The Buccal Drug Delivery System Biology Essay

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Oral drug delivery is the simplest and easiest way of administering drugs. A viable alternative from conventional oral dosage form is the buccal mucosa for local disease treatment (oral cavity pathologies, such as gingivitis, periodontitis, stomatitis, dental diseases, oral ulcers, bacterial, and fungal infections), as well as systemic administration especially of hydrophilic macromolecular therapeutic agents (such as peptides, proteins, and polysaccharides). Attempts have been made earlier to formulate various buccoadhesive devices, including tablets , films, patches, disks and strips. Natural polysaccharides have been widely used as bioadhesive polymers because of their biocompatibility and biodegradability properties. A wide range of polymers of synthetic, semi synthetic and natural origin like carbopol, polucabophill, sodium carboxymethylcellulose(SCMC), xanthan and hydroxyl propyl methylcellulose have been described for the formulation of bioadhesive systems.

KEYWORDS: buccal drug delivery, mucoadhesive, polymers, formulation

INTRODUCTION

Various routes of drug delivery such as oral, parental, transdermal, nasal are used to deliver the drugs to the systemic circulation[1].Oral drug delivery is the simplest and easiest way of administering drugs [2].But it has certain disadvantages such as hepatic first pass metabolism, gastric irritation, and enzymatic degradation within the gastrointestinal tract have been noted [3-5].Conventional formulations for local oral delivery are principally lozenges, mouthwashes, mouth paints, oral gels, pastes and suspensions. Release of drugs from these preparations involves an initial burst of activity, whose level rapidly declines to sub-therapeutic concentrations [6,7].

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Recent approaches to increasing the gastric residence time of drug delivery systems include bioadhesive devices, swelling devices that increase their size, low density devices, floating systems, high density systems, magnetic systems, unfoldable and expandable systems, superporous, biodegradable hydrogel systems and microparticulate systems [8,9].

Hence a viable alternative from conventional oral dosage form is the buccal mucosa for local disease treatment (oral cavity pathologies, such as gingivitis, periodontitis, stomatitis, dental diseases, oral ulcers, bacterial, and fungal infections), as well as systemic administration especially of hydrophilic macromolecular therapeutic agents (such as peptides, proteins, and polysaccharides) [10-13].

ADVANTAGE OF BUCCAL FORMULATIONS[10].:

Good accessibility for application and removal of a drug delivery device in emergencies

Route is well vascularized with venous blood draining the buccal mucosa reaching the heart directly via the internal jugular vein[3]

High permeability and faster, richer and higher blood flow

Lesser thickness of the buccal mucosa versatility in designing unidirectional or multidirectional release system for local or systemic action[14, 15]

Enhanced bioavailability[14, 16]

Rapid onset of action[14, 17]

Sustained delivery[3]

resistance to external stresses

problems such as high first-pass metabolism and drug degradation in the harsh gastrointestinal environment can be circumvented by administering the drug via the buccal route [16, 18, 19]

buccal drug absorption can be promptly terminated in case of toxicity by removing the dosage form from the buccal cavity[16]

Extended-release dosage forms with prolonged residence times in the stomach are highly desirable for drugs with narrow absorption windows, stability problems in the intestinal or colonic environments, locally acting in the stomach, and poor solubility in the intestine [8]

It permits the localization of the delivery system.

Patients are well adapted to oral administration of drugs.

Patient acceptance and compliance is good compared to other drug delivery system.

Its ability to easily recover after local treatment is prominent.

Allows a wide range of formulations that can be used e.g. buccoadhesive patches and ointments.

Drug is easily administered and extinction of therapy in emergency can be facilitated.

Drug release for prolonged period of time.

In unconscious and trauma patient's drug can be administered.

Drugs bypass first pass metabolism so increases bioavailability.

Some drugs that are unstable in acidic environment of stomach can be administered by buccal delivery.

Drug absorption by the passive diffusion.

Flexibility in physical state, shape, size and surface.

Maximized absorption rate due to close contact with the absorbing membrane.

Rapid onset of action. [1]

Various  bioadhesive  mucosal  dosage  forms  have been developed,  which  included  adhesive  tablets1, gels , patches  and more recently films[20]. Drug classes used topically in the mouth include antimicrobials[21], topical corticosteroids[22], local anaesthetics [23], antibiotics [24], and anti-dental caries drugs [25]. Oral candidal infections require prolonged therapy with antifungal agents and hence it may be advantageous to deliver these drugs in a sustained manner[6].

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DISADVANTAGE OF BUCCAL FORMULATIONS[10].:

Most buccal formulations, despite high initial activity, do not allow prolonged action with true efficacy, due to the flushing action of saliva or ingestion of foodstuffs that lead to the need for frequent treatments [4].

Other limitations include[1,27]:

a) Drugs which are unstable at buccal pH cannot be administered.

b) Drugs which have a bitter taste or unpleasant taste or an obnoxious odor or irritate the mucosa cannot be administered by this route.

c) Drug required with small dose can only be administered.

d) Those drugs which are absorbed by passive diffusion can only be administered by this route.

e) Eating and drinking may become restricted.

Mucoadhesion, defined as the ability to adhere to the mucus gel layer, is a key element in the design of these drug delivery systems[16,26]. Hence mucoadhesive dosage forms are used to enhance drug retention in the buccal cavity, reduce the drug dose and the consequent minimization of the degree of systemic side effects.

ADVANTAGE OF MUCOADHESIVE DRUG DELIVERY:

they can be readily attached to the buccal cavity

extended residence time of the drug at the site of application

relatively large permeability of the mucus membranes that allow rapid uptake of a drug into the systemic circulation

enhanced bioavailability of therapeutic agents resulting from the avoidance of some of the body's natural defense mechanisms

ability to retain the drug delivery systems in the desired region of the GI tract

prolong the GI transit time of drugs through a closer contact with the GI membrane and improve the drug absorption, and thus ensuring its optimal bioavailability [2, 28,29.30]

biocompatibility and biodegradability properties [14]

ADVANTAGES OF BUCCAL TABLETS[31]:

Oral disintegrating tablets and oral jerry preparations have been developed for patients with dysphagia or aphagia[32-34]

The jerry preparations have an advantage of taking without choke and are useful for elderly patients but are bulky in many cases

Oral disintegrating tablets are readily disintegrated but the disintegrated materials are insoluble and remain until swallowing.

Attempts have been made earlier to formulate various buccoadhesive devices, including tablets [35], films [36], patches [37], disks [38] and strips [39]. Natural polysaccharides have been widely used as bioadhesive polymers because of their biocompatibility and biodegradability properties. These polymers swell in aqueous media to form a gel through which the drug has to diffuse thus; they can also be used to control the rate of drug release. However, buccal films are preferable over adhesive tablets. [16]

ADVANTAGES OF BUCCAL FILMS[18]:

Buccal films are preferable over adhesive tablets in terms of flexibility and comfort and used as oral care products [18,19] [19, 32,40,41]

These preparations easily dissolve in saliva, thereby requiring no water to take[32]

Several benefits due to its small size, thickness and improved patient compliance compared to and delivery been tablets gels [14, 42]

The oral disintegrating thin film preparation appears to be useful for patients with eating and swallowing disturbance[32]

Fast-dissolving thin polymer films for rapid oral delivery are becoming an increasingly popular formulation option because of their wide and varied benefits. The films are designed to dissolve upon contact with a wet surface, such as the tongue, within a few seconds, meaning the consumer can take the product without the need for additional liquid. This convenience provides both a marketing advantage and increased patient compliance. Rapid dissolution is assured because the polymeric matrix is predominantly amorphous and the drug is dispersed throughout it, either as a molecular dispersion or as discrete particles[43]

ADVANTAGES OF BUCCAL PATCHES[6]:

Highly flexible

Much more readily tolerated by the patient than tablets

Ensure more accurate dosing of the drug compared to gels and ointments.

ADVANTAGES OF BUCCAL PELLETS[2]:

Most commercial coatings of buccal pellets suffer from the problems such as the use of toxic organic solvents, high-energy consumption and aging phenomena during storage [44, 45]. Hence buccal pellets dry-coated with bioadhesive polymers provide an attractive alternative [46]. Also, due to the absence of large amounts of solvents or water, the processing times are much shorter [47, 48].

Dry powder technique is noted to impart mucoadhesive function and rapid release of poorly soluble drugs.

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CRITERIA FOR DEVELOPMENT OF BUCCAL DRUG DELIVERY SYSTEM[14]:

Size of 1-3 cm

Daily dose of 25 mg or less

Maximal duration of buccal delivery: approximately 2-6 h [49]

Utilization of the polymers with suitable physicochemical properties, such as bioadhesive, viscous, hydrogen binding property or hydrophobic interaction, biocompatibility, etc.[50- 52]

FORMULATION[43]:

Coating and matrix formation can be employed for protection of various solid dosage forms like tablets, pellets, granules and powders[1,53]. Buccoadhesive patch should be flexible, elastic, soft and strong to withstand breakage due to stress from mouth activities. Buccal patches also show good buccoadhesive strength so that it can be retained in the mouth for a desired duration. There are critical and essential evaluation of buccal patches such as mucoadhesion, swelling properties and mechanical properties.

Bioadhesive polymers are used to control the buccal drug delivery due to their ability to localize the dosage form in specific regions to enhance drug bioavailability[1].

Formulation of these systems is usually straightforward; the polymer and drug are dissolved (or dispersed) in a solvent (often ethanol or water) and a film is cast by solvent evaporation. Because of the high molecular weight of the polymer, films are frequently amorphous and may have complicated physical forms. In the simplest cases the films may be monophasic (if the drug is molecularly dispersed) or multiphasic (if the drug is dispersed as discrete particles); depending on solubility and miscibility factors, drug-rich or drug-poor regions may also exist. In any case they are described by the term solid dispersion. From a pharmaceutical perspective, determining the stability of the film is of critical importance if the formulation is to be commercially viable. If the API is freely soluble in the polymer then the system should have excellent physical stability. If the API is not freely soluble in the polymer and is present at a supersaturated concentration then stability is an issue; it is likely that the API will phase-separate from the polymer phase and subsequently crystallise. Since crystallisation of a dispersed component necessarily requires movement of molecules, molecular mobility and diffusion rates will be central to the stability profile of the system; this means that both the storage temperature and the level of residual solvent in the system will be important. Monitoring the stability of these products is not straightforward. Visual inspection of the formation of crystals over time is possible, but requires a significant fraction of crystallisation to have occurred. Many classical analytical techniques cannot make measurements directly on heterogeneous samples where, as in this case, maintenance of physical form during the experiment is paramount. Differential scanning calorimetry (DSC) is widely used to study crystallisation of polymers, but its use is limited in cases such as the thin films discussed here where only the minor fraction of a sample is crystallising, simply because of the small sample mass of a typical experiment.

Recent approaches to increasing the gastric residence time of drug delivery systems include bioadhesive devices, swelling devices that increase their size, low density devices, floating systems, high density systems, magnetic systems, unfoldable and expandable systems, superporous, biodegradable hydrogel systems and microparticulate systems. Floating and bioadhesive drug delivery systems have advantages such as efficient absorption and enhanced bioavailability of drugs owing to a high surface-to-volume ratio, a much more intimate contact with the mucus layer, and specific targeting of drugs to the absorption site[8,9].

A wide range of polymers of synthetic, semi synthetic and natural origin like carbopol, polucabophill, sodium carboxymethylcellulose(SCMC), xanthan and hydroxyl propyl methylcellulose have been described for the formulation of bioadhesive systems but none of these polymer possess all the characteristics of an ideal polymer for a bioadhesive drug delivery system.

Chitosan unique, non-toxicity, antimicrobial characteristic, solubility, polycationic character, physical attributes, biocompatibility and biodegradability make it an attractive biopolymer for many pharmaceutical and biomedical applications 8, ointments[21].

Various mucoadhesive polymers can broadly be categorized as follow[54]:

(I) Synthetic polymers:

1. Cellulose derivatives (Methylcellulose, Ethyl cellulose, Hydroxy ethyl cellulose, Hydroxyl propyl cellulose, Hydroxy propyl methylcellulose, Sodium carboxy methylcellulose).

2. Poly (Acrylic acid) polymers (Carbomers, Polycarbophil).

3. Poly hydroxyl ethyl methylacrylate.

4. Poly ethylene oxide.

5. Poly vinyl pyrrolidone.

6. Poly vinyl alcohol.

(II) Natural polymers:

1. Tragacanth

2. Sodium alginate

3. Guar gum

4. Xanthan gum

5. Soluble starch

6. Gelatin

7. Chitosan

POLYMER

PROPERTIES

ADVANTAGE/APPLICATION

Chitosan

Chitosan a derivative form of chitin is a naturally occurring biopolymer. Chitosan is a linear polysaccharide composed of randomly distributed ß (1-4)-linked D-glucosamine (deacetylated unit) and Nacetyl-D-glucosamine (acetylated unit). Commercial chitosan is derived from the shells of shrimp and other sea crustaceans, including Pandalus borealis[55].

Properties of chitosan[56]

1. Used in trans-dermal drug delivery.

2. Mucoadhesive nature

3. Chitosan ability to produce many different form when.

4. In drug delivery, it shows positive charge under acidic conditions.108

5. Chitosan is insoluble in neutral and basic environments.

6. Chitosan may form many translational metal ions.

7. Ability to attach itself to other molecules.

8. Ability of specific cellular action for target drugs.

9. It has bacteriostatic and fungistatic effect.

Advantage of chitosan[57]

Chitosan have good biocompatibility and low toxicity that makes it a good pharmaceutical excipient in both conventional and novel applications.

12

Application of chitosan[58-63]

Various applications of chitosan and its derivatives in pharmaceutical field:

1. It is a good diluent for direct compression of tablets formulation.

2. It is used as binder for wet granulation.

3. Chitosan shows controlled release of drugs from tablets, granules and in film.

4. It increases viscosity in solutions during hydrogels preparation.

5. Chitosan improves the dissolution of poorly soluble drugs and enhances the absorption of drug in nasal and oral drug delivery system.

6. A novel mucoadhesive polymer used for transmucosal drug delivery system

7. Microcrystalline chitosan has high capacity for retaining water so this is advantageous in development of slow release formulation, formulation of gels that control drug release.

8. The hydrophilic nature of microcrystalline chitosan aid in, controlling rate of drug release for

mucoadhesive formulations in stomach.

9. The cationic form of chitosan polymer has potential for DNA complexation and could be useful for non viral vectors for gene therapy.

Chitosan protects DNA against DNAase degradation.

Guar gum

Guar gum is naturally occurring form of galactomannan and also called guaran[64]. It is primarily ground endosperm of guar beans. Guar gum contains about 80% galactomannan, 12% water, 5% protein,

2% acid soluble ash, and 0.7% fat. The molecular weight of guar gum is approximately 1 million thatgive high viscosity in solution. The high viscosity of guar gum is due to its long chain structure and high molecular weight. Guar gum is a polysaccharide composed of the sugars galactose and mannose. [65-67]

Properties of guar gum

Guar gum is rapidly soluble in cold and hot water but insoluble in many organic solvents. Guar gum has excellent properties such as emulsifying agent, thickening, stabilizing and film forming agent. Guar gum has ability to control rheology by water phase management. The viscosity of guar gum is affected by temperature, pH, salts and other solids[68]. Guar gum is used in colon delivery due to its drug release retarding property. Guar gum has also susceptable to microbial degradation in the large intestine[69].

Pharmaceutical Application

In the pharmaceutical industry guar gum is used as binder or as disintegrates in tablets. It is also used in some bulk-forming laxatives. In cosmetics and toiletries industries, guar gum is applicable as thickener in toothpastes and conditioner in shampoos.

Tragacanth

Tragacanth is a natural gum obtained from the dried juice of several species of the genus Astragalus, including A. adscendens, A. gummifer, A. brachycalyx and A. tragacanthus. [70,71]

Tragacanth gum is a viscous, odorless, tasteless and water-soluble mixture of polysaccharides.

Pharmaceutical application of Tragacanth

1. It is used as adhesive agent for tablets and pills.

2. Tragacanth used as emulsifying oil droplets in creams, paste and lotions.

3. Used as thickening agent.

[72]

Sodium alginate

Alginic acid or alginate is an anionic polysaccharide, also called as algin and obtained in the cell walls of brown algae. It has ability of binding with water and forming a viscous gum. Alginic acid is capable of absorbing 200-300 times its own weight in water when water extracted from alginate.

[73]

Alginate is mainly extracted from seaweed. Alginic acid is mainly produced by two bacterial genera such as Pseudomonas and Azotobacter. These play an important role in the preparation of its biosynthesis pathway. [74]

Sodium alginate is the sodium salt of alginic acid. Its formula is NaC6H7O. Sodium alginate is a gum which extracted from the cell walls of brown algae. Sodium alginate is slowly soluble in water and insoluble in ethanol and ether.

Pharmaceutical application of sodium alginate

1. It is flavorless gum and used to increase viscosity in the food industry.

2. It is used as emulsifier.

3. Used in indigestion tablets and the preparation of dental impressions.

4. It is used for pulling radioactive toxins from the body because of their good chelating property.

5. It is also used in immobilizing enzymes by inclusion.

[75,76]

EVALUATION OF CERTAIN BUCCAL DRUG DELIVERY SYSTEMS:

CARVEDILOL [16]

(mucoadhesive buccal patches with interpolymer complexes of chitosan-pectin)

The bioadhesive patches displayed sufficient bioadhesive strength and in vitro drug release. The optimized patch with interpolymer

complex of CH-PE in ratio of 20:80 showed an increased bioavailability of about 2.14 times when compared to oral route. The buccal delivery of carvedilol in rabbits showed a significant improvement in bioavailability of carvedilol from patches when compared to oral route.

RIZATRIPTAN BENZOATE[14]

(tamarind seed xyloglucan-based

Mucoadhesive buccalfilms)

Cheap and abundantly available natural polysaccharide TSX could be a promising vehicle for systemic delivery of a soluble drug like RB through route. The in vitro studies have shown that this is a potential drug delivery system for RB with considerable good stability and release profile. But, in vivo studies in future would be needed to confirm these results.

MICONAZOLE [20]

(mucoadhesive buccal films)

Chitosan film formulation can be considered as a successful candidate for miconazole buccal film since it showed significant enhancement of

miconazole in vitro release and antifungal activity against Candida albicans in comparison to the reference

LIDOCAINE [10]

(mucoadhesive multiparticulate patch)

Absorption of the drug through a model mucosa occurs without problems, while the presence of a second layer of ethylcellulose provides unidirectional release.

Multiparticulate systems prepared embedding lidocaine as solid dispersion with Compritol in the gel matrix allow control and bimodal release of the drug; this system appears very promising for interesting developments.

GLIPIZIDE[8]

(mucoadhesive films)

Glipizide/hydroxypropyl cellulose/PEG 400 (2.5:1:0.5) (GF5) was found to be the optimal composition for a novel mucoadhesive stomach formulation that showed good peelability, relatively high swelling index, moderate tensile strength,

and stayed on rat stomach mucosa up to 8 h. In vivo testing

of the mucoadhesive films with glipizide demonstrated a potential hypoglycemic effect. The results obtained during this investigation suggest that glipizide muco adhesive films possessed desirable aesthetic, pharmaceutical and biological properties.

The in vivo study demonstrated potential hypoglycemic activity of the mucoadhesive film with glipizide.

DEXAMETHASONE [31]

(fast dissolving oral thin film)

A possible application to antiemesis during cancer chemotherapy.

The preparation revealed excellent uniformity and stability of dexamethasone and rapidly disintegrated in water. There were no significant differences in pharmacokinetic parameters obtained from rats with oral administration of dexamethasone suspension and those with topical application of the film to the oral cavity. Therefore, the present fast-disintegrating oral film containing dexamethasone is considered to be potentially useful for cancer patients with disturbance in eating and swallowing who receive radiotherapy and/or high- to moderate emetogenic anticancer drugs.

TETRACAINE [77]

(oral gel)

It was used in in patients treated with radiotherapy

for head-and-neck cancer: final results of a phase II study

The results of our study showed that tetracaine oral gel

reduced mucositis-related oral cavity pain in a sizeable proportion of treated patients receiving radiation for headand-neck cancer without relevant side effects. In our opinion, local application of anesthetic agents should be encouraged but larger prospective randomized trials are required to confirm these data.

DIBUCAINE [78]

(Pain relief of oral ulcer by film)

When the affected site was highly moist due to the ulceration, the film fell off the affected sites or was moved from its initial position due to uncontrolled slipping. The three-layered HPC film reported here has improved the clinical applicability of this preparation. The addition of ethyl cellulose prevented sticking to the fingers during application; the addition of pectin increased its adhesive strength to the mucous. Dibucaine did not give rise to any complaints about the taste of the film

It provided effective pain relief when used on oral ulcers and we consider that this film may improve the quality of life of patients with eating dysfunction and help maintain their physical strength.

DILTIAZEM HYDROCHLORIDE[3]

(Buccal Mucoadhesive Films)

It is an antihypertensive.

buccal mucoadhesive film formulations containing diltiazem hydrochloride had been prepared with satisfactory physicochemical characterizations. The release patterns and

bioadhesion properties can be controlled by changing the polymer type and concentration. The diltiazem hydrochloride administered to healthy rabbits via buccal route showed a significant improvement in bioavailability when compared to oral route. This increased bioavailability of diltiazem hydrochloride from designed formulations may also result in substantial dose reduction. The present study indicates a good potential of the prepared buccal mucoadhesive films containing diltiazem hydrochloride for systemic delivery with added advantages of circumventing the hepatic first pass metabolism and substantial dose reduction. This study confirmed the potential of the above buccal dosage forms as a promising candidate for buccal delivery of diltiazem hydrochloride.

PROCHLORPERAZINE[79]

(oral disintegrating film)

None of the parameters, including Tmax, Cmax, area under curves, clearance and steady-state distribution volume was significantlydifferent between oral disintegrating film and oral solution. These findings suggest that the present

prochlorperazine-containing oral film is potentially useful to control emesis induced by anti-cancer agents

or opioid analgesics in patients who limit the oral intake.

MICONAZOLE NITRATE[6]

(Mucoadhesive buccal patches)

Study of the in vivo release from this formulation revealed uniform and effective salivary levels with adequate comfort and

compliance during at least 6 h. On the contrary, in vivo release of the commercial oral gel product resulted in a burst and transient

release of miconazole, which diminished sharply after the first hour of application. Storage of these patches for 6 months did

not affect the elastic properties, however, enhanced release rates were observed due to marked changes in the crystal habit of

the drug.

VALSARTAN [2]

(mucoadhesive pellets containing prepared by a dry powder-coating technique)

The coated pellets displayed distinct mucoadhesive property in vitro and delayed gastrointestinal (GI) transit in vivo. Furthermore, the coated pellets exhibit significantly higher AUC(0-12 h) and Cmax, as compared to the core pellets and drug suspension. It was concluded that

the mucoadhesive pellets could render poorly water soluble drugs like VAL with a rapid drug release,

delayed GI transit and enhanced oral bioavailability.

GINSENOSIDE RB1 [80]

(oral mucosal adhesive films on

5-fluorouracil-induced oral mucositis in hamsters)

there were significant differences between doses of 10−6

and 10−4 g/g film. These results suggest that topical application of films that contain ginsenoside

Rb1 has a healing effect on severe oral mucositis induced by chemotherapy.

LIMITATIONS OF BUCCOADHESIVE DRUG DELIVERY[1]: -

There are some limitations of buccal drug delivery system such as

a) Drugs which are unstable at buccal pH cannot be administered.

b) Drugs which have a bitter taste or unpleasant taste or an obnoxious odor or irritate the mucosa cannot be administered by this route.

c) Drug required with small dose can only be administered.

d) Those drugs which are absorbed by passive diffusion can only be administered by this route.

e) Eating and drinking may become restricted.

APPLICATION

Patients with oral carcinoma usually develop acute radiation-induced oral mucositis during radiation therapy. This is a very painful condition that seriously affects the patient's quality of life because it makes oral feeding painful and difficult, further hampering efforts to improve the general condition of the patient. Consequently, it is important to develop an effective therapy for this adverse effect of radiation therapy. To keep good oral hygiene, rinses are effective in cleaning off mucosal debris before the application of therapeutic agents. Topical anesthetics and systemic nonnarcotic or narcotic analgesics are required for almost all patients. Anti-microbial agents are necessary to treat secondary oral or submucosal infections. Topical coating agents are effective, not only in prompting healing of the mucosal wound, but also in delivering therapeutic agents to the compromised oral soft tissues. Palatable, nutritional foods that do not traumatize the oral mucosa are also an important part of treatment. However, although these supportive measures have been widely encouraged, the results have not been successful. Therefore, we aimed to find a way to treat patients with radiation-induced oral mucositis more effectively and safely. The usefulness of the watersoluble polymer mucosa-adhesive film (AD film) on che-motherapy- or radiation-related mucositis was originally reported by a group of researchers from the Department of Pharmacy, Nagoya University Hospital, Nagoya, Japan[81].

Oral ulceration is common in patients who have undergone chemotherapy and/or radiotherapy. It often causes severe discomfort, interferes with the ability to sleep, interferes with eating and drinking, and may require interruption of therapy until the pain becomes tolerable [82]. Topical treatment is an effective and safe method delivering anesthetic agents to the mucosal area [83]. The present commercial local anesthetic preparations such as lotions, gels or ointments are easily displaced from the affected area and demonstrate limited effectiveness due to their brief activity [84]. Several studies have examined oral mucosal adhesive systems containing lidocaine to prolong pain relief. However, the systems may cause irritation to the damaged mucosa because they must be removed from the application site after extraction of lidocaine[85-87][78].

Mucositis is the most common oral complication in nonsurgical therapy of head-and-neck cancer. It represents the main dose-limiting acute toxicity for these patients. No therapy has thus far been found to be efficacious in reducing mucositis or mucositis-associated pain in patients treated with radiotherapy for head-and-neck cancer [77,80].