These system allow the medication to bypass the first pass metabolism thereby making the medication more bioavailable ^[4].

Flow chart for the Continuos development of oral solid dosages forms:

Special features of mouth dissolving strips^[5]:

· Thin elegant film

· Available in various size and shapes

· Unobstructive

· Excellent mucoadhesion

· Fast disintegration

Advantages of Oral Strips^[6]:

· Accessibility of larger surface area that leads to quickly disintegrate and dissolution in the oral cavity within seconds.

· Orodispersible 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 tablet.

· No need of water has led to better satisfactoriness amongst the dysphasic patients.

· The large surface area available in the film dosage form allows rapid wet 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

· Useful for pediatric, geriatric patients.

Disadvantages^[^5]

· High doses cannot be incorporated.

· Dose uniformity is a technical challenge.

Mechanism of action

The surface of buccal cavity comprises of stratified squamous epithelium which is essentially separated from the underlying tissue of lamina propria and submucosa by an undulating basement membrane. The epithelia of oral cavity are also composed of an intercellular ground substance called as mucus which basically consists of proteins and carbohydrates. It maintains hydrated condition of the oral cavity, provides adequate lubrication .While the major salivary glands consist of lobules of cells that secrete saliva; the minor salivary glands are located in the lips, buccal mucosa, and in linings of the mouth and throat.^[1]

Classification^[4]

These are of three types:

1. Flash release.

2. Mucoadhesive melt away.

3. Mucoadhesive sustained release.

Table 1: Property of different type of strip:

Property	Flash release	Mucoadhesive melt away	Mucoadhesive sustained release
Area cm²	2-8	2-7	2-4
Thickness	20-70	50-500	50-250
Structure	Single layer	Single or multilayer	Multilayer
Excipient	Soluble, highly hydrophilic polymer	Soluble. hydrophillic polymer	Non soluble polymer
Drug phase	Solid solution	Solid or suspended drug particle	Solid or suspended drug particle
Application	Tongue	Ginjival or upper buccal surface	Ginjival
Disintegration Time	Maximum 60 sec	Few minutes	Take 8 to 10 hrs.

Formulation Approaches:

1. Strip forming polymers : ^[7]

A different variety of polymers are available for preparation of Oral Strip . Hydrophilic polymers are used in the preparation so that film can dissolve rapidly in the oral cavity and drug is delivered to the systemic circulation via dissolution when it comes in contact with the saliva in the buccal cavity. The polymers can be used alone or in combination in a film to get the desired film properties. At present time both natural and synthetic polymers are used in the oral cavity. Natural polymers are safe, effective and devoid of side effect so more preferred than synthetic. The film obtained should be tough enough so that there won't be any damage while handling or during transportation. The robustness of the strip depends on the type of polymer and the amount in the formulation. The various polymers available, pullulan, gelatin and hypromellose are most commonly used for preparation of Oral Strip.

Table 2: Formulation of fast dissolving oral strips:

S.No

Components

Concentrations

Drug

Polymer

Plasticizer

Super disintegrate

Saliva stimulant

Sweetner

Flavour

Colouring agent

1-25%

40-50%

0-20%

2-6%

3-6%

10%w/w

NMT 1% w/w

2. Plasticizers:

Plasticizer is a vital ingredient of the fast dissolving films. Plasticizer helps to improve the flexibility of the strip and reduces the brittleness of the films. It significantly improves the film forming properties by reducing the glass transition temperature of the polymer. The chemical structure and concentration of plasticizers play an important role in alleviating the glass transition temperature of the polymers. Examples include: Glycerol, Propylene glycol, Low molecular weight polyethylene glycols, Citrate derivatives like triacetin, acetyl citrate, Phthalate derivatives like dimethyl, diethyl, dibutyl derivatives, Castor oil etc.^[5,8]

3. Saliva stimulating agent: ^[8,3]

The purpose of using saliva stimulating agents is to increase the rate of production of saliva that would aid in the faster dissolution of the film formulations. Generally acids which are used in the preparation of food can be utilized as salivary stimulants. Citric acid, malic acid, lactic acid, ascorbic acid and tartaric acid are the few examples of salivary stimulants, citric acid being the most preferred amongst them More saliva production helps in the faster disintegration of the fast dissoving film formulations.

4. Flavouring agent:

Any flavor can be added, such as intense mints, sour fruit flavors or sweet confectionery.

5. Sweetening Agents:

Sweeteners have become the important component for those nutraceuticals as well as pharmaceutical products whose dissolution occurs in the oral cavity. The classical source of sweetener is sucrose, dextrose, fructose, glucose, liquid glucose and isomaltose. Fructose is sweeter than sorbitol and mannitol and thus used widely as a sweetener. Polyhydric alcohols such as sorbitol, mannitol and isomalt can be used in combination as they additionally provide good mouth-feel and cooling sensation.

6. Surfactants:

Surfactants act as solubilizing or wetting or dispersing agent in formulation so that the film is getting dissolved within seconds and release active agent quickly. Some of the commonly used are sodium lauryl sulfate, benzalkonium chloride, tweens etc. One of the most important surfactant is polaxamer 407.

Method of preparation:

One or more of the following process can be used combinly to manufacture the mouth dissolving films.

· Solvent casting

· Semisolid casting

· Hot melt extrusion

· Solid dispersion extrusion

· Rolling

· Solvent casting method:

It is the most preferable method used in the oral strip formulation because it is more easy method. In this method excipients are dissolved in water, then water soluble polymers and in last drug is added and stirred to form homogeneous solution. Finally solution is casted in to the Petri plate and dried.And finally cut into desire shaped.

Semisolid casting:

· In this method at first a solution of water soluble film forming polymer is prepared. Then the resulting solution is added to a solution of acid insoluble polymer (e.g. cellulose acetate phthalate) which was prepared in ammonium or sodium hydroxide. The ratio of the acid insoluble polymer to film forming polymer should be 1:4. A gel mass is obtained on addition of suitable amount of plasticizer. By the means of heat controlled drums, finally the gel mass is casted in to the films or ribbons.

· Rolling:^[9]

Solvents mainly used in this method are water and mixture of water and alcohol. By the means of high shear processor, active agent and other ingredients are dissolved in small portion of aqueous solvent. Water soluble hydrocolloids are dissolved in water to form homogenous viscous solution. Then the resultant solution or suspension containing drug is rolled on a carrier. Finally the obtained film is cut into desired shapes and sizes

Solid dispersion extrusion:

Firstly solid dispersion is prepared by extruding immiscible components with drug and then shaped in to films by the means of dies.

Hot melt extrusion:

In hot melt extrusion method at first drug is mixed with carriers in solid form. Then the mixture is molten by the means of extruder having heaters. Lastly the melt is shaped in to films by the dies.

Technologies for Fast Dissolving Strips:

Soluleaves:

In this technology the oral strip is produced in order to release the active ingredients on coming in contact with saliva, immediately. This method is especially useful for pediatric and geriatric patients who may have difficulty swallowing conventional tablets. SOLULEAVES are designed in such a way that they adhere to mucous membrane in order to release the drug slowly in 15mins.^[3]

Foamburst:

FOAMBURST is a new patent granted in September 2004 which is for capsules made of foamed film. Gas is blown into the film during production, resulting in a film with a honeycombed structure. The voids in the film may be gas-filled, empty or filled with other materials to produce specific taste-burst characteristics or to deliver active drugs. The light honeycombed structure results in capsules that dissolve rapidly, causing a melt-in-the mouth sensation. ^[10]

XGel:

XGel film Technology developed by BioProgress was causing a revolution in the product offerings and manufacturing methods, which was now available to the pharmaceutical industry. XGel film, potentially enhance the product stability. The films may be coloured or printed during manufacture for branding and coding which is a useful mechanism to enhance product identification and has also been developed for non-ingestible applications such as cosmetic, ostomy pouches, sanitary and healthcare devices.^{[10, 11]}

Wafertab

WaferTab is a unique, innovative, and highly stable edible film dose form. WaferTab is a drug delivery system which incorporates pharmaceutical actives into an ingestible film strip. It provides rapid dissolution and release of active pharmaceutical ingrdient when the strip comes into contact with saliva in the mouth. The WaferTab film strip can also be flavoured for additionally improved taste-masking. The active ingredient is integrated into the body of a fused. The film can be prepared in a variety of shapes and sizes and is an ideal method for deliverying medicines which require fast release and also for use by patients who have difficulty swallowing.^[12]

Evaluation parameters: ^{[5, 13, 14]}

1. Mechanical properties

· Thickness :

· The thickness of film is determined by screw gauge or micrometer at different points of the films. This is essential to ascertain uniformity in the thickness.

· Dryness/Tack test :

· Tack is the tenacity with which the strip adheres to an accessory (a piece of paper) that has been pressed into contact with the strip.

· Tensile strength :

· Tensile strength is the maximum stress applied to a point at which the strip specimen breaks.

· Tensile strength = Load at breakage/ Strip thickness × Strip Width

· Percent elongation :

· When stress is applied, a strip sample stretches and this is referred to as strain. Strain is basically the deformation of strip divided by original dimension of the sample. Generally elongation of strip increases as the plasticizer.

· % Elongation = Increase in length ×100 / Original length

· 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.

· Tear resistance :

· Tear resistance of plastic film or sheeting is a complex function of its ultimate resistance to rupture. Basically very low rate of loading 51mm (2in)/min is employed and is designed to measure the force (that is generally found near the onset of tearing) required to tear the specimen is recorded as the tear resistance value in Newton.s (or pounds-force).

· 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.

2. Organoleptic evaluation: ^[15]

For evaluation of psychophysical evaluation of the product, special controlled human taste panels are used. In-vitro methods of utilizing taste sensors, specially designed apparatus and drug release by modified pharmacopoeial methods are being used for this purpose.

3. Morphology Studies:

Scanning electron microscopy (SEM) study refers the differences between upper and lower side of the films. It also helps in determination of the distribution of API. Near-infrared chemical imaging (NIR-CI) study helps in determining the difference between drug distributions in drug loaded films and recrystallization.

4. Surface pH of strip:

Surface pH of films is determined by placing the film on the surface of 1.5% w/v agar gel followed by placing pH paper (pH range 1-11) on films. The change in the color of pH paper was observed and reported.

5. Swelling property:

Film swelling studies is conducted using simulated saliva solution. Each film sample is weighed and placed in a pre-weighed stainless steel wire mesh. The mesh containing film sample is submerged into 15ml medium in a plastic container. Increase in the weight of the film was determined at preset time interval until a constant weight was observed.

6. Disintegration time: ^[16]

The disintegration time limit of 30 s or less for orally disintegrating tablets described in CDER guidance can be applied to fast dissolving oral strips. Although, no official guidance is available for oral fast disintegrating films strips, this may be used as a qualitative guideline for quality control test or at development stage. Pharmacopoeial disintegrating test apparatus may be used for this study. Typical disintegration time for strips is 5–30 s 18.

7. Dissolution test:^[17,14]

Dissolution testing can be performed using the standard basket or paddle apparatus described in any of the pharmacopoeia. The dissolution medium will essentially be selected as per the sink conditions and highest dose of the API 19. Many times the dissolution test can be difficult due to tendency of the strip to float onto the dissolution medium when the paddle apparatus is employed.

7. Assay/drug content and content uniformity :

This is determined by any standard assay method described for the particular API in any of the standard pharmacopoeia. Content uniformity is determined by estimating the API content in individual strip Limit of content uniformity is 85-115 %.

Storage and Packaging of Strips: ^{[8, 18]}

A variety of storage and packaging options are available for fast dissolving films. The packaging stage provides product flexibility to the drug manufactures. Single packaging is mandatory for films, which are pharmaceutical products; an aluminum pouch is the most commonly used packaging format. APRLabtec has developed the Rapid card, a proprietary and patented packaging system, which is specially designed for the Rapid films. The rapid card has same size as a credit card and holds three raid films on each side. Every dose can be taken out individually.

Application of Fast dissolving oral Strips: ^[19]

· It could become a preferential method for the therapies like dental pain, sleep difficulties, allergies and different type of central nervous disorder.

· It is used to cure and prevent oral disease.

· It is used as a freshening agent with its rapid action and providing more patient compliance.

· It is used in treatment of headache, minor pains and muscular aches.

· It is also beneficial for Allergy, Cold and Cough, Xerostomia, Acidity, Anxiety, Motion sickness etc.

Commercial Oral Strips: ^[20]

There are not yet somany medications available in a thin film form on the market. Those that are include:

· Zuplenz: The first oral soluble film approved by the FDA as a prescription medication.

· Benadryl (diphenhydramine product, anti-cholinergic anti-histamine used for allergies and as a mild sedative).

· Gas-X (simethicone product for bloating, gas, and gastrointestinal complaint).

· Melatonin PM (hormonal product sold as a "dietary supplement" marketed for insomnia).

· Orajel Kids (benzocaine product for dental pain

· Sudafed (phenylephrine or pseudoephedrine product for nasal congestion).

· TheraFlu (combination product of pain reliever, anti-pyretic and decongestant).

· Triaminic (children's anti-tussive product).

On July 2, 2010, Strativa Pharmaceuticals, the proprietary products 77777division of Par Pharmaceutical, received approval from the US FDA for Zuplenz (ondansetron) oral soluble film (OSF) for the prevention of postoperative, highly and moderately emetogenic cancer chemotherapy-induced, and radiotherapy-induced nausea and vomiting.

CONCLUSION:

The growing success and popularity of fast dissolving oral strips recently in global market is evidence to the need for effective taste masked, "without water" pharmaceutical formulations. Fast Dissolving Stips have several advantages over the conventional dosage forms. They combine the greater stability of a solid dosage form and good applicability of the liquid and thus bridge the gap between the two ideas, incorporating positive elements from both solid and liquid dosage forms into an elegant, stable and effective delivery vehicle. Due to this they have a great importance during the emergency cases such as allergic reactions and high patient compliance .Fast dissolving oral strips have evolved as consumer friendly dosage form due to its attractive forms as well as easy to use.

This technology option can also provide a good platform for patent non‐infringing product development.

REFERENCE:

1. Dixit R.P., Puthli S.P. Oral strip technology: Overview and future potential. J Pharm Bioallied. 139(2); 2005, 94–107.

2. Arya A, Chandra A, Sharma V, Pathak K. Fast dissolving oral films: An innovative drug delivery system and dosage form. International Journal of ChemTech Research. 2 (1);2010: 576-583

3. Siddiqui MDN, Garg G, Sharma PK. A Short Review on “A Novel Approach in Oral Fast Dissolving Drug Delivery System and Their Patents. Advances in Biological Research. 5(6); 2011: 291-303.

4. Aggarwal J, Singh G, Saini S, Rana AC. Fast Dissolving Films: A Novel Approach to Oral Drug Delivery. International Research Journal of Pharmacy. 2(12); 2011: 69-74.

5. Bhyan Bhupinder , Jangra Sarita, Kaur Mandeep, Singh Harmanpreet. Orally Fast Dissolving Films: Innovations in Formulation and Technology. Int. J Pharm Sci Rev & Res. 9; 2011: 2-9.

6. Patel FV, Liu F, Brown MV. Advances in oral transmucosal drug delivery. Journal of Controlled release. 153(2); 2011: 106-116 .

7. Kaur Mandeep, Rana AC, Seth Nimrata. Fast Dissolving Films: An Innovative Drug Delivery System. International Journal of Pharmaceutical Research & Allied Sciences. 2(1); 2013: 14-24.

8. Koland M, Charyulu N. Fast dissolving sublingual films of ondansetron hydrochloride: Effect of additives on in vitro drug release and mucousal permeation. Journal of Young Pharm. 2(3); 2010: 216-221.

9. Kalyan.S, Bansal M. Recent Trends in the Development of Oral dissolving Film. International Journal of PharmTech Research. 4(2); 2012: 725-733.

10. Available from URL: http://www.bioprogress.com/technology_ platf orms.asp

11. Available from URL: http://www.bioprogress.com/pages/ content/i ndex.asp?PageID=50

12. Hirani JJ, Rathod DA, Vadalia KR. Orally Disintegrating Tablets: A Review. Tropical Journal of Pharmaceutical Research. 8(2); 2009: 161-172.

13. Vijaykumar Ghorwade, Ajaykumar Patil, Satishkumar Patil, Karunasri Srikonda, Raghavender Kotagiri and Priya Patel.Development and Evaluation of Fast-Dissolving Film of Montelukast Sodium. World Journal of Medical Pharmaceutical and Biological Sciences.1(1); 2011: 06-12.

14. Mashru RC, Sutariya BC, Parikh PP. Development and evaluation of fast dissolving films of salbutamol sulphate. Drug Dev Ind Pharm.31; 2005: 25-34.

15. Chen X, Ji ZL, Chen YZ. TTD: Therapeutic Target Database. Nucleic Acids Res. 1(30); 2002: 412-415.

16. Dinge A, Nagarsenker M. Formulation and evaluation of fast dissolving films for delivery of triclosan to the oral cavity. AAPS Pharm Sci Tech. 9(2); 2008: 349-56.

17. Sharma Renuka, Parikh RK, Gohel MC, Soniwala MM. Development of taste masked film of Valdecoxib for oral use. Indian J PharmSci, 69(2); 2007: 320-323.

18. Nishimura M, Matsuura K, Tsukioka T, Yamasitha H, Inagaki N, Sugiyama T, Itoh Y. In vitro and in vivo characteristics of prochlorperazine oral disintegrating film. International Journal of Pharmceutics. 10; 2008: 1016.

19. Parakh SR, Gothoskar AV. A Review of Mouth Dissolving Tablet Technologies. Pharma Technology. 27(11); 2003: 92–100

20. Available from URL:http://en.wikipedia.org/wiki/Thin-film_drug_delivery.

Received on 25.06.2013

Modified on 24.07.2013

Accepted on 01.08.2013

Research Journal of Pharmaceutical Dosage Forms and Technology. 5(5): September-October, 2013, 257-262

	Product	Drug or supplements
Novartis	Theraflu Thin strip Long acting cough	Dextromethorphan
Novartis	Theraflu Thin strip Multi-symptoms	Diphenhydramine
Novartis	Thaminic Thin strip Long acting Cough	Dextromethorphan
Novartis	Triaminic Thin strip cough & runny nose	Diphenhydramine
Novartis	Gas-X Thin strip anti gas	Simethicone
Prestige Brands	Little colds sore throat strips	Pectin
InnoZen	Suppress cough strips	Dextromethorphan
InnoZen	Suppress herbal cough relief strips	Mentol
Prestige Brands	Chloaseptic relief strips	Benzocain Menthol