
§ Better content uniformity
§ An anhydrous process.
4) Rolling Method:
· A solution or suspension containing the drug is rolled on a carrier.
· Solvent : water or water and alcohol
· The film is dried on the rollers and cut into desired size In rolling method, a solution or suspension containing drug is rolled on a carrier. The solvent is mainly water and mixture of water and alcohol. The film is dried on the rollers and cutted in to desired shapes and sizes. Other ingredients including active agent are dissolved in small portion of aqueous solvent using high shear processor. Water soluble hydrocolloids dissolved in water to form homogenous viscous solution.
Evaluation[2,6,17-19,21]
1) Thickness:
As the thickness of film is directly concern with drug content uniformity, it is necessary to ascertain uniformity in the thickness of the film. It can be measured by micrometer screw gauge or calibrated digital vernier calipers at different strategic locations.
2) Folding Endurance:
Folding endurance is determined by repeated folding of the strip at the same place till the strip breaks. The number of times the film is folded without breaking is computed as the folding endurance value.
3) Disintegration Time:
Disintegration of orally fast dissolving films requires U.S.P. disintegration apparatus. The disintegration time limit of 30 seconds or less for orally disintegrating tablets described in C.D.E.R. guidance can be applied to fast dissolving oral strips. Disintegration time will vary depending on the formulation but typically the disintegration range from 5 to 30 seconds. Although, no official guidance is available for oral fast disintegrating films.
4) Morphology Study:
Morphology of the prepared film can be observed under a motic electron photomicrograph. Motic electron photomicrographs can be recorded at 100 X Magnification.
5) Tensile strength:
Tensile strength is the maximum stress applied to a point at which the strip specimen breaks. It is calculated by the applied load at rupture divided by the cross‐sectional area of the strip as given in the equation below By using above equation tensile strength of film can be calculated.
Load at breakage
Tensile strength =
Strip thickness × Strip width
6) Weight of films:
Oral fast dissolving films can be weighed on analytical balance and average weight can be determined for each film. It is desirable that films should have nearly constant weight. It is useful to ensure that a film contains the proper amount of excipients and API.
7) Content Uniformity:
Drug content can be determined by dissolving the film in 100 ml of suitable solution to get 20 μg/ml solutions. An aliquot of 2ml sample can withdraw and diluted to 10 ml with solution. Then solution can be filtered through whatman filter and solution analyzed spectrophotometrically
8) Young's modulus:
Young's modulus or elastic modulus is the measure of stiffness of strip. It is represented as the ratio of applied stress over strain in the region of elastic deformation.
It is represented as follows-
Force at corresponding strain 1
Young’s modulus
= ×
Cross sectional area Corresponding strain
9) In Vitro Dissolution Studies:
The in vitro dissolution study can be carried out in 500 ml pH 6.8 phosphate buffer or 0.1N HCl using (USP) XIV paddle apparatus II at 370±0.5°C and at50 rpm. Each square cut film sample is submerged into the dissolution media and appropriate aliquots were withdrawn at specific intervals for 30 min. The drug concentration is measured by a UV spectro-photometer.
10) Stability Studies:
Stability studies on the optimized formulation of oral fast dissolving film is carried out to determine the effect of temperature and humidity on the stability of the drug. The film can be stored in an aluminium foil and subjected to stability at room temperature. The sample can withdraw at 90 days and 180 days and subjected for disintegration test and in vitro dissolution studies to determine disintegration time and cumulative % drug release.
11) pH value:
The pH value can determine by dissolving one oral film in 10ml distilled water and measuring the pH of the obtained solution. It is necessary that film should have nearly uniform pH value.
12) In vitro drug release:
Dissolution studies of films are performed by U.S.P. XXIII type II apparatus in 6.8 phosphate buffer (500ml) and 0.1N HCl (500ml). The temperature required is 37±0.5°C and the rotation speed should generally 50 rpm. The samples are needed to withdrawn at various time intervals and should analyze spectrophotometrically.
Applications of Fast Dissolving Film
1) Gastro retentive dosage systems:
Dissolvable films are being considered in dosage forms for which water-soluble and poorly soluble molecules of various molecular weights are contained in a film format. Dissolution of the films could be triggered by the pH or enzyme secretions of the gastrointestinal tract and could potentially be used to treat gastrointestinal disorders.
2) Diagnostic devices:
Dissolvable films may be loaded with sensitive reagents to allow controlled release when exposed to a biological fluid or to create isolation barriers for separating multiple reagents to enable a timed reaction within a diagnostic device.
3) Topical applications:
The use of dissolvable films may be feasible in the delivery of active agents such as analgesics or antimicrobial ingredients for wound care and other topical conditions.
Conclusion
The oral route is most popular route for the administration of therapeutic agents by mouth dissolving film because of the low cost of therapy and ease of administration which lead to increase in patient compliance. The mouth dissolving film are barely described and investigated in literature, but seem to be an ideal dosage form for use in young children, especially in geriatric and pediatric patients. They combine the greater stability of a solid dosage form and the good applicability of a liquid. Mouth dissolving oral films has several advantages over the conventional dosage forms. So they are of great importance during the emergency cases such as allergic reactions and asthmatics attacks whenever immediate onset of action is desired. And more importantly, mouth dissolving films are travel friendly dosage forms where water may not be carried by person or patient. And hence, mouth dissolving film becomes unique, elegant, selective and needful dosage form.
REFERENCES:
1. Sharma S, Gupta G, et al. Orodispersable tablet: a review. Pharmainfo.net.html, 2008, 6(5).ophilic polymers.
2. Dixit RP., Puthli SP., Oral strip technology: Overview and future potential, J of Cont Release 2009; 139: 94–107
3. Arya A, Chandra A, et al. Fast Dissolving Oral Films: An Innovative Drug Delivery System and Dosage Form, International Journal of ChemTech Research, 2010 2(1), 576-583.
4. Goel Honey, et al. Orally Disintegration systems: Innovations in formulation and Technology. Recent Patents on Drug Delivery & Formulation. 2: 2008: 258-274.
5. Bhowmik Debjit, et al. Fast Dissolving Tablet: An Overview. Margret R Chandira, Fast Dissolving Tablet: An Overview. Journal of Chemical and Pharmaceutical Research, 2009: 163-177.
6. Bhyan B, et al. Orally fast dissolving films: innovations in formulation and technology. International Journal of Pharmaceutical Sciences Review and Research, 2011; 9(2): 50-57.
7. Gavaskar B, Kumar S, et al. Overview on fast dissolving films, International Journal of Pharmacy and Pharmaceutical Sciences, 2009; 2: 29-33
8. Bhura N, et al. “A review on fast dissolving film”, IJPRBS, 2012; 1 (3): 66-89.
9. Debjit Bhowmik, et al. Fast Dissolving Tablet: An Overview, Journal of Chemical and Pharmaceutical Research, 2009, 1(1): 163-177
10. Nehal Siddiqui MD, et al. A Short Review on Novel Approach in Oral Fast Dissolving Drug Delivery System and Their Patents. Advances in Biological Research 2011 ;( 5 suppl 6):291-303.
11. Harris, D. etal. Drug delivery via the mucous membranes of the oral cavity. J. Pharmaceutical Sci., 81: 1-10.
12. Dinge A, et al. Formulation and Evaluation of Fast Dissolving Films for Delivery of Triclosan to the Oral Cavity, Ame. Asso.Of Pharma Scientists PharmSciTech. 2008 June; 9(2): 349–356.
13. Dahiya M., et al. A review on mouth dissolving films, Curr. Drug Deliv. , 2009 Oct ; 6(5):469-76.
14. Shimoda H, et al. Preparation of fast dissolving oral thin film containing dexamethasone: A possible application to antiemesis during cancer chemotherapy.European Journal of Pharmaceutics and Biopharmaceutics, 2009; 73: 361-365.
15. Nishimura M, et al. In vitro and in vivo characteristics of prochlorperazine oral disintegrating film.International Journal of Pharmaceutical Sciences, 2009:98–102
16. Siddiqui N, et al. A Short Review on “A Novel Approach in Oral Fast Dissolving Drug Delivery System and Their Patents”Advances in Biological Research 2011, 5 (6): 291-303.
17. Banker G.S. Film coating theory and practice, J. Pharm. Sci., 1966; 55: 81.89.
18. KunteS.,andTandale P., Fast dissolving strips: A novel approach for the delivery of verapamil , J Pharm Bioallied Sci. , 2010 Oct-Dec; 2(4): 325–328
19. 19. Prabhu P., et al. Formulation and evaluation of fast dissolving films of levocitirizine di hydrochloride , International Journal of PharmaInvestigation, 2011 ; 1(2) : 99-104
20. Prasanna P. et al. Mouth Dissolving Films: Innovative Vehicle for Oral Drug Delivery, International Journal of PharmaResearch and Review, Oct 2013; 2(10):41-47.
21. M. Sunitha Reddy et al. Fast Dissolving Drug Delivery System - A Review, Research J. Pharm. and Tech., January 2013; 6(1): 3
Received on 16.08.2014 Modified on 06.09.2014
Accepted on 11.09.2014 © RJPT All right reserved
Research J. Pharm. and Tech. 7(10): Oct. 2014 Page 1196-1200