Polymers used in buccal film: a review

Abstract

Patient compliance always remains the major concern of research for all researchers working in the field of pharmacy and specially pharmaceutics. In the resent era research is carried out extensively to formulate and fabricate a drug delivery system with improved effectiveness, safety and patient compliance. One of those delivery systems is buccal film dosage form. Mucosal membrane of oral cavity allows high permeation to certain drugs having high blood perfusion. Drugs with poor bioavailability as well as with shorter half-life can be administered easily. Buccal films can release the topical drugs with sustained and controlled effects and advantageous over the traditional drug delivery systems that are used in the curement of various disease. Buccal films also have the advantages of improved patience compliance because of their reduced size with suitable thickness as compared to certain other delivery system like buccal tablets and lozenges. Buccal film favors the delivery of drugs having danger of wastage through first pass effect, having low permeability, enzymatic degradation and can be affected by the variable environment of the gastro intestinal tract. The purpose of the present work is to provide a review of various aspects of buccal films as a suitable drug delivery system.

Keywords:

• buccal film
• mucosal membrane
• novel drug delivery system
• oral cavity
• patient compliance

1. Introduction

A drug can be administered in the body through many routes, for instance; oral, parenteral, transdermal, sub mucosal etc. Oral route is most widely accepted route for drug administration among all these routes.[1] Reasons of admiration of oral route are low therapy cost, comfort of administration and self‐medication.[2] Above 70% of the marketed drugs are in the form of oral dosage forms due to pain evasion and adaptability. But around 50% of population, generally pediatric and elderly patients avoid taking solid oral preparations such as tablets and capsules due to choking hazard, leading to patient’s incompliance.[3,4]

Purpose of recent advances in novel drug delivery systems is to augment safety and effectiveness of drugs by formulating a dosage form that is convenient for administration and better in achieving patient compliance.[5] Modification in the oral drug delivery lead to the evolution of dosage form, from ordinary solid dosage forms to altered release tablets/capsules to oral dispersible tablet and finally development of fast mouth dissolving films (MDFs). They rapidly dissolve or disintegrate in the oral cavity, without need of water, offering a suitable way of medicating to special population groups who have difficulty swallowing, as well as to the general population.[6] MDFs are fabricated by formulating the drug with selective oral mucosal permeation enhancers to deliver the drug systemically and thus offering additional compensation over oral and parenteral delivery systems. After absorption through oral mucosa, drugs enter to the systemic circulation directly, as the oral mucosa is rich in capillary network, bypassing the gastrointestinal tract and first-pass metabolism in the liver. So the drugs, that have low oral bioavailability due to extreme hepatic metabolism, are absorbed readily showing rapid action in more comfortable and convenient way than the parenteral route. Thus it offers shortening onset time, enhancing bioavailability and reducing the probability of first pass side effect with improved patient compliance.[7]

MDFs are very thin films having size and shape almost similar to postage stamp, which is simply placed on tongue, where it readily hydrates by saliva and release drug. MDFs have been approved in US, EU and Japan for prescription which are the three major regions. It seems that these films will dominate over other oral dosage forms having same active pharmaceutical agents and their market will significantly grow.[8] In this review mucosal lining of the oral cavity, biopharmaceutical aspects, their characteristics, their Ideal properties, formulation aspects, manufacturing techniques and characteristics are discussed.

2. Overview of mucosal lining of oral cavity

The oral mucosa consists of an outermost layer of stratified squamous epithelium followed by a basement membrane, a lamina propria and finally by the sub mucosa as the innermost layer. Permeability of the buccal mucosa is expected to be 4–4000 times higher than the skin, which differs in different regions. The order is such that; sublingual > buccal > palatal according to thickness and keratinization of these regions. Across the oral mucosa: paracellular and transcellular routes are the two permeation pathways for passive drug delivery. Intercellular spaces and cytoplasm are hydrophilic in nature, so help penetrate hydrophilic drugs while cell membrane is lipophilic in nature and facilitate the permeation of lipophilic drugs. In addition high blood supply, robustness, short recovery time after stress or damage and virtual lack of Langerhans cells makes the oral mucosa tolerant to potential allergens. One of the major limitations associated with oral mucosal drug delivery is the low flux leading to low drug bioavailability of certain drugs, so there may always be a need to add permeation enhancer.[9] Figure 1 showed overview of buccal mucosa.

Figure 1. Overview of oral mucosa.[10]

3. Biopharmaceutical aspects

MDFs disintegrate quickly in the mouth, facilitating the absorption of drug through the oral mucosa of mouth, pharynx and esophagus.[11] Absorption depends largely on factors like age, nature of the oral cavity and blood flow to oral cavity. Every drug has its own tissue permeability, perfusion rate, tissue binding, drug interaction profile and excretion rate so distribution and duration of action vary according to the drug. Any therapeutic agent can be incorporated to MDFs but those having lower doses and need a rapid onset of the action are preferred.[11]

4. Characteristics of MDFs/important features

MDFs should have the properties like non-tacky like nature, convenience of dosing, easy to handle, suitable for labeling and packing, 1–10 mm in thickness, 1–20 cm² in surface area, Rapid hydration and softening to release medicament, typical disintegration time in saliva 1–30 s, un obstructive, should not leave any residue in the mouth after disintegration and should provide a pleasant mouth feel.[12]

5. Ideal properties of candidate drugs

Different drugs are reported in the previous literature. Drugs showed have the pleasant taste, low doses, having smaller or moderate molecular weight, good stability in water as well as in saliva, should partially unionized at the pH of oral cavity, and should permeate oral mucosal tissues.[8]

6. Drugs that can be incorporated

Therapeutic categories that can be formulated in MDFs may include cough/cold remedies (antitussives, expectorants), sore throat drugs, erectile dysfunction drugs, antihistamines, anti-asthmatics, drugs for gastrointestinal disorders, nausea, pain and CNS (e.g. anti‐Parkinson’s disease). Other applications may include caffeine strips, snoring aid, multivitamins, sleeping aid etc.[13]

7. Advantages of buccal drug delivery system

Due to larger surface area rapid disintegrating and dissolution occurs in the oral cavity. MDFs are flexible and easily transported and handled, so they are superior to oral disintegrating tablets that are brittle and fragile and require special packaging for protection during storage and transportation. As compared to liquid oral formulations, dose is more précised in form of the strips. As no is required so these dosage forms are most friendly for dysphagic patients. They are rapidly wetted due to larger surface area and can be consumed anywhere as per suitability of the individual. Drugs can absorbed directly from the highly vascularized buccal mucosa and enter the systemic circulation bypassing first‐pass hepatic metabolism. This helps improving the bioavailability of the drugs that undergo extensive first pass effect. Due to least hepatic metabolism, dose is reduced leading to decrease probability of dose related side effects. Mentally ill, disabled and uncooperative patients can be easily medicated. The product can be a substitute with more clinical advantage. The manufacturing of these MDFs is cost-effective with reasonably priced end‐products. MDFs are alternative to ODTs as they have to face product identification for OTC drugs.[3,14]

8. Drawbacks/limitations

Different drawbacks like high dose, difficulty in dose uniformity, hygroscopic nature of drug, and requirement of special packaging for stability and safety of product are reported

9. Formulation aspects of buccal films

9.1. Drugs

Various therapeutic substances can be delivered through buccal film but still there are few restrictions and limitation as drugs with high dosage and high molecular weights are difficult to be formulated as buccal film. Normally 5–30% (w/w) of drug can be used to formulate the buccal film. Hydrophilic drugs are in the form of dissolved material or in solid solution state while hydrophobic drugs are evenly dispersed in the buccal film.[15] Release of the drug can be modified and desired release profile can be achieved by using therapeutic moiety as milled, micronized or as nanoparticles. Consistency, dissolution profile and uniformity of the drug contents of buccal film can be enhanced and improved by using micronized particle of the drug. Cough, allergy, motion skinless, pain disorder and certain local oral disease condition can be best treated by using drug in the form of buccal film.[16] Different polymers used in the fast dissolving films are shown in Figure 2.

Figure 2. Examples of fast dissolving films formulated with different polymers.[17]

9.2. Excipients

The contact between buccal mucosa and the film is very important to deliver the drug efficiently and this is the reason due to which the main focus is to the mucoadhesive polymers in the formulation of buccal drug delivery system especially buccal film.[18,19] list of mostly used polymers with their uses and characteristics are described in Table 1.

Table 1. Some commonly used film forming polymers and their characteristics.

S. no.	Name of the polymer	Characteristics	Reference
1	Pullulan	Water soluble, neutral, non-toxic, non immunogenic, biodegradable, non-mutagenic, non-carcinogenic, impermeable to oxygen, high adhesion and film forming abilities, non ionic polysaccharide and is blood compatible	[20]
2	Lycoat NG 73	Easily dispersible in cold water, lumps free dispersion, gives homogenous solution, simple cooking by heating will develop its film forming ability and can be used alone as film forming polymer to formulate buccal films	[21]
3	Maltodextrin	Film forming polymers and can be used to form the buccal film by film casting method as well as extrusion method. It can form a homogenous film	[20]
4	Hydroxypropyl Cellulose	Non-ionic, water soluble, thermoplastic polymer, can be used to prepare flexible films because of it gives low surface and interfacial [4]	[22]
5	Hydroxypropyl Methyl Cellulose	Extensively used film former, available in different grades, E3, E5 and E15 etc. it has high glass transition temperature, it forms tough and flexible films from aqueous solutions. Lipophilics contents can be incorporated in films formulated by HPMC	[20]
6	Poly Vinyl Pyrrolidone	Water soluble, good wetting characteristics, non-ionic, pH-stable, resist the temperature, used to form films readily and it is colorless. Forms films with rapid and easy disintegration	[23]
7	Kollicoat	hydrophilic having very high water soluble characteristics, good film forming abilities, internal plasticizer providing good flexibility, maintain the flexibility during storage	[23]

9.3. Penetration enhancers

Substances that are used to enhance the penetration of the active moiety are called penetration enhancers. They should not produce irritation and have reversible effect. One of the simple examples of penetration enhancer is the use of water. When the skin gets hydrated it gradually increases the permeability as water cause the opening of the compact structure [24,25] of needle base. There are various chemical that has the ability to enhance the penetration that includes surfactants (such as Tween) fatty acids (such as oleic acid), terpenes (like eucalyptus) and solvents (like ethanol).[26] Others are bile salts, azone, currently chitosan, its derivatives, and polymers with the property of mucoadhesion also have the potential of being penetration enhancer.

9.4. Taste masking and Sweetening agents

To enhance the patient compliance it is important to mask the bitter taste of drugs. Taste masking agents are certain methods can be used to mask the bitter taste like formation of complex or technology for salting out etc. (buccal film). Sweetening agent is the important component in orodispersble formulation especially formulations designs for peads. Both natural and artificial sweeteners are included in the formulations. Sucrose, dextrose, fructose, glucose, liquid glucose and maltose are the examples of natural sweeteners while saccharin, aspartum, sucralose, all-time, neotameacesulame-K etc. are the examples of artificial sweeteners.[15] Different active pharmaceutical ingredients, their dose, and therapeutic uses are listed in Table 2.

Table 2. Active pharmaceutical ingredients that can be loaded in buccal films.[27,28]

S. no.	Name of the drug	Dose (mg)	Therapeutic use
1	Chlorpheniramine maleate	4.0	Used to treat the allergic conditions
2	Diphenhydramine hydrochloride	25.0	Used to treat the allergic conditions
3	Triplolidine hydrochloride	2.50	Used as anti histaminic
4	Acrivastine	8.0	Used as anti histaminic
5	Azatidine maleate	1.0	Used as anti histaminic
6	Loratadine	10.0	Used as anti histaminic
7	Levocetrizine	75.0	Used as anti histaminic
8	Chlorohexidine	12.0	Used as anti septic
9	Salbutamol	4.0	Used as anti asthmatic
10	Loperamide	2.0	Used as anti diarrhoeal
11	Famotidine	10.0	Used to reduce the stomach acidity
12	Ondensteron	2.50	Used as anti emetic
13	Sumatriptan succinate	35.0–70.0	Used to treat the migraine
14	Ketoprofen	12.50	Used to treat the pain
15	Nicotine	2.0	Used for smoking cessation
16	Psuedoephedrine hydrochloride	30.0	Used as bronchodilator
17	Dextromethorphan Hydrochloride	10.0–20.0	Used as cough suppressant

9.5. Saliva stimulating agent

These agents are used to enhance the production of saliva which assists in the disintegration of the buccal film. Saliva stimulating agents include acids like citric acid, tartaric acid, ascorbic acid and malic acid. These acids can be used alone as well as in combinations. Few sweetening agents like glucose, fructose, xylose, maltose, lactose etc.[15]

9.6. Flavoring agents

Orodispersable system can includes another substance known as flavoring agent. Palatability and acceptance of an orodispersable dosage form like buccal film depends initial flavor quality, observe within few seconds after administration of the drug. Flavoring agents include various agents and few of them are Peppermint oil, cinnamon oil, spearmint oil, oil of nutmeg, vanilla, cocoa, coffee, chocolate, citrus, apple, raspberry, cherry and pineapple etc.[15,26]

9.7. Coloring agents

Coloring agents are use to improve the appearance of buccal film. There are different FD&C approved coloring agents.[15,29]

10. Manufacturing techniques

Following techniques are used for the manufacturing of buccal film

10.1. Film casting technique

Film casting method is one of the most widely used methods for the manufacturing of buccal film. It has advantages of easy preparation, being cheap and can easily be adopted at lab scale. It involves following steps.[30,31]

1. Prepare casting solution

2. Deaerate the solution

3. Pour the solution into a mold

4. Dry the casting solution

5. Cut the final dosage form containing desired amount of drug

6. Packing

10.2. Hot melt extrusion technique

In this method mixture of pharmaceutical ingredients is melted. In order to achieve homogeneous mixture in various dosage form like tablets, granules, pallets or film, the melted material is pushed to pass through a small opening (orifice of a die).[32–34] Although this method is rarely used for the manufacture of film but there are certain evidence in the literature that this method can be use for film preparation.[29,31,35]

11. Characterizations

11.1. Chemical stabilities studies

Chemical compatibility studies are performed to identify any possible interaction between the ingredients. Fourier transformer infra-red spectrum, differential scanning calorimetery and X-ray diffraction are the techniques usually used to conduct the compatibility studies.[36]

11.2. Thickness measurements

Electronic digital micrometer, digital vernier caliper or micro screw gauge can be used to measure the thickness of the patch. Thickness of the different location (corners and the center) is measured to assess the average thickness of the film.[31,32]

11.3. Swelling study

Swellability of the film is measured by placing the sample film continuing agar plate in an incubator kept at 37 + 2 °C. Increase in diameter of the film and weight gain by the film is calculated is calculated at different time intervals (1–5 h). Swellabilityis calculated as:[37](1)

where X_o = original weight or diameter of the film and X_t = weight or diameter at time t.

11.4. Surface pH

It is important to measure the surface pH of the films to assess the any side effect that may be produce inside the body. Acidic or basic pH can be the cause of irritation to mucosal. Initially the film is placed in 1.0 ml distilled water having pH 6.5–0.05 for 2 h. Specially designed glass tube is used for this purpose. To measure the surface pH combined glass electrode is brought near the surface for a time interval of 1 min.[38]

11.5. Folding endurance

Folding endurance is used to observe the flexibility of the film which is an important physical property of a buccal film. It is measured by folding the selected sample of the film at an angle of 180 and observes when it breaks. Another way to measure the flexibility of the film is to fold the film 300 times without breaking. Value of folding endurance is calculated in terms of numbers of fold without breaking the film.[39]

11.6. Moisture content

% Moisture contents of the film are calculated by finding the difference between the weights measured initially prior to the placement of film in the desiccators and after specific time interval. Calcium chloride is placed in the desiccators and the whole apparatus is kept for 24 h. Following equation is used to measure the % moisture uptake.[40](2)

11.7. Moisture uptake

Sample film is taken and weighed and then keep it in desiccators at room temperature. After 24 h film is taken out and expose to 84% relative humidity. Saturated solution of potassium chloride is used in desiccators till a constant weight is obtained. Following formula is used for the calculation of % moisture uptake.[41](3)

11.8. Surface morphology

Various techniques are used to observe the surface morphology. It includes SEM (scanning electron microscopy), electron microscopy and scanning tunneling microscopy. SEM is most widely used. Shape, size and number of pores present on the surface of the film are observed by SEM.[36]

11.9. In-vitro dissolution studies

In-vitro drug release is calculated for given formulation using USP dissolution apparatus. Temperature is kept at 37 ± 0.5 °C and the rotation speed is adjusted at 50 revolutions per min and dissolution media of 900 ml is used. Samples are drawn at different time intervals. Sample is replaced with same volume of fresh medium. % drug release is observed by analyzing the sample using spectrophotometer at specified wave length.[32]

12. Organoleptic evaluation

Organoleptic evaluation is done to observe and check sweetness and flavor, whether they are acceptable or not. An electronic tongue measurement is design having test sensors to observe the taste in vitro.[42]

12.1. Ex–vivo Permeation Studies

Ex-vivo studies are performed using modified Franz diffusion. There are two compartments one of them is donor while other is receptor compartment that has the capacity of 18 ml with 0.785 cm² area for diffusion. 37 °C temperature is maintained with the help of water jacket. Artificial mucosal membrane or mucosal membrane of animal (rabbit) is used for permeation studies. Membrane is mounted between two chambers. Phosphate buffer of pH 7.4 is used to fill the receptor compartment. Membrane is stabilize in an hour. Once the membrane is stabilized the film is placed and samples are taken. The taken volume is replaced with fresh media.[43] Name of the commercially available buccal films are listed in Table 3.

Table 3. Commercially available buccal films.[28,44]

S. no.	Name of the drug	Marketed brand	Manufacturer
1	Cool mint	Listerine	Pfizer
2	Diphenhydramine HCl	Benadryl	Pfizer
3	Phenylephrine HCl	Sudafed	Pfizer
4	Diphenhydramine HCl	Triaminic	Novartis
5	Dextromethorphan HBr (7.5 mg)	Triaminic	Novartis
6	Dextromethorphan HBr (15 mg)	Theraflu	Novartis
7	Simethicone	Gas-X	Novartis
8	Menthol/Pectin	Orajel	Del
9	Menthol	Suppress	InnoZen
10	Benzocaine/Menthol	Chloraseptic	Prestige
11	Clonazepam	Klonopin Wafers	Solvay Pharmaceuticals

Acknowledgment

Authors are very much thankful to Faculty of Pharmacy, Bahauddin Zakariya University and Higher Education Commission Pakistan for providing the search opportunities.