oral thin films

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ORAL THIN FILMS- Preparation and evaluation:

ORAL THIN FILMS- Preparation and evaluation 1

Oral thin films:

Oral thin films Oral thin film drug delivery systems are solid dosage forms, which dissolve in a short period of time when placed in the mouth without drinking water or chewing. These are also called as: Fast dissolving Oral films Buccal films/strips Oral strips 2

Special features:

Special features Thin elegant film Available in various sizes and shapes Less fragile when compared to ODT Excellent mucoadhesion Dosage accuracy Rapid release Can be administered without water Most acceptable dosage form for dysphagic patients. 3

Advantages :

Advantages Easy to administer and handle Improved Patient compliance Rapid disintegration and dissolution Bypasses first pass metabolism Improved bioavailability Suitable for wide variety of drugs Taste masking Enhanced stability Reduced side effects of the drugs. 4


Advantages Used for local and systemic delivery Rapid onset of action Lowers the dosing frequency Increased therapeutic index 5

Disadvantages :

Disadvantages Hygroscopic in nature High dose cannot be incorporated Drugs with obnoxious odor cannot be given. Should be tough enough Drugs unstable in buccal pH cannot be administered Eating and drinking may be restricted. 6

Applications :

Applications Vaccine delivery: Oral Quick-Dissolve Strips For Rotavirus Vaccine for children were developed Protein drug delivery: Nanoparticles Incorporated in Bilaminated Strips, Nano Particle-Film consisting of carboxylation chitosan-grafted nanoparticles (CCGNs) - developed for oral delivery of protein drug. Nutra3 Complex(R) Develops New fast melting Oral Strips: The unique feature of Nutra3 Complex Strip Melts is that the fast-melting oral strips contain the highest load of active ingredients in an oral strip product. It provides the nutritional support the body needs to protect against cellular damage from free radicals and promote an anti-aging effect. 7

Classification :

Classification Three types: Flash release Mucoadhesive melt away wafer Mucoadhesive sustained release wafers. 8

Properties of the films:

Property/ subtype Flash release water Mucoadhesive melt-away wafer Mucoadhesive sustained release wafer Area (cm 2 ) 2-8 2-7 2-4 Thickness (µm) 20-70 50-500 50-250 Structure Film: single layer Single or multilayer system Multilayer system Excipients Soluble, highly hydrophilic polymers Soluble, hydrophilic polymers Low/non soluble polymer Drug phase Solid solution Solid solution/ suspended drug particles Suspension or solid solution Application Tongue(upper plate) Gingival or buccal region Gingival(or other region of oral cavity ) Dissolution Maximum 60 sec Disintegration in few min, forming gel Maximum 8-10 hrs Site of action Systemic or local Systemic or local Systemic or local Properties of the films 9

Formulation :

Formulation Polymers Plasticizers API Sweetening agents Saliva stimulating agents. Flavouring agents Coloring agents Surfactants 10

Polymers :

Polymers Used alone or in combination- atleast 45% w/w Robustness of the strip depends on the polymer used and the amount in the formulation. Should have the property to disintegrate in seconds. Various polymers include 11 Pullulan SodiumCMC Gelatin HPMC HEC Xanthum gum Pvp Locust bean gum Modified starches Gaur gum Polyviny alcohol Carrageenan Polyethylene oxide Low viscosity HPC


Plasticizers Vital ingredient, affects Absorption rate Improves flexibility, reduces brittleness by reducing glass transition temperature Selection depends on solvent and polymer used Inappropriate use- film cracking, splitting, peeling Cellulosic hydrophilic polymers- plasticized with OH containing PEG, propylene glycol, glycerol, polyol Less Cellulosic hydrophilic polymers- plasticized with esters of citric acid, phthalic acid Polyvinyl alcohol- glycerol HPMC- diethyl glycol 12

Different plasticizers:

Different plasticizers Plasticizers used Plasticizers used glycerol Citrate der : triacetin , acetyl citrate, PG Citrate der : tributyl , triethyl Low MW PEG Phthalate der : di-methyl,ethly,butyl 13


API Variety of APIs can be administered 5 % w/w to 30 % w/w can be incorporated, multivitamin – up to 10 % w/w of dry film Water soluble API- present in dissolved / solution form Water insoluble API – dispersed uniformly throughout the film with water miscible polymer Taste should be masked before incorporating the API Special classes of drugs that can be administered by OTF technology include: local anesthetic, drugs for migraine, sore throat, allergy, also for administration of vitamin( b12) and melatonin 14

Drugs that can be incorporated in OTF:

Drugs that can be incorporated in OTF Drug Dose Therapeutic class Chlorpheniramine maleate 4 mg Antiallergic Triplolidine hydrochloride 2.5 mg Antihistaminic Lopiramide 2 mg Antidiarroheal Famotidine 10 mg Antacid Azatidine maleate 1 mg Antihistaminic Sumatriptine succinate 35-70 mg Antimigraine Ketoprofen 12.5 mg Analgesic Nicotine 2 mg Smoking cessation Pseudoephedrine hydrochloride 30 mg Bronchodilator Acrivastine 8 mg Antihistaminic Dextromethorphan hydrochloride 10-20 mg Cough suppressant Loratadine 10 mg Antihistaminic Diphenhydramine hydrochloride 25 mg Antiallergic 15

Sweetening agents:

Sweetening agents Important incase of pediatrics- natural/ artificial can be used, usually in the conc.- 3-6 % w/w Water soluble natural sweeteners : xylose, ribose, glucose, sucrose, maltose, fructose Water soluble artificial sweetener : Ca/Na saccharine, cyclamate, acesulfame-k salts Dipeptide based sweetener : aspartame Protein based sweetener : thaumatin I and II Polyhydric alcohols : sorbitol, mannitol, isomalt, maltitol- if used in combination, provide good mouth feel and cooling sensation 16

Saliva stimulating agents :

Saliva stimulating agents Increases the saliva production rate, aids in faster disintegration of OTF Conc.- 2 -6 % w/w Examples – citric acid , malic acid, lactic acid, ascorbic acid, tartaric acid Flavoring agents: may be selected from syn. Flavor oils, oleoresins, from plant parts. Amount depends on the flavor type and strength Important flavors: peppermint, cinnamon, nutmeg, vanilla, cocoa, coffee, chocolate, citrus, apple, cherry, raspberry, pineapple. 17

Coloring Agents:

Coloring Agents Usually TiO 2 or FD and C approved colors are used Conc. – not exceeding 1 % w/w Surfactants: Used as solubilizing or wetting or dispersing agent Commonly used: Na lauryl sulphate, benzalkonium chloride, benzthonium chloride, tweens, polaxomer 407 Other ingredients: Stabilizers, thickening Sometimes emulsifying agents 18

Manufacturing methods:

Manufacturing methods There are various methods: Solvent casting Semisolid casting Hot-melt extrusion Solid dispersion extrusion Rolling Solvent casting Water soluble ingredients are dissolved in H 2 O and API and other agents are dissolved in suitable solvent to form a clear viscous solution. Both the solutions are mixed Resulting solution is cast as a film Film is collected 19

Drugs formulated by solvent casting method::

Drugs formulated by solvent casting method: S.no Drug Polymers Plasticizers Sweeteners 1. Ondansetron Polyvinyl alcohol, Polyvinyl pyrrolidine , Carbopol 934P Propylene glycol or PEG 400 Mannitol or sodium saccharin 2. Maltodextrin Polyvinyl alcohol Glycerol Glycerin 3. Salbutamol HPMC Glycerol Aspartame 20

Semisolid casting:

Semisolid casting Solution of water soluble film forming polymer is prepared. Resulting solution is added to a solution of acid insoluble polymer Appropriate amount of polymer is added so that gels mass is obtained. Finally the gel mass is casted into the films or ribbons using heat controlled drums. The thickness of the film should be about 0.015-0.05 inc. 21

Hot melt extrusion:

Hot melt extrusion The drug is mixed with carriers in solid form. Extruders having heaters melts the mixture Finally the melt is shaped in films by the dies. 22

Solid dispersion extrusion:

Solid dispersion extrusion Drug is dissolved in a suitable liquid solvent Then solution is incorporated into the melt of polyethylene glycol, obtainable below 70c. Finally the solid dispersions are shaped into films by means of dies. 23

Rolling method:

Rolling method Prepare pre mix with film forming polymer, polar solvents and other additives except a drug. Add premix to master batch feed tank. Fed it via a 1 st metering pump and control valve to either or both of the 1 st and 2 nd mixer. Add required amount of drug to the desired mixer. 5. Blend the drug with master batch premix to give a uniform matrix. 6. Then a specific amount of uniform matrix is then fed to the pan through 2 nd metering pumps. 7. The film is finally formed on the substrate and carried away via the support roller. 8. The wet film is then dried using controlled bottom drying. 24

Storage and packaging:

Storage and packaging variety of packaging options are available Single packaging is mandatory for film - an aluminum pouch is the most commonly used APR- Labtec has developed the Rapid card- specially designed patented size as a credit card holds three raid films on each side Materials usually used for packaging: Foil, paper or plastic pouches Single pouch and Aluminum pouch Blister card with multiple units Barrier Films 25

Evaluation :

Evaluation Mechanical properties: Thickness: carried out using electronic micrometer Thickness measured at 5 locations(center and 4 corners) and mean thickness is calculated. Samples with air bubbles, nicks or tears and mean thickness greater than 5% are excluded b)Dryness tests/tack tests: Tenacity with which the film adheres to an accessory when pressed into contact with strip Mean thickness variation greater than 5 % excluded c)Tensile strength: Tensile strength = 26

Evaluation :

Evaluation d) Percent elongation: % elongation = e) Tear resistance: Max stress or force required to tear the film Loading 51 mm ( 2 in.)/min is employed to measure force to initiate tearing Calculated in Newtons (or pounds- force) f)Folding endurance: Determined by repeated folding of strip at same place till film breaks No. of times folded without breaking gives its value 27

Evaluation :

Evaluation g) Young's modulus/elastic modulus: Measure of stiffness of strip Young’s modulus = . Disintegration time: Time at which film breaks when brought in contact with water or saliva Typical disintegration time is 5-30 s In vitro dissolution test: Amt of drug substance that goes into soln per unit time under std conditions of liq/solid interface, temp, and solvent conc. Carried out in simulated saliva soln pH 6.4 phosphate buffer using paddle apparatus at 37 ± 0.5 c Samples are withdrawn at regular time interval and analyzed by UV-visible spectrophotometer 28

Evaluation :

Evaluation Dissolution rate by conductivity method: Beaker filled with 300g deionized water & test conductivity of water Adhere film inside 800ml beaker and arrange probe & impeller To this pour 300ml water and start timer and impeller at 250rpm Take readings for every 10sec 29

Evaluation :

Evaluation Assay/drug content: Determined by estimating the API in each strip Limit – 85-115 % Taste evaluation: Measured by taste panel consisting human volunteers(n=6) 10mg drug and film sample with 10mg of drug in mouth until disintegration Spat out & bitterness values recorded. += very bitter ++ = moderate to bitter +++ = slightly to bitter ++++ = tasteless/taste masked 30

Evaluation :

Evaluation Swelling property: Conducted in stimulated salivary fluid Film sample is weighed and placed in preweighed stainless steel sieve – submerged in 50 ml saliva solution Increase in weight is determined till constant weight SI = (w t – w o ) / w o Contact angle: Measured with goniometer Drop of water placed on film & images recorded within 10 s 5 measurements taken at different positions Measured on both sides of drop and averaged 31

Evaluation :

Evaluation Drug excipients interaction studies: Fourier transform IR spectrum, DSC , TLC, X-RD Permeation studies: Carried by Franz diffusion cell using porcine buccal mucosa Stability studies: Carried according to ICH guidelines Films are evaluated for drug content, disintegration and physical appearance 32

Marketed OTF :

Marketed OTF 33

FDA approved OTF:

FDA approved OTF Drug Year Company Suboxone® (Bupreonorphine & Naloxone ) 31/08/2010 Reckitt Benckiser Pharmaceuticals Inc. Zulpenz January 2010 Pharmfilm ® Technology. Ondansetron 23 rd march 2010. APR Applied Pharma research s.a (“APR”) and Labtech GmbH (“Labtech”) Zelapar October 2005 Valeant Pharmaceuticals International Inc 34

Conclusion :

Conclusion Pharmaceutical industries have recognized the potential for delivering medicinal products through OTF and have launched several products for the OTC market using this technology. Recently RDFs have gained popularity as dosage forms for the mouth fresheners Gaining importance as they are ideal dosage form for use in young children, as well as genatric patients. Also, many industries have pipelines of molecules of shifting their existing tablets preparation to oral strips. 35

References: :

References: Alpesh R. Patel, Dharmendra S.Prajapati , Jignyasha A. Raval . Fast dissolving films as a newer venture in fast dissolving dosage forms. Indian journal of drug development and research. April - June 2010, vol-2, issue- 2, page. no: 232-246. Frey P. Film Strips and Pharmaceuticals, Pharma . Mfg and Packg . Winter 2006, 92-93. Zhang.H . Zhang J, Streisand J.B. Oral mucosal drug delivery: clinical pharmaco -kinetics and therapeutic applications, Clin . Pharmacokinet . 2002; 41 (9): 661.680. Y. Madhusudhan Rao , jittan AV, Advances in drug delivery, Volume I, Page no: 165-171. Apporva Mahajan , Neha Chhabra , Geetha Agarwal , Scholars research library, Formulation and characterization of fast dissolving buccal films, volume 3, issue1, page.no : 152-165. Arun Arya , Amrish Chandra, Vijay Sharma Kamla Pathak International journal of chemtech research. Jan-Mar 2010, vol-2, No-1, page no: 576-583. Renuka Mishra and Avani Amin , Design and development of rapidly dissolving films using ion exchange resin for taste masking. International journal of drug formulation and research. Mar- apr 2011, vol-2(2), pg.no 314-343. Vollmer U, Galfetti P. Rapid film: Oral thin films as an innovative drug delivery System and dosage form. Drug Dev Report. 2006; 64-67. http:// www.apr.ch Vondrak B, Barnhart, Scott. Dissolvable Films: Dissolvable Films for Flex Product Format in Drug Delivery. Pharmatech . 2008; 1-5 Jayjock E, Schmitt R, Chein C. Determination of fast dissolve oral film dissolution rate via conductivity. Dow Chemical Company. 2005; 1-4. 36

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