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Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

Copyright  © 2011-2022 The  Author(s): This is an open-access article distributed under the terms of the CC BY-NC 4.0 which permits unrestricted use, distribution, and reproduction in any medium for non-commercial use provided the original author and source are credited

Open Access   Full Text Article                                                                                                                                                    Review Article 

Oral Fast Disintegrating Films of Phytochemicals: A Novel Drug Delivery System

Adnanulhaque M. Sayed* , Abhijeet D. Kulkarni , Pooja U. Pardeshi , Chinmay R. Kapile , Akshay D. Nehe 

Department of pharmaceutics, Sanjivani College of Pharmaceutical Education and Research, Kopargaon, Ahmednagar, Maharashtra, India

Introduction

The oral route is widely used for the administration of therapeutic agents because of its simplicity of administration, non-invasiveness, flexibility, and patient acceptance, the oral route is the most favored mode of drug administration for systemic impact.^{1, 2} Because of the convenience of manufacture, shipping, and patient acceptance, tablets are the most used dosage form. Patients who are geriatric, pediatrics, nauseated, or non-compliant have difficulty swallowing traditional oral dose forms. It is believed that half of the population is afflicted by this issue, which leads to a higher risk of non-compliance and inefficient treatment. To master this, oral fast disintegrating drug delivery systems were developed by scientists at Wyeth Laboratories in late 1970s in the United Kingdom as a replacement of tablets, capsules, and syrups for children and elderly people who have a tough time administering conventional solid dosage forms for oral administration. Mouth dissolving tablets and oral fast disintegrating films (OFDF) are two types of oral fast disintegrating dosage forms.  Although their fast disintegration or dissolution times, there is still a dread of taking mouth dissolving tablets. Mouth dissolving tablets are related to some issues, including the presence of residue in the mouth, which produces a grittiness in the mouth and there is fear of choking and trouble administering tablets. To overcome the problems associated with mouth dissolving tablets, a novel drug delivery technology called oral fast disintegrating films (OFDF)/ oral dispersible films/ mouth dissolving films was developed. ^{2, 3} 

OFDF was created using the same technology as transdermal patches for oral medication administration. OFDFs are made of hydrophilic polymers that dissolve fast when applied on the tongue or in the buccal cavity, where the film absorbs saliva and hydrates quickly, allowing the medication to be absorbed orally. The rapid disintegrating action is mostly due to the surface area of the film wetting rapidly when exposed to the moist oral environment^{2, 3}. OFDFs improve bioavailability, reduce therapeutic costs, and make administration easier, all of which patient compliance increases.  Films are administered through the oral mucosal route to achieve a minimum disintegration time in the oral mucosa in order to reach systemic circulation with the quickest onset of action⁴. Over the last two years, consumers have been introduced to this approach through the release of several breath refreshing products. Today, OFDFs are already a proven and welcomed technique used for the systemic administration of APIs in OTC medications. ³ 

Phytochemicals can be incorporated in the formulation and development of OFDFs to produce pharmacological activities. Recent studies show that phytochemicals produce a wide range of therapeutic effects and help in the management of certain disorders. Phytochemicals such as flavonoids, polyphenols, glycosides, saponins, etc. and active constituents present in them are employed in the formulation. Active phytoconstituents such as quercetin, herpetrione, curcumin, etc. can be formulated with film-forming polymers and other ingredients to obtain film. Certain herbal extracts of peanut, propolis, olive leaf, etc. can also be used as natural active compounds in the formulation and development of OFDFs for therapeutic roles. The extracts are obtained by several extraction techniques such as ethanol extraction, bleaching, decoction and maceration. These natural active compounds have anti-inflammatory, antiviral, immunomodulatory, antimigraine, antiarrhythmic, antioxidant and antibacterial activities. Phytochemical-based OFDFs can be used in the management of Alzheimer’s disease, dementia and cerebral insufficiency. Researchers have developed many OFDFs using phytochemicals as an active ingredient.

Absorption pathway through oral mucosa:^{4, 5}

For passive drug diffusion over the oral mucosa, there are two penetration pathways: route paracellular and transcellular. Permeants can use both pathways at the same time. However, according to the physicochemical features of the diffusing medication, one route is generally favored over the other. Owing to the lipophilic nature of the cell membrane, hydrophilic solutes will have difficulties passing through it because of the partition coefficient. As a result, the intercellular space is the primary barrier to lipophilic solute penetration, whereas the cell membrane is the primary barrier to hydrophilic compound transport. The penetration of the compound via the oral epithelium may employ a mixture of these methods. ⁴ 

Perks of OFDFs:

• Effective in conditions requiring a quick initiation of effect, such as motion sickness, allergic reactions, sneezing, or asthma.
• OFDFs are more flexible than other conventional medicaments and therefore provide more patient compliance.⁷
• Oral film drug administration offers the potential to enable the production of sensitive drug targets that would otherwise be difficult to obtain in solid or liquid formulations.⁸ 
• From a business aspect, marketing innovative dosage form (OFDF) would help the business to gain more revenue.³ 

Limitations of OFDFs:

• Dose termination is impossible, as they disintegrate rapidly.

• The physiochemical properties of the drug must be desirable in order for it to permeate from the buccal mucosa.⁹ 
• Drugs that are reactive at buccal pH and drugs that irritate the mucosa are not suitable for this route of administration.¹⁰ 

Classification of OFDFs:⁶

OFDFs are categorized into three types.

1. Flash release
2. Mucoadhesive melt-away wafers
3. Mucoadhesive sustained released wafers

Formulation and Development of Phytochemical Loaded OFDFs:

Hydrophilic polymers and one or more active phytochemical constituents make up oral fast disintegrating films (OFDFs). Polymer science obtained from traditional solid transdermal and oral drug formulations is used in the development of OFDFs. Manufacturers can efficiently develop novel medicines within a shorter development period by using their similarities. Because of the versatility in the formulation of oral thin film technology, manufacturers can pick from a wide range of phytocompounds and excipients when developing new products. Material selection depends on film disintegration rates and absorption rates, such that a drug that is similar to or better than existing formulations such as pills, liquids, and capsules may be designed.¹¹ Several breath-freshening OFDFs have been released in the previous two years, introducing customers to this method.³ 

Formulation Aspect:

Mechanical characteristics, taste concealing, quick-dissolving, personal features, and tongue feel are all factors to consider while formulating.¹² OFDF is a thin film/strip incorporating an active constituent with a surface area of 1-20 cm2 (depending on dosage and drug loading). The active ingredient can be incorporated up to  30 mg in one dosage.⁶ All ingredients included in the composition of thin film should be generally considered suitable and approved for use in oral pharmaceutical dosage forms, according to regulatory guidelines.¹³ Table 1 displays the composition of OFDFs as well as the numerous chemicals employed in their production.

   Table 1: Standard composition of OFDFs:^{1, 3, 4}

1.  Drug

A number of active phytochemicals can be integrated into the fast-dissolving oral thin film technique. The ideal components for the formulation of oral thin films are low dosage active phytoconstituents. 

Characteristics of drugs to be included in OFDFs^{2, 14}

• The therapeutic dosage of the drug should not exceed 30mg, and it should generally account for 5-30% w/w of the final dosage form.¹² 
• The drug’s solubility and stability in water/saliva and mouth should be excellent.

a) Table 2 lists suitable phytoconstituents and herbal extracts for inclusion into thin film formulations.

Table 2: Suitable phytoconstituents and herbal extracts for incorporation into thin film formulation 

2. Film-forming polymers

The most important significant element for the effective design of oral thin film formulation is the selection of film-forming polymers.⁶ For the development of oral disintegrating film, a range of film-forming polymers are available, which are utilized at a concentration of around 40-45 % w/w of total film weight, but can be raised to 65 % w/w of film weight alone or in combination to achieve desirable oral film qualities.²

Characteristics of polymer

• It should be tasteless, non-toxic and non-irritant.⁶ 
• It should possess good shelf life.³ 
• It should not cause infection in the buccal cavity.

Recently at this time, both natural and synthetic polymers are utilized to make oral thin films.⁶ Table 3 lists the natural and synthetic polymers.

Table 3: Natural and synthetic polymers^{4, 6, 12}

METHODS USED FOR FORMULATION OF OFDF 

To prepare OFDFs, one or a combination of the following traditional methods can be employed.¹⁵

1. Solvent casting method 

Hydrophilic polymers are dissolved in water at 1000 rpm and heated to 60 °C in this technique. After that, all of the additional excipients are dissolved independently. The two solutions are then completely combined while rotating at 1000 rpm. The active phytochemical ingredient is dissolved in a suitable solvent and added to the resulting solution. The resultant solution is then cast as a film and allowed to dry before being cut into appropriate size pieces.^{3, 6, 16} 

2. Semisolid casting

When the film constituent is an acid-insoluble polymer, this approach is favored. The first step is to dissolve water-soluble polymers in water. The resulting solution is then mixed with the acid-insoluble polymer solution that has been prepared separately. Both solutions have been thoroughly combined. Following the mixing of the two solutions, a sufficient quantity of plasticizer is added to the final solution to get the gel's mass. Finally, heat control drums are used to cast the gel mass onto the films or ribbons. The film thickness should be between 0.015 and 0.05 mm. The acid-insoluble polymer should be used at a 1:4 ratio with the film-forming polymer. Cellulose acetate phthalate and cellulose acetate butyrate are examples of acid-insoluble polymers.⁶ 

3. Hot melt extrusion (HME)

In contrast to the solvent casting method, HME is a solvent-free process that uses heat to produce the films. A screw extruder heats and homogenizes the excipients and API until they are completely mixed. The mixture is extruded via a flat extrusion die, which forms the extrudate into the appropriate film shape. It is then cooled, trimmed to size, and packed.¹⁷ 

4. Solid dispersion extrusion

The purpose is to diffuse the active ingredient into a melted polymer solution so that it may be loaded more easily. There can be one or more active ingredients that are dissolved in a suitable liquid solvent that functions as an inert carrier. This occurs in the presence of an amorphous hydrophilic polymer at 70°C without the requirement to remove the liquid solvent in order to get the solid dispersion required. Finally, the dyes are used to form the solid dispersions into films.⁴ 

5. Rolling method

The film is first formed by premix preparation, then combined with drug solution and put to the roller in the rolling procedure. Film-forming polymers, solvents, additional ingredients and additives make up the premix, but no active ingredient is included. The premix is poured into the masterbatch tank, which is then fed by a first metering pump and controlled by one or both of the first and second mixers.¹⁸ After that, the needed amount of active component is added to the desired mix, which is then blended with the masterbatch premix to create a consistent matrix. Second metering pumps provide a certain quantity of homogeneous matrix to the pan, and the film is eventually created and dragged away by a support roller, and the wet film is subsequently dried using controlled bottom drying.⁴ 

Bio-progress has created some thin film manufacturing technologies, which are mentioned below.

1) SoluleavesTM

2) XGelTM

3) WaferTabTM

CURRENT RESEARCH ON PHYTOCHEMICAL LOADED OFDFs

Recent studies show that phytochemicals produce a wide range of therapeutic effects and help in the management of certain disorders. Phytochemicals such as flavonoids, polyphenols, glycosides, saponins, etc. and active constituents present in them are employed in the formulations. Phytochemicals can be incorporated in the formulation and development of OFDFs to produce pharmacological activities. Recent research and studies showed a significant therapeutic role of phytochemicals in OFDF formulation when integrated as an active ingredient. In recent years, researchers have developed OFDFs by incorporating active phytoconstituents and/or herbal extracts to produce significant therapeutic activity. Active phytoconstituents such as quercetin, herpetrione, curcumin, etc. can be formulated with film-forming polymers and other ingredients to obtain oral thin film. Certain herbal extracts of peanut, propolis, olive leaf, etc. can also be used as natural active compounds in the formulation and development of OFDFs for therapeutic roles. The extracts are obtained by several extraction techniques such as ethanol extraction, bleaching, decoction and maceration. These natural active compounds have anti-inflammatory, antiviral, immunomodulatory, antimigraine, antiarrhythmic, antioxidant and antibacterial activities. Phytochemical-based OFDFs can be used in the management of Alzheimer’s disease, dementia and cerebral insufficiency. Researchers have developed many OFDFs using phytochemicals as an active ingredient. Table 4 displays a brief data of various researches carried out on phytochemical integrated OFDFs.

 Table 4: Recent research on phytochemical loaded OFDFs

 DT- Disintegration time, T- Thickness, DC- Drug content, TS- Tensile strength

Conclusion

Oral fast disintegrating film (OFDFs) is a novel approach in the oral drug delivery system that fulfills an unmet need in a wide range of populations, including children, paralyzed, nauseated, and non-compliant patients. There is no need for water, measurement and after disintegration; the drug gets absorbed in oral mucosa providing quick onset of action. Phytochemical incorporated thin films can be formulated and used in the management of CNS-related diseases or disorders. Active phytoconstituents have a wide range of therapeutic roles. The drug loading is restricted to roughly 30 mg, so the drug to be integrated into the film formulation should be highly potent.

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