ORAL DISSOLVING FILM

       Arpita Chakraborty
Bengal school of technology
  (A college of pharmacy)
         
ABSTRACT

Mouth dissolving film is the most advanced oral solid dosage form due to its flexibility and comfort in use. Mouth dissolving films are oral solid dosage form that disintegrate and dissolve within a minute when placed in mouth without taking water or chewing. This dosage form allows the medication to bypass the first pass metabolism so bioavailability of medication may be improved .Mouth dissolving film has potential to improve onset of action lower the dosing and eliminate the fear of chocking. Formulation of mouth dissolving films involves both the visual and performance characteristics as plasticized hydrocolloids, API taste masking agents are being laminated by solvent casting and semisolid casting method. Solvent casting method being the most preferred method over other methods because it offers great uniformity of thickness and films prepared having fine glossy look and better physical properties. Mouth dissolving films are evaluated for its various parameters like thickness, physical property like folding endurance, disintegration and dissolution time. This review gives an idea about formulation techniques, evaluation parameters, overview on packaging and some available marketed products of mouth dissolving films.

1. INTRODUCTION TO ORAL DRUG DELIVERY:

Oral drug delivery (ODD) is the most preferred and convenient route of drug administration due to high patient compliance, cost-effectiveness, least sterility constraints, flexibility in the design of dosage form and ease of production. However, the challenges faced in oral drug delivery include poor bioavailability of drug, which is determined by three vital factors, namely, dissolution, permeability, and solubility. In order to achieve effective drug absorption in-vivo, various mathematical models have been designed to predict the dissolution and solubility rate of drug. Likewise, permeability is determined by cellular and non cellular models. In addition, behavior of the drug in gastrointestinal tract (GIT) is dependent on intrinsic factors of drug and physiological aspects, namely, pH, microbial colonization, and enzymes. Several pharmaceutical techniques have been contrived to stabilize and solubilize the active compounds in GIT, but it failed to attain a controlled and targeted release of the oral drug. The strategy to override such drawbacks by ushering in various nanotechnology platforms like polymer based nanocarriers, lipid based nanocarriers, metal, andinorganic-based nanoparticles.

2. TYPES 0F ORAL SOLID FORMULATION

 TABLET

• Compressed tablet

• Multiple compressed tablet

• Enteric coated tablet

• Sugar coated tablet

• Film coated tablet

• Chewable tablet

• Sublingual tablet

• Buccal tablet

 CAPSULE

 SYRUP

3. ORAL DISSOLVING FILM:

Orally fast-dissolving film is new drug delivery system for the oral delivery of the drugs. Almost 90% of the drugs are administered to the body via oral route for the treatment of various disorders and diseases as it is regarded as the safest, most convenient and most economical method of drug delivery and have the highest patient compliance. The drug is either dissolved or swallowed, which then enters into the systemic circulation to produce the desired effect. Fast dissolving oral thin films is an ultra thin film that employs a hydrophilic polymer that rapidly hydrates or adheres when placed on the tongue or in the buccal cavity. These films disintegrate or dissolve within seconds to release the active agent without drinking and chewing. The instant bioavailability results from bypassing first pass metabolism. So they are generally designed for the drugs having high first pass metabolism for achieving better bioavailability.

 (i) ADVANTAGES

1. Easy transportation.

2. No need of water for administration.

3. Oral strip technology provides an alternate route for drugs with first pass metabolism

4. Ease of administration of film to the patients suffering from dysphagia, repeated emesis, motion sickness, and mental disorders

5. Large surface area provides rapid disintegration and dissolution in the oral cavity.

 (ii) DISADVANTAGE

1. Drugs which are unstable at buccal pH cannot be administered.

2. Dose uniformity is a technical challenge.

3. Hygroscopic in nature.

4. High doses cannot be incorporated (<40 mg/4cm2piece)

5. Require special packaging for products stability and safety.

4. FORMULATION:

•  Active pharmaceutical ingredient
• 
  
•  Film forming polymers
• 
  
•  Plasticizer
• 
  
•  Sweetening agent
• 
  
•  Flavoring agent
• 
  
•  Coloring agent
• 
  
•  Surfactants

(i) Active pharmaceutical ingredient :-

Various classes of drugs can be incorporated into ODFs e.g., anti-histamine, anti- diarrheal, anti-depressants, vasodilators, antiasthmatic, anti-emetic, etc. (Chauhan et al., 2012). Dimenhydrinate can also be incorporated into ODFs for taste masking. Common examples of drugs incorporated into ODFs are salbutamol sulfate, rizatriptan

benzoate, verapamil, ondansetron, dexamethasone, rofecoxib, cetirizine, pilocarpine, tianeptine sodium, indomethacin, etc. An ODF of anti-emetic agent like prochlorperazine was also formulated by employing microcrystalline cellulose and other film forming polymers.

(ii) Film forming polymers :-

Water-soluble polymers are used as film formers as they provide quick disintegration, good mouth feel, and mechanical strength to the films. The robustness of the strip depends on the type of polymer and its amount in the formulations. A variety of polymers are available for preparation of films of which pullulan, gelatin and hypromellose are most commonly used. Examples of water-soluble polymers include: Pullulan, Gelatin, guar gum, xanthan gum, Hydroxyl propyl methyl cellulose (HPMC), Modified starches, PVPK30, PVA etc.

Ideal properties of the polymers used in the oral film:

1. Polymers should be non toxic, non- irritant and non-bitter.

2. Polymers should be tasteless

3. It should be devoid of leachable impurities

4. It should be inexpensive and readily available

5. It should not be an obstacle in the disintegration time

6. It should have good wetting and spreadibility property

7. It should exhibit sufficient peel, shear and tensile strength

8. It should not cause secondary infection in the oral cavity and should have sufficient shelf life.

(iii) Plasticizer:-

Plasticizer is a crucial ingredient of the mouth dissolving films. The selection of plasticizer depends upon its compatibility with the polymer and the type of solvent employed in the casting of film. It helps to improve the flexibility of the film and reduces the brittleness of the film. Plasticizer significantly improves the strip properties by reducing the glass transition temperature of the polymer. Typically the plasticizers are used in the concentration of 1 - 20%w/w of dry polymer weight. The Plasticizer should be volatile in nature. Examples include: Glycerol, Propylene glycol, Low molecular weight polyethylene glycols, Phthalate derivatives like dimethyl, diethyl, dibutyl derivatives, Citrate derivatives like triacetin acetyl citrate, etc.

(iv) Sweetening agent :-

Sweeteners have become an important part of the food products as well as pharmaceutical products intended to be disintegrated or dissolved in the oral cavity. Natural sweeteners as well as artificial sweeteners are used to improve the palatability of the mouth dissolving formulations. Some suitable sweeteners include:

(1) Water soluble natural sweetener: xylose, ribose, glucose, sucrose, maltose, stevioside etc.

(2) Water soluble artificial sweetener: sodium or calcium saccharin salts, acesulfame- K etc.

(3) Dipeptide based sweetener: aspartame

(v) Flavoring agent:-

Flavours used in the formulation must be non-toxic, soluble, stable and compatible with the excipients. The quantity of flavouring agent required to mask the taste depends on the flavor type and its strength.

(vi) Coloring agent :-

Generally incorporated colouring agents have FD&C approved colours, natural colours, pigments such as titanium dioxide etc. The colouring agents should not exceed concentration levels of 1%w/w.

(vii) Surfactants:-

Surfactants are used as solubilizing or wetting or dispersing agents as a result that the film gets dissolved within seconds and release active agent immediately. Surfactants also improve the solubility of poorly soluble drugs in fast dissolving buccal films. E.g.: Polaxamer 407, sodium lauryl sulfate, benzalkonium chloride, benzthonium chloride, tweens and spans etc.

5. TECHNIQUES OF OF FORMULATION

• (i) SOLVENT CASTING METHOD

Fast dissolving films are preferably formulated using the solvent casting method, whereby the water soluble ingredients are dissolved to form a clear viscous solution and the drug along with other excipients are dissolved in suitable solvent then both the solutions are mixed and stirred and finally casted in to the Petri plate and dried.

Water soluble ingredients are dissolved in water and API and other agents are dissolved in suitable solvent to

form a clear viscous solution

                             ⬇️

both the solution are mixed

                              ⬇️

degassed under vacuum

                             ⬇️

resulting solution is cast as a film

                              ⬇️

film is dried in drying oven and collected

• (ii) SEMISOLID CASTING METHOD

This method is preferably adopted when acid insoluble polymers are to be used in the preparation of the films. Acid insoluble polymers used to prepare films include: cellulose acetate phthalate, cellulose acetate butyrate. Acid insoluble polymer and film forming polymer should be used in the ratio of 1:4.

solution of water soluble film forming polymer is prepared

                              ⬇️

resulting solution is added to a solution of acid insoluble polymer

                                 ⬇️

appropriate amount of plasticizer is added so that gels mass is obtained

                                   ⬇️

Finally the gel mass is casted in to the films or ribbons using heat controlled drums.

• (iii) HOT MELT EXTRUSION METHOD

Hot melt extrusion method has various benefits; those are fewer operation units, minimum product wastage, better content uniformity, an anhydrous process, absence of organic solvents.

In hot melt extrusion method-

Drug is mixed with carriers in solid form

                                 ⬇️

The extruder having heaters melts the mixture

                                 ⬇️

Finally the melt is shaped in films by the dies.

• (iv) SOLID DISPERSION EXTRUSION METHOD

The term solid dispersions refer to the dispersion of one or more active ingredients in an inert carrier in a solid state in the presence of amorphous hydrophilic polymers.

Drug is dissolved in a suitable liquid solvent

                               ⬇️

Then solution is incorporated into melt of polyethylene glycol, obtainable below 70oC

                                 ⬇️

Finally the solid dispersions are shaped into the films by means of

dies

• (v) ROLLING METHOD

In this method the film is prepared by preparation of a premix, addition of an active and subsequent formation of a film.

Prepare pre-mix with film forming polymer, polar solvent and other additives except a drug add pre mix to master batch feed tank
                                  ⬇️

Fed it via a 1st metering pump and control valve to either or both of the 1st and 2nd mixer

                                   ⬇️

Add required amount of drug to the desired mixer

                                  ⬇️

Blend the drug with master batch pre mix to give a uniform matrix

                                  ⬇️

Then a specific amount of uniform matrix is then fed to the pan through 2nd metering pumps.

                                  ⬇️

The film is finally formed on the substrate and carried away via the support roller.

                                 ⬇️

The wet film is then dried using controlled bottom drying

6. EVALUATION PARAMETER

• Mechanical properties

 Thickness

 Dryness/tack test

 Tensile strength

 Young's modulus

 Tear resistance

 Folding endurance

• Organoleptic test

• Surface pH test

• Swelling property

• Transparency

• Assay/content uniformity

• Disintegration test

• In-vitro dissolution test

(i) MECHANICAL PROPERTIES

Thickness

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.

Dryness/Tack test

About eight stages of film drying process have been identified and they are set-to- touch, dust-free, tack-free (surface dry), dry-to-touch, dry-hard, dry through (dry-to- handle), dry-torecoat and dry print-free. Although these tests are primarily used for paint films, most of the studies can be adapted intricately to evaluate pharmaceutical orally fast dissolving film. 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. Instruments are available for this study.

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

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

Percentage 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.

Hard and brittle strips demonstrate a high tensile strength and young’s modulus with small elongation.

Tear resistance

Tear resistance of plastic film or strip is a complex function of its ultimate resistance to rupture. Basically very low rate of loading 51mm (2 in)/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.

(ii) ORGANOLEPTIC TEST

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. These in-vitro taste assessment apparatus methodologies are well suited for high throughput taste screening of oral pharmaceutical formulations.

(iii) 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.

(iv) SURFACE pH OF FILM

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.

(v) 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.

The degree of swelling was calculated using parameters

S.I = Wt – Wo/Wo

Where ,

S.I is the swelling index,

Wt is the weight of the film at time‟t‟, Wo is the weight of film at t = 0.

(vi) TRANSPARENCY

The transparency of the films can be determined using a simple UV spectrophotometer. Cut the film samples into rectangles and placed on the internal side of the spectrophotometer cell. The determine transmittance of films at 600 nm. The transparency of the films was calculated as follows:

Transparency = (logT600)/b = - €c

Where,

T600 is transmittance at 600 nm b the film thickness (mm)

c is concentration.

(vii) ASSAY/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 percent.

(viii) DISINTEGRATION TIME

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.

(ix) DISSOLUTION TEST

Dissolution testing can be performed using the standard basket or paddle apparatus. The dissolution medium will essentially be selected as per the sink conditions and highest dose of the API. 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.Recent research

8. CONCLUSION

Oral drug delivery has proved a promising pathway for delivering drug systemically and orally. The main advantage of the oral drug delivery is improved patient compliance and safe drug delivery. A novel concept of oral dissolving films has emerged as an effective tool in prolonging the time and efficacy of drug availability. Many categories of drug like analgesic, antipyretics, antihistaminic etc have already been formulated into oral films. It not only provides immediate therapeutic effect but also a safeguard towards effective bioavailability. They can be easily installed in the buccal cavity and the drug will be released slowly for an extended period of time.

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