Abstract

The review explores the medicinal properties of Simarouba glauca, a plant with a rich history in traditional medicine. Focusing on its morphology, distribution, cultivation, commercial uses and phytochemical composition. Also, the paper delves into the diverse bioactive compounds present in various plant parts, emphasizing their potential therapeutic applications. Simarouba glauca exhibits notable anti-inflammatory, antioxidant, anticancer and antimicrobial activities, attributing to compounds like quassinoids, flavonoids, alkaloids, triterpenes, steroids, anthraquinones and coumarins. These bioactive constituents contribute to the plant's efficacy in treating various ailments, including infections, inflammation-related disorders, oxidative stress-related conditions and few other pharmacological actions. The review consolidates findings from in vitro and in vivo studies, shedding light on the plant's pharmacological evaluation and exploring its potential in drug development. Moreover, the paper addresses the plant's role in traditional medicine across different cultures, underscoring its historical significance. The synthesis of scientific evidence underscores Simarouba glauca as a promising source for novel Pharmaceuticals and Nutraceuticals. Overall, the comprehensive analysis presented in this review highlights the need for further research and clinical trials to unlock the full therapeutic potential of Simarouba glauca in modern medicine.

Keywords

Fast dissolving films, mouth dissolving film, film’s Composition, Formulation methods, evaluation parameters

Introduction

 

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Table 2: List of few drug that can be incorporated in fast dissolving film[19].

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Hydrophilic polymers[20]:

The films' quick disintegration, pleasant mouthfeel, and mechanical qualities are all made possible by the water-soluble polymers.By raising the molecular weight of the polymer film bases, the rate of polymer disintegration is slowed down. HPMC E-3 and K-3, Methyl cellulose A-3, A-6, and A-15, Pullulan, carboxmethylcellulosecekol 30, Polyvinylpyrollidone PVP K-90, Pectin, Gelatin, Sodium Alginate, Hydroxypropylcellulose, Polyvinyl alcohol, Maltodextrins, and EUDRAGITRD10 are a few examples of water-soluble polymers used as film formers.One new polymer that forms films is polymerized rosin.

Plasticizers:

It has been reported that formulation factors (plasticizer, etc.) have a significant impact on the mechanical properties of films. The addition of plasticizers has also enhanced the mechanical qualities of the films, such as tensile strength and elongation. These attributes could be impacted by variations in their concentration. Common plasticizers include polyethylene glycols, di-butylphthallate, and glycerol.

Surfactants[20]:

In order to dissolve films quickly and release active agents right away, surfactants are utilized as solubilizing, wetting, or dispersing agents. Benzalkonium chloride, bezthonium chloride, sodium lauryl sulfate, tweens, and others are a few of the often utilized. As a solubilizing, wetting, and dispersion agent, polaxamer 407 is one of the most significant surfactants.

Saliva stimulating agent:

The goal of using saliva stimulating chemicals is to boost saliva production in order to facilitate the quick disintegration of fast-dissolving film formulations. Generally speaking, salivary stimulants can be made from acids that are used in meal preparation. Ascorbic acid, tartaric acid, lactic acid, malic acid, and citric acid, for example. Between 2 and 6% w/w of the film’s weight, these agents are used alone or in combination.[20]

Sweetening agents:

Sweeteners are now a crucial component of pharmaceutical preparations meant to dissolve or disintegrate in the mouth. Sucrose, dextrose, fructose, glucose, liquid glucose, and isomaltose are the traditional sources of sweeteners. The use of artificial sweeteners in pharmacological formulations has grown in popularity. The first generation of artificial sweeteners includes aspartame, cyclamate, and saccharin. The second generation includes acesulfame K, sucralose, alitame, and neotame.

Flavoring agents:

Flavoring agents can be chosen from a variety of plant components, such as leaves, fruits, and flowers, as well as synthetic flavor oils and oleo resins. You can use flavors separately or in combination. Any taste Addable like water or aromatic oils menthol soluble extracts and strong mints like wintergreen, peppermint, sweet mint, spearmint, cinnamon, clove, and sour fruit fragrances like lemon, orange, or chocolate; sweet confectionary flavors like vanillin; or fruit essences like pineapple, apple, raspberry, cherry, and raspberry. The type and strength of the flavor determine how much flavor is required to cover up the taste.

Coloring agents:

When making Orally Fast Dissolving Films, approved coloring agents (FD & C) are employed, with concentration levels not to exceed 1 percent w/w. [20], e.g. Dioxide of Titanium

METHODS:

The oral dissolving films can be made using one or more of the following processes.[20]

1. Solvent casting
2. Semisolid casting
3. Hot melt extrusion
4. Solid dispersion extrusion
5. Rolling methods

1. Solvent casting method:

In the solvent casting process, the medicine is added after the excipients have been dissolved in water and the mixture has been agitated to create a homogenous solution. Next, water-soluble polymers are added. Lastly, the solution is cast into the petri-plate and then subject it for drying. 

2. Semisolid Casting:

This approach creates a homogenous viscous solution by mixing a solution of an acid-insoluble polymer (such as cellulose acetate butyrate) with a solution of a water-soluble polymer that forms films.It is coated on untreated casting film following sonication. After drying, the film should have a thickness of between 0.015 and 0.05 inches. The acid insoluble polymer to film-forming polymer ratio need to be 1:4.

3. Hot Melt Extrusion:[20]:

Using the hot melt extrusion process, the medication is first combined with solid carriers. The mixture is then melted by the extruder, which has heaters, and the melted material is then formed into films by the dies. Hot melt extrusion has some advantages, such as:

1. 1. Fewer operating units
   2. Improved content homogeneity
   3. Anhydrous processing

D. Solid dispersion extrusion[21]:

The dispersion of one or more active substances in an inert carrier in a solid state while amorphous hydrophilic polymers are present is referred to as a solid dispersion. An appropriate liquid solvent is used to dissolve the drug. After that, the solution is added to the polyethylene glycol melt, which can be reached below 70°C. Ultimately, dies are used to form the solid dispersions into the films.

5. Rolling Method:

A drug-containing solution or suspension is rolled on a carrier in the rolling technique. Water and a combination of water and alcohol make up the majority of the solvent. After being cured on rollers, the film is cut into the appropriate sizes and shapes. Using a high shear processor, other ingredients, including the active agent, are dissolved in a tiny amount of aqueous solvent. A homogenous, viscous solution was created by dissolving water-soluble hydrocolloids in water[20].

EVALUATION PARAMETERS[22]:

1. Physical Parameters:

1. Appearance:

It is possible to verify if all of the created films appear clear or opaque. Although surface qualities are usually determined visually, tools like as microscopes can also be employed.

2. Thickness:

Micrometer screw gauges can be used at various key spots to measure the thickness of the produced film. Five places on the film, namely the center and each of the four corners, should be measured in order to establish the mean thickness. Ensuring consistency in the thickness of the film is crucial since it has a direct impact on the accuracy of the dose in the strip.

3. Weight variation:

It is necessary to weigh each film individually and compute the average weights. Subtracting the average weight of the films from each individual film is the next step. A significant variance in weight suggests an ineffective method of administration and maybe non-uniform medication content.

d. Contact angle:

At room temperature, the Goniometer (AB Lorentz and wettre, Germny) can be used to measure the contact angle. This can be accomplished by taking a dry film and put a droplet of distilled water to its surface. A digital camera is used to capture pictures of the water droplets within ten seconds after their deposition. Both sides of the descent can have the contact angle measured, and an average is taken.

4. Transparency:

The films’ transparency can be assessed with a basic UV spectrophotometer. After cutting the film into a rectangle, insert it into the spectrophotometer cell. Find the film’s transparency at 600 nm.One can compute the film’s transparency using the formula below:

Transparency= (log T600)/b = ??C

Where,

T600= transmittance at 600nm

b= film thickness (mm)

C= concentration.

5. Moisture content:

The degree of moisture has an impact on the friability and brittleness of films. In essence, the product’s ingredients control the amount of moisture in a given film. Generally speaking, the Karl Fisher titration method, moisture content testing equipment, or weighing method can be used to determine the quantity of moisture present in the film. A pre-weighed film of a specific size is typically heated to between 100 and 120 °C until it achieves a steady weight; the weight disparity shows the amount or degree of moisture in the film. To calculate moisture content, use the following formula:

% Moisture content= [(Initial weight – Final weight) ×100/Initial weight].

The moisture content in an ideal film should be <5>

2. Chemical Parameters:

1. Surface pH test:

The surface pH of the film can be tested by laying it on 1.5% w/v agar gel and then applying pH paper (pH range 1-11) to the film. The color of pH paper is monitored and reported.

2. Disintegration time:

The disintegration time of a film gives information on its dissolution and disintegration properties. A stainless steel wire mesh containing 25 ml of simulated salivary fluid with a pH of 6.8 is filled with film of the requisite size (2 x 2 cm2). The duration required for a film to shatter and disintegrate is known as the in-vitro disintegration period.

3. In vitro dissolution test:

Any of the pharmacopoeia’s standard basket or paddle gear can be used to conduct a dissolution test. The maximal dose of the API and the sink conditions will largely determine which dissolving medium is used. Because the strip has a propensity to float onto the dissolving medium when the paddle equipment is used, the dissolution test can frequently be challenging.

4. Thermal analysis:

A differential scanning calorimeter can be used to record thermograms of the samples, revealing information on the drug molecules’ state within the film. Any change in the endothermic or exothermic peak, as well as the extension of the peak area, suggests that the drug molecule trapped within the film is undergoing a phase transition, recrystallization, or molecular interaction. To test, heat the sample in an aluminum pan at a predefined rate (~10°C/min) from room temperature to a high temperature (~500°C).

5. Crystallinity:

Using an X-ray diffractometer for X-ray crystallographic examinations, it is feasible to easily determine if the drug molecule is crystalline or amorphous within the film. The films can be placed in the sample holder, and XRD transmission diffractograms can be generated using a specific X-ray source with a start-to-finish diffraction angle, scan range, and scan speed.

6. Assay / Content uniformity:

Any standard pharmacopoeia describing the individual API’s assay method will be utilized to determine this. Estimating the API content in each strip enables us to evaluate content consistency. The content uniformity range is 85–115%.

3. Mechanical Parameters:

a. Dryness / Tack test:

Tenacity is the degree to which the film adheres to any piece of paper put against the strip; on the other hand, dryness is the property used to determine the solvent or water content of the film. The film drying process consists of eight stages that is, set-to-touch, dust-free, tack-free, dry-to-touch, dry-hard, dry-through, dry-to-recoat, and dry paper free. These properties can now be measured using a number of technologies. To accomplish this, push your thumb against the film at lab scale.

b. Tensile strength:

Tensile strength is defined as the maximum stress applied to the point at which the film specimen breaks. The applied load at rupture can be computed using the following equation, which uses the mean of three measurements and the cross-sectional area of the fragmented film:

Tensile strength = [Breaking force  /Cross sectional Area of sample]

c. Percentage elongation:

One sort of distortion is elongation. Anything that is under stress experiences a straightforward change in shape, which may be measured with a texture analyzer. To put it another way, a sample that experiences tensile stress deforms, lengthens, or elongates. The following formulae can be used to compute it by measuring the increase in film length following tensile measurement:

Percent Elongation = [L-L0] X 100 / L0

Where L be the final length and L0 is initial length.

d. Young’s Modulus:

Film stiffness is measured by its elastic modulus, also known as Young's modulus. Here, too, the tensile strength measurement techniques might be applied. It can be shown as the following ratio of applied stress to strain in the elastic deformation region

Young’s Modulus= Slope x 100/ Film thickness x cross head Speed

A hard, brittle film with little elongation exhibits a high Young’s modulus and tensile strength.

5. Tear Resistance:

Plastic film or sheeting’s resistance to tearing is a complicated byproduct of its final resilience to rupturing. To quantify the force required to induce tearing, a relatively low rate of loading—51 (2 in.) /min—is essentially used. The value of tear resistance in Newtons (or pounds-force) represents the maximum stress or force—which is often found close to the beginning of tearing—necessary to tear the specimen.

6. Folding endurance:

One essential physical attribute required for simple deployment on the administration site is the film’s flexibility. The film’s flexibility can be quantitatively assessed using folding endurance. This is ascertained by folding the film 300 times without breaking or repeatedly at a 180° angle to the same plane until it breaks. The folding endurance value is calculated as the number of times the film can be folded without breaking.

4. In Vivo test:

Two approaches to simulating in vivo disintegration include contact angle measurements and thermomechanical studies of film swelling behavior. In vivo testing, which is carried out with the help of a tasting panel and human volunteers, focuses on the taste of the films as well as their in vivo disintegration time. An electronic tongue tester is also used to examine the films flavor.

5. Other tests:

The viscosity of the polymer solution, content homogeneity, and residual solvent determination are other methods for characterizing and controlling the quality of ODFs. Garsuch and Breitkreutz found that ODFs with varying top and lower surfaces showed signs of caffeine recrystallization through the use of near-infrared chemical imaging, X-ray diffraction, and scanning electron microscopy. Technologies like Raman and near-infrared spectroscopy can be used to identify and measure the active ingredients in the films. The glass transition temperature and crystallinity are examined using X-ray diffraction, thermo-mechanical analysis, and differential scanning calorimetry. Gaisford et al. used isothermal calorimetry to track the crystallization of medications derived from ODFs. Weight and dynamic vapor sorption are employed to determine hygroscopic and residual water content. Given established standards, more research into microbiological investigations and stability testing is required.

CONCLUSION

As this review shows, mouth-dissolving films are a novel strategy in the pharmaceutical industry. These days, several pharmaceutical companies and organizations use this technique to prolong the patent life of their current drugs. MDF can be prepared using a variety of methods. The primary motivation behind the creation of MDFs was to solve the difficulty that dysphasic medical specialty, geriatric, and psychiatric patients had ingesting regular oral dose forms. By delivering the medication straight into the bloodstream, the formulation increases safety, decreases side effects, and enhances absorption. Because it doesn’t need water to be administered, this dosage form is affordable and portable. Mouth dissolving film therefore becomes a special, tasteful, essential, and selective dosage form.

ACKNOWLEDGMENTS

None. Contributions from anyone who does not meet the criteria for authorship should be listed, with permission from the contributor, in an Acknowledgments section.

CONFLICT OF INTEREST

None. Any interest, financial relationship, personal relationship, religious or political beliefs that might influence the objectivity of the author can be considered as a potential source of conflict of interest. All manuscripts submitted to the journal must include a conflict of the interest disclosure statement or a declaration by the authors that they do not have any conflicts of interest to declare

FINANCIAL SUPPORT :

N.A (Not applicable)

ETHICS STATEMENT :

None.

REFERENCES

1. 1. Amir HS, J. Pharm. Pharmaceut. Sci., 1998; 1(1): 15-30.
   2. Satishbabu BK, Shrinivasan BP, Ind. J. Pharmceut. Sci. 2008; 175-179.
   3. ipikaParmar,Dr. Upendra Patel, Orally Fast Dissolving Film As Dominant Dosage For Quick Releases, International Journel Pf Pharmaceutical Research And Bio Science,2012;1(3):24-41.
   4. Hang H, Zhang J and Streisand JB, Oral Mucosal Drug Delivery: Clinical Pharmacokinetics and Therapeutic Applications. Clinical Pharmacokinetics,2002; 41: 661-680
   5. Dixit RP, PuthliSP.Oral strip technology: Overview and future potential. J. Control. Release, 2009; 139(2): 94-107.
   6. Arya A, Chandra A, Sharma V, Pathak K. Fast dissolving oral films: An innovative drug delivery system and dosage form. Int. J. Chem Tech. Res.,2010; 2(1): 576-583.
   7. Arya A, Chandra A, Sharma V and Pathak K. Fast Dissolving Oral Films: An Innovative Drug Delivery System and Dosage Form. Int J Of ChemTech Research 2010; 2(1):576- 583.
   8. Dixit RP, Puthli SP, Oral strip technology: Overview and future potential. Journal of Controlled Release. 2009; 139: 94–97.
   9. Bhyan B, Jangra S, Kaur M and Singh H, Orally Fast dissolving films: innovations in Formulation and technology. International Journal of Pharmaceutical Sciences Review And Research 2011; 9(2): 50-57.
   10. Gavaskar B, Kumar S, Guru S and Ray M. Overview on fast dissolving films, International Journal of Pharmacy and Pharmaceutical Sciences 2009; 2: 29-33.
   11. Bhura N, Sanghvi K, Patel U, Parmar V and Patel D, “A review on fast dissolving film”, IJPRBS, 2012; 1 (3): 66-89.
   12. Choudhary DR, Patel VA, Chhalotiya UK, Patel HV, Kundawala AJ. Development and characterization of pharmacokinetic parameters of fast-dissolving films containing levocetirizine. Sci. Pharm, 2012; 80: 779–787.
   13. Zhang H, Zhang J, Streisand JB. Oral mucosal drug delivery: clinical pharmacokinetics and therapeutic applications. Clin. Pharmacokinetic, 2002; 41(9):661?680.
   14. Jangra PK, Sharma S, BalaR.Fast dissolving oral films: Novel way for oral drug delivery. Int. J. Uni. Pharm. Bio. Sci., 2014; 3(1): 6-27.
   15. Heer D, Aggarwal G, Kumar SLH. Recent trends of fast dissolving drug delivery system-An overview of formulation technology. Pharmacophore, 2013; 4(1):1-9.
   16. Mahajan A, Chhabra N, Aggarwal G. Formulation and Characterization of Fast Dissolving Buccal Films: A Review. Der Pharm Lett., 2011; 3(1): 152-165.
   17. Kulkarni, N, Kumar LD. Fast dissolving orally consumable films containing an anti- tussive and a mucosa coating agent, U.S. Patent. 2003/206942.
   18. Kulkarni AS, Deokule HA, Mane MS Ghadge DM. Exploration of different polymers for use in the formulation of oral fast dissolving strips. J Current Pharm Res 2010; 2(1): 33-35
   19. Priyanka Gupta, Amrita Bisht and Dr. N. G. Raghavendra Rao, Fast Dissolving oral films:  A comprehensive review. wjpmr, 2019,5(7), 116-127
   20. Prasanna P. Ghodake, Kailas M. Karande, Riyaz Ali Osmani, Rohit R. Bhosale, Bhargav R. Harkare, Birudev B. Kale, Mouth Dissolving Films: Innovative Vehicle for Oral Drug Delivery.IJPRR, 2013; 2(10)
   21. Pandya Ketul, K.R.Patel, M.R.Patel, N.M.Patel. Fast Dissolving Films: A Novel Approach to Oral Drug Delivery. IJPTP, 2013, 4(2), 655-661.
   22. Tarjani S. Naik et al / Int. J. Pharm. Phytopharmacol. Res. 2014; 4 (1): 62-65
   23. Tatwashil Kshirsagar, NareshJaiswal, GitanjaliChavan, KrushnaZambre, Sawandkar Ramkrushna and Deshmukh Dinesh, Formulation and evaluation of fast dissolving oral film. WJPR, 2021, 10(9), 503-561.
   24. Ankita Chaudhari, Sandip Tadavi, Bhagyashri Patil  and Sunil Pawar, Formulation and In Vitro Characterization of Mouth Dissolving Film of Clopidogrel Hydrogen Sulphate, Eng. Proc. 2023, 56, 268.
   25. Sandip Tadavi  and Sunil Pawar, Mucoadhesive Pentoxifylline Microsphere for Non-Invasive Nasal Drug Delivery, Eng. Proc. 2023, 56, 319
   26. Tadavi S. Amarsing, Pawar S. Pandit, Development of Nasal In-situ Gel Formulation of Fexofenadine HClUsing Gellan Gum (Gelerite®), International jouranal of Pharmaceutical Quality Assurance, 2023 14 (1), 1-7.