WO2009043588A2

WO2009043588A2 - Ph regulating antibacterial films for the oral or vaginal cavity

Info

Publication number: WO2009043588A2
Application number: PCT/EP2008/008391
Authority: WO
Inventors: Giorgio Reiner; Nadia Giarratana; Valentina Reiner; Ulrich Becker; Amin Breitenbach; Peter Klaffenbach
Original assignee: APR Applied Pharma Research SA; Labtec Gesellschaft fuer Technologische Forschung und Entwicklung mbH; Labtec GmbH
Current assignee: APR Applied Pharma Research SA; Labtec Gesellschaft fuer Technologische Forschung und Entwicklung mbH; Labtec GmbH
Priority date: 2007-10-02
Filing date: 2008-10-02
Publication date: 2009-04-09
Anticipated expiration: 2010-04-02
Also published as: WO2009043588A3

Abstract

The present invention relates to antibacterial films that may regulate pH and control bacterial growth in the oral or vaginal environment and methods of use thereof. The films may include a pH adjusting ingredient, an antimicrobial essential oil, and a polymer. The polymer may include polyvinyl alcohol, polyethylene glycol, and rice starch. The oral films and methods of use may prevent tooth decay, and the vaginal films and methods of use may treat infections in the vagina.

Description

PH REGULATING ANTIBACTERIAL FILMS FOR THE ORAL OR

VAGINAL CAVITY

CROSS REFERENCE TO RELATED APPLICATIONS

[001 ] This application claims benefit of U.S. Provisional Application No. 60/976,819, filed October 2, 2007. The application is incorporated herein by reference.

FIELD OF THE INVENTION

[002] The present invention relates to antibacterial films, and more particularly relates to antibacterial films that regulate pH and control bacterial growth in the oral or vaginal environment. BRIEF DESCRIPTION OF THE DRAWINGS

[003] FIG. 1 is an illustration showing a normal tooth and a tooth with three types of cavities.

[004] FIG.2 is a graph showing the pH of dental plaque at various times before and after a glucose mouth rinse and before and after tooth brushing.

[005] FIG. 3 is a graph showing the pH of dental plaque at various times after a rinse with sucrose solution.

[006] FIG. 4 is a graph showing the effect of saliva restriction on the pH of dental plaque at various times after a rinse with sucrose solution.

[007] FIG. 5 is a graph measuring the cariogenic challenge to a tooth after a rinse with sucrose solution.

[008] FIG. 6 is a graph measuring a series of carogenic challenges over a typical 24 hour period.

[009] FIG. 7 is a graph showing the bacterial count of human saliva in response to the application of one embodiment of the antibacterial films described herein.

[010] FIG. 8 is a graph showing the bacterial count of human saliva in response to the application of one embodiment of the antibacterial films described herein.

[011] FIG. 9 is a graph showing the pH of an acidified water solution in response to the application of one embodiment of the antibacterial films described herein.

[012] FIG. 10 is a diagram showing the pH of the mouth before coffee drinking, after coffee drinking, and after the application of one embodiment of the antibacterial films described herein.

[013] FIG. 11 is a diagram showing the pH of the mouth after eating an apple, and after the application of one embodiment of the antibacterial films described herein.

[014] FIG. 12 is a graph showing the pH of an artificial saliva solution in response to the application of one embodiment of the antibacterial films described herein. BACKGROUND OF THE INVENTION

I. Health Problems of the Oral Cavity

[015] Cavities (dental caries) are decayed areas in the teeth, the result of a process that gradually dissolves a tooth's hard outer surface (enamel) and progresses toward the interior. Fig. 1 shows a normal tooth and a tooth with three types of cavities.

Etiology and Pathophysiology

[016] Caries are caused by acids produced by bacteria retained within dental plaque. Plaque is, at first, a soft, thin film of food debris, mucin, dead epithelial cells, and bacteria that develops on the tooth surface within about 24 hours after the tooth is cleaned. Streptococci mutans is a group of related bacteria causing caries. Some strains are more cariogenic than others. Eventually, the soft plaque becomes hard with calcium and other minerals (hard plaque), and cannot easily be removed with a toothbrush. [017] Many teeth have open enamel pits, fissures, and grooves, which may extend from the surface to the dentin. These defects may be wide enough to harbor bacteria, yet too narrow to effectively be cleaned. Thus, these defects may predispose teeth to caries. Untreated caries lead to tooth destruction, infections, and the need for extractions and replacement prostheses.

[018] A tooth surface is more susceptible to caries when it is poorly calcified or in an acidic environment. Typically, decalcification begins when the pH at the tooth falls below 5.5 (as occurs with colonization by acid-producing bacteria and/or with the drinking of cola beverages containing phosphoric acid).

Biochemistry Of Caries Formation

[019] Dental caries are caused when oral bacteria on vulnerable parts of the tooth are exposed to fermentable carbohydrates. Fig. 2, a classic graph known as Stephan's Curve, shows the rapid drop in plaque pH after oral bacteria are exposed a glucose rinse. The drop in pH is the result of fermentation of carbohydrates by some plaque bacteria. The gradual return of the pH is the result of natural buffers present in plaque and saliva. Provided the pH does not drop below 5.3 the enamel remains intact, but below this critical level the crystals of apatite (the main constituent of enamel) may dissolve. Fortunately, both plaque and saliva are saturated with calcium and phosphate ions, so that if the pH returns fairly rapidly above the 5.3 level, ions will go back into the enamel and recrystallize. This process of remineralization takes longer in an acidic environment, but is rapid if the fluid next to the enamel is neutral or even alkaline. Caries are therefore uncommon in those parts of the mouth near the outflow of salivary glands, like the lower incisors, where the teeth are constantly bathed with the buffers and concentrated calcium ions of saliva. If the total outflow of saliva is increased, there is a greater chance of protection of all the teeth in the arch. Some foods, like cheese, stimulate the flow of saliva. Sugar also is a good stimulator of saliva, but also provides the most favored nutrients for plaque bacteria. However, sugar substitutes, while of no use to bacteria, also are effective saliva stimulants, as is the mere act of chewing. Thus, chewing a gum which is artificially sweetened is helpful in arresting caries.

[020] If the flow of saliva is reduced as it is every night, the oral environment is particularly susceptible to plaque acids. Sweets at bedtime thus have a far greater impact on acid production than sweets do during the day.

[021] Fig. 2 shows the effect of tooth brushing on the pH reached by plaque after a second glucose mouth rinse. At (1), the pH drops due to acid produced by bacteria fermenting the sucrose. Once the pH reaches 5.3, enamel begins to dissolve. At (2), the pH rises due to the buffering action of plaque and saliva. At (3), one side of the arch is brushed and the pH rises to a neutral value of 7.0. At (4), a second glucose rinse causes the plaque pH on the unbrushed side to drop below 5.3. The pH of the brushed side also drops, but not below the critical pH level (After Stephan and Miller, 1943). [022] For this reason, reducing the plaque mass raises the resting pH and reduces the downward dip of the curve after a second glucose rinse. The mass of plaque bacteria can also be reduced with antibacterial mouthwashes such as chlorhexidine. Early Enamel Caries

[023] Enamel is almost entirely mineral by weight (96%) but only 87% mineral by volume. Thus, 13 % of the space in enamel is water and soluble and insoluble proteins. The organic and water component of enamel allows diffusion of ions from plaque and saliva into and out of enamel. The mineral part of enamel consists mostly of varieties of biological apatites.

[024] There is evidence that an early lesion in enamel can be reversed and remineralized if plaque is removed. Arrested enamel lesions often are seen on an interproximal surface some time after an adjacent tooth is extracted. Simply making the area more self cleansing helps to reduce plaque mass. Fluoride accumulates in remineralizing enamel, making the enamel more resistant to subsequent acid attack.

Microbiology Of Dentine Caries

[025] Although a large number of organisms have been isolated from dental caries, a few genera have been found to predominate. The most frequently isolated are the members of the Streptococci spp., and in particular S. mutans in occlusal and smooth surface caries. Actinomyces spp. are the dominant genus in root surface caries. Deep dentinal caries show a predominance of Lactobacillus organisms with several other gram positive rods and filaments.

Stephan 's Curve

[026] Stephan' s Curve describes the change in dental plaque pH in response to a challenge. The type of challenge is usually some element of the diet. However, the challenge could be an inert substance placed in the mouth with the aim of determining its effect on plaque pH (for example, mechanical stimulation of the salivary glands caused by masticating a chewing-gum base). This would be of interest in an investigation into the effect of saliva flow on the pH-changes in plaque after a challenge by a cariogenic food. [027] Fig. 3 illustrates the characteristics of Stephan's Curve. In this example, dental plaque was challenged with a fermentable carbohydrate by asking a healthy volunteer to rinse his mouth with lOmls of 10% sucrose solution for 10 seconds. Average plaque samples were removed at intervals and the pH recorded.

[028] Characteristically, Fig. 3 (Stephan's Curve) reveals a rapid drop in plaque pH, followed by a slower rise until the resting pH is attained. The time course varies between individuals and the nature of the challenge. The initial drop is usually rapid with the lowest pH being attained within a few minutes. However, pH recovery can take between 15 and 40 minutes depending to a large extent on the acid-neutralizing properties of the individual's saliva.

The Initial Drop In pH

[029] The initial rapid drop in pH is due to the speed with which plaque microbes are able to metabolize sucrose. Larger carbohydrates, such as starch, diffuse into plaque slowly and must be broken down before assimilation by the microbes. In the case of starch, salivary amylase will produce a mixture of glucose and maltose together with incompletely digested material comprising the branch points of the starch molecule (limit dextrins). The glucose and maltose are then be taken up by plaque bacteria and metabolized. The rate of starch breakdown slows down acid production, producing a less steep drop in pH.

The Lowest pH

[030] The lowest pH achieved depends greatly on several factors:

1. the microbial composition of the dental plaque,

2. the nature of the fermentable carbohydrate source, and

3. the rate of diffusion of substrates and metabolites into and out of the plaque.

[031] Thus, the presence of significant numbers of aciduric, acidogenic bacteria in a sheltered site with a low diffusion rate coupled with a readily fermentable carbohydrate such as sucrose or glucose will produce the lowest pH. Under these conditions a pH level in the range of 4.5, or even lower, may be attained. [032] Conversely, a plaque community with fewer aciduric, acidogenic microbes exposed to a carbohydrate which is metabolized slowly will result in less acid production and a higher terminal pH.

Rate Of Diffusion

[033] The rate of diffusion of material into and out of plaque is governed by the density of the plaque and access by saliva. Less dense plaque fully exposed to saliva flow will more rapidly exchange metabolites with the surroundings. This will enable substrates to diffuse into the plaque rapidly and at the same time allow microbial by-products to diffuse out of the plaque. The terminal pH following a challenge to the plaque will reflect the relative rates of diffusion of both substrate and metabolites.

The Rise In pH

[034] The pH starts to rise after a few minutes due to:

1. acid by-products diffusing out of the plaque, and

2. salivary bicarbonate diffusing into the plaque and neutralizing the acid byproducts.

[035] In addition, the low pH will inhibit microbial metabolism and thereby slow the rate of acid production. This will allow the processes of diffusion and neutralization to exert a greater effect on plaque pH. Also, as before, plaque which is less dense and fully exposed to saliva flow will show a faster rate of pH recovery.

[036] It normally takes at least 20 minutes for the plaque pH to reach its resting value, but it can take considerably longer depending on the factors described above.

Saliva Flow Rate

[037] One of the most important factors governing the overall shape of Stephan's Curve, and in particularly the pH recovery section, is saliva flow rate. The effect of saliva on the Stephan Curve is easily demonstrated by isolating some dental plaque from saliva using cotton wool pads. Fig. 4 is a graph showing the effect of saliva restriction on the pH of dental plaque at various times after a rinse with sucrose solution. [038] Saliva exerts two effects. First, it dilutes and carries away metabolites diffusing out of the plaque. Second, it supplies bicarbonate ions which diffuse into plaque and neutralize the by-products of fermentation (organic acids) in situ. Bicarbonate-mediated acid neutralization is enhanced by the increase in salivary bicarbonate due to increased saliva flow during eating.

[039] Acid neutralization by bicarbonate is accelerated by salivary carbonic anhydrase, an enzyme that catalyzes the following reaction:

HCO₃ ^' + H⁺ -* H₂O + CO₂

[040] Carbonic anhydrase is secreted by acinar cells of the parotid and submandibular glands and is the only example of a secreted carbonic anhydrase in mammals. [041] The scientific value of the Stephan Curve is that it provides a means by which the cariogenic challenge to a tooth may be measured. Fig. 5 shows how cariogenicity may be measured using the area delimited by the critical pH and Stephan's Curve. Fig. 6 shows a graph measuring a series of six separate cariogenic challenges over a typical 24 hour period.

Orally Consumable Films

[042] U.S. Patent No. 6,923,981 to Leung et al. discloses edible films of xanthan gum and pullulan. The films contain the essential oils thymol, methyl salicylate, eucalyptol, and menthol to provide antimicrobial efficacy. The films do not contain a pH adjusting ingredient.

[043] U.S. Patent Publication No. 2006/0198873 to Chan et al. discloses orally dissolving films of Eudragit polymer for delivering nicotine to the mouth. The films comprise an alkaline neutralizing agent to raise the pH of the mouth to alkaline levels so as to enhance the absorption of nicotine through the mouth. The films contain menthol as a flavoring agent only. The films do not contain a combination of essential oils to provide antimicrobial efficacy. II. Health Problems of the Vagina

[044] The vaginal cavity is formed by the fibromuscular tubular tract leading from the uterus to the exterior of the body. A healthy vagina exhibits an acidic pH due to estrogen, vaginal secrete, and typical microflora comprising microorganisms such as Lactobacillus crispatus and Lactobacillus jensenii. The secrete and microflora are important for the physiological function of the vagina and serve to protect the vagina against infections. [045] Unfortunately, conditions in the vaginal environment may allow unwanted organisms to gain a foothold and multiply. For example, antibiotics, stress, immune system defects, alterations in hormone levels, tight clothing, or sexual intercourse may cause an imbalance of the vaginal microflora and/or vagina pH levels so as to allow unwanted organisms to flourish. These organisms may in turn produce toxins which affect the body's natural defences and make re-colonization of healthy bacteria more difficult. [046] One common vaginal infection is bacterial vaginosis (BV), which is a misbalance of the microflora of the vagina characterized by atypical bacteria and/or the unusually high occurrence of certain types of bacteria. The flora associated with BV include Gardnerella vaginalis and anaerobic bacteria such as Prevotella, Mobiluncus, Peptostreptococcus, and genital Mycoplasma. Current treatment of BV consists of the local application of antibiotics and the modification of the pH-value in the vagina (lowering of the pH to 4 to 4.5). By restoring the physiological pH-value, the growth of atypical bacteria is inhibited and the growth of the physiological microflora is promoted.

[046] Another common infection known to occur in 3 out of 4 women at least once a lifetime is vaginal candidosis, otherwise known as a yeast infection. Candidosis is caused by atypical pH-values of greater than 4.5. It has been shown that normal low pH-values inhibit the growth of fungi of the Candida species. Treatment of candidosis is usually performed by the local application of antimycotic substances. Additionally, modification of the pH with suitable acidic substances or specially cultivated bacteria is recommended. [047] It is known from traditional medicine that the essential oil tea tree oil (from, for example, Melaleuca alternifolia) may be effective at killing certain types bacteria, fungi and viruses. For this reason, tea-tree oil has been used to treat yeast infections and bacterial vaginosis. For example, vaginal suppositories containing tea-tree oil have been used by healthcare professionals to treat vaginal infections. However, films containing tea-tree oil have not previously been used to treat yeast infections and bacterial vaginosis. [048] U.S. Patent No. 6,706,276 to Garg et al. discloses methods for preventing sexually transmitted diseases and/or pregnancy by applying a trapping gel to the vagina. The gel contains a buffering agent such as lactic or malic acid to maintain the pH of the vagina within its normal acidic range, and may be applied in a dosage form such as a film. The gel does not contain antimicrobial ingredients such as tea tree oil, and does not significantly impair the natural microbial balance within the vagina.

SUMMARY OF THE INVENTION

[049] The present invention relates to fast dissolving films for simultaneously adjusting pH and lowering the amount of bacteria in the oral or vaginal environments. [050] It is difficult to conveniently control the pH and microbial levels of the oral cavity. Traditional methods of treating the oral environment such as brushing with toothpaste are too inconvenient to be used during many points in the day. Furthermore, the mere placement of an antibacterial ingredient and a pH adjusting ingredient in the mouth may not improve the oral environment, as these ingredients are quickly eliminated from the mouth by mechanisms such as transbuccal absorption and swallowing.

[051] These difficulties are even further magnified by (a) delivering ingredients within a film vehicle and (b) simultaneously delivering an antimicrobial ingredient and a pH adjusting ingredient. Traditional polymer films, although convenient to apply to the mouth, may stick to the surfaces of the oral cavity and thereby enhance the problematic transbuccal absorption of active ingredients. Furthermore, it is well known that pH adjusting ingredients enhance the transbuccal absorption of many active ingredients.

[052] This invention therefore is based on the unexpected discovery that a unique combination of a specific type of film vehicle and particular type and amount of antimicrobial ingredient may be used effectively to reduce the number of bacteria in the oral cavity despite the presence of a pH adjusting ingredient. Those familiar with the art of cavity prevention are familiar with a large number of diverse antimicrobial ingredients. However, it has never been expected that specific types and amounts of these active ingredients may be effective in the presence of a pH adjusting ingredient, and it certainly has never been expected that these particular active ingredients would be effective in the presence of a pH adjusting ingredient within a problematic delivery device such as a film. Likewise, those familiar with the art of oral films are familiar with a large number of diverse film ingredients. However, it has never been expected that a specific type of film vehicle may avoid problematic transbuccal absorption so as to effectively administer both a pH adjusting ingredient and an antimicrobial ingredient.

[053] In one embodiment, the film is a fast dissolving oral film that includes (1) a pH adjusting ingredient in an amount effective to neutralize the pH of the oral cavity, and (2) an antimicrobial ingredient in an amount effective to reduce the number of bacteria in the oral cavity, in the absence of a systemically acting drug. Importantly, the combination of the neutralizing effect of the pH adjusting ingredient and the antibacterial properties of the essential oils provides a useful tool in preventing plaque formation and teeth caries. [054] In another embodiment, the film is a fast dissolving oral film of polyvinyl alcohol (PVA), polyethylene glycol (PEG), and starch that includes (1) a pH adjusting ingredient in an amount effective to neutralize the pH of the oral cavity, and (2) an antimicrobial ingredient in an amount effective to reduce the number of bacteria in the oral cavity. Because of the unique combination of polymer and starch, the film disperses within seconds of being placed in the oral cavity, thus promoting the release of the active ingredients in the mouth. Furthermore, the combination of the neutralizing effect of the pH adjusting ingredient and the antibacterial properties of the essential oils provides a useful tool in preventing plaque formation and teeth caries. In a particular embodiment, the film further comprises a pharmaceutically active agent.

[055] In yet another embodiment, the film is a fast dissolving vaginal film that includes (1) a pH adjusting ingredient in an amount effective to reduce the pH of the vagina to the optimal 4.2-4.5 range, and (2) an antimicrobial ingredient in an amount effective to reduce the number of bacteria in the vagina. DETAILED DESCRIPTION OF THE INVENTION

[056] Improved methods and films have been developed for adjusting pH and lowering the amount of bacteria in the oral or vaginal environments.

[057] Studies of the oral cavity have shown that low pH and high levels of plaque bacteria may cause dental caries in vulnerable parts of the teeth. It has now been discovered that by combining the neutralizing effect of a pH adjusting ingredient and the antibacterial properties of essential oils in a fast dissolving film, one can prevent dental caries quickly and conveniently.

[058] Likewise, studies of the vaginal environment have shown that high pH and changes in the natural flora of vaginal bacteria may result in infections such yeast infections and bacterial vaginosis. It has now been discovered that by combining the acidifying effect of a pH adjusting ingredient and the antibacterial properties of essential oils in a fast dissolving film, one can treat yeast infections and bacterial vaginosis. [059] The present invention may be understood more readily by reference to the following detailed description of preferred embodiments of the invention and the non- limiting Examples included therein.

Definitions

[060] Unless specified otherwise, the term "wt. %" as used herein with reference to the final product (i.e., the film, as opposed to the formulation used to create it), denotes the percentage of the total dry weight contributed by the subject ingredient. This theoretical value can differ from the experimental value, because in practice, the film typically retains some of the water and/or ethanol used in preparation.

The Orally Dissolvable Film

[061] In one embodiment, the orally dissolvable film comprises a pH adjusting ingredient and an antimicrobial essential oil, wherein the pH adjusting ingredient is present in the film in an amount effective to neutralize the pH of the oral cavity, wherein the antimicrobial essential oil is present in the film in an amount effective to reduce the number of bacteria in the oral cavity, and wherein the film does not comprise a systemically acting drug.

[062] The film may be characterized by various physical characteristics, including its structure, size and shape. For example, in one embodiment, the film is a single layer homogeneous film. In another embodiment, the film is a multi-layer film. The film may have a weight of from about 30 to about 150 milligrams, preferably from about 40 to about 120 milligrams. The film may vary in thickness from about 10 to about 200 microns, and preferably does not exceed 7 or 8 cm² in surface area. The characteristics of film may allow the film to be quickly placed in the oral cavity for the convenient prevention of dental caries

[063] The pH adjusting ingredient may comprise essentially any ingredient that is effective to increase the pH of the oral cavity to above a value of approximately 6.0. In particular embodiments, the pH adjusting ingredient is selected from the group consisting of alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkali earth metal carbonates, alkali earth metal bicarbonates, alkali earth metal hydroxides, and combinations thereof. Non-limiting examples of suitable pH adjusting ingredients include sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium phosphate dibasic, sodium phosphate tribasic, potassium phosphate dibasic, potassium phosphate tribasic, calcium carbonate, magnesium carbonate, sodium hydroxide, magnesium hydroxide, potassium hydroxide, aluminum hydroxide, and combinations thereof. In a particularly preferred embodiment, the pH adjusting ingredient comprises sodium bicarbonate.

[064] The pH adjusting ingredient may be present in the film in an amount in the range of about 1% to about 15% by weight. Desirably, the pH adjusting ingredient is present in the film in an amount in the range of about 3% to about 10% by weight, and even more desirably in the range of about 5% to about 8% by weight. In a particularly preferred embodiment, the film will comprise an ingredient having the alkalizing power of from about 2 to about 5 milligrams of sodium bicarbonate, and even more preferably about 3 milligrams of sodium bicarbonate. The amount of pH adjusting ingredient may be sufficient to prevent the decay of teeth in the oral cavity. Furthermore, the amount of pH adjusting ingredient may be low enough to prevent the pH of the mouth from rising into undesirable alkaline levels that may result in transbuccal absorption of the ingredients in the film.

[065] The antimicrobial essential oil may comprise any essential oil that is effective to reduce the number of bacteria in the oral cavity. Non-limiting examples of suitable essential oils include eucalyptus oil, menthol, peppermint oil, crisp mint oil, spearmint oil, Pelargonium sidoides root extract, and combinations thereof. [066] The antimicrobial essential oil may be present in the oil in an amount in the range of about 0.1% to about 10% by weight. Desirably, the pH adjusting ingredient is present in the film in an amount in the range of about 1% to about 8% by weight, and even more desirably in the range of about 2% to about 5% by weight. In one embodiment, the film will comprise eucalyptus oil in an amount in the range of about 0.1% to about 10% by weight, and even more desirably in an amount of approximately 0.5% by weight. In a particularly preferred embodiment the film includes from about 0.05 milligrams to about 3.0 milligrams of eucalyptus oil, and even more preferably from about 0.1 to about 0.5 milligrams of eucalyptus oil. Importantly, the amount of essential oil is effective to reduce the number of bacteria in the oral cavity, and not merely an amount sufficient to flavor the film.

[067] Desirably, the film comprises one or more polymers that act as water soluble binding agents and/or hydrophilic polymers. Non-limiting examples of suitable polymers include polyvinyl alcohol, polyethylene glycol (PEG), propylene glycol, polyethylene oxide, and starches, celluloses, gelatins and the like. The film preferably comprises from about 40 to about 80 wt.% of these ingredients, and more preferably from about 50 to about 75 wt.%. The formulation may be surfactant free, or it may contain one or more surfactants.

[068] The polyvinyl alcohol in the polymer may be hydrolysed to a degree that allows the film to be more easily manufactured, packaged, and/or administered. For example, the polyvinyl alcohol may be hydrolysed to a degree that allows the film to be rigid but not overly brittle. In one embodiment, the degree of hydrolysis of the polyvinyl alcohol is less than 90% so as to avoid brittleness. In a particular desirable embodiment, the degree of hydrolysis of the polyvinyl alcohol is in the range of about 70%-90%, and even more desirably about 88%. The use of polyvinyl alcohol with a degree of hydrolysis below 90% may provide the film with fUrther advantageous properties such as increased solubility, increased flexibility, increased water sensitivity, increased adhesion to hydrophobic surfaces, and/or decreased adhesion to hydrophilic surfaces. [069] Additionally, the polyethylene glycol in the polymer may have a molecular weight that allows the film to be more easily manufactured, packaged, and/or administered. For example, the polyethylene glycol may have a molecular weight that allows the film to be more flexible (i.e. more plasticized). In one embodiment, the average molecular weight of the polyethylene glycol is in the range of about 500 to about 1500 daltons, and even more desirably about 1000 daltons (referred to herein as PEG 1000).

[070] The film may comprise glycerol as an additional ingredient in the film. The glycerol may soften the film and allow it additional flexibility. In one embodiment, the glycerol is present in the film in the range of about 0.5% to about 5% by weight, and even more desirably about 2% by weight.

[071] In a particular embodiment, the polymer in the orally dissolvable film comprises (1) polyvinyl alcohol in an amount in the range of about 40% to about 60% by weight, (2) polyethylene glycol in an amount in the range of about 10% to about 20% by weight, and (3) rice starch in an amount in the range of about 15% to about 30% by weight. In a particularly preferable embodiment, the polymer comprises (1) approximately 50% polyvinyl alcohol by weight, (2) approximately 15% polyethylene glycol by weight, and (3) approximately 20% rice starch by weight. The polymer composition of the film may allow the film to quickly dissolve in the mouth without adhering to the mucosal surface of the oral cavity, so as to prevent the transbuccal absorption of the ingredients in the film.

[072] In particular embodiments, the film comprises at least one of the following additional ingredients: water, antimicrobial agents, water soluble diluents such as plasticizing agents, softeners and fillers, flavoring agents, saliva stimulating agents, cooling agents, stabilizers, surfactants, stabilizing agents, emulsifying agents, thickening agents, binding agents, coloring agents, sweeteners, fragrances, triglycerides, preservatives, polyethylene oxides, propylene glycol, and the like. Oral Films Comprising Ondansetron

[073] In another embodiment, the orally dissolvable film comprises (a) a polymer, and (b) ondansetron or a pharmaceutically acceptable salt thereof, wherein the polymer comprises (1) polyvinyl alcohol in an amount in the range of about 30% to about 50% by weight, (2) polyethylene glycol in an amount in the range of about 5% to about 15% by weight, and (3) rice starch in an amount in the range of about 10% to about 30% by weight. In a particular desirable embodiment, the polymer comprises (1) approximately 40% polyvinyl alcohol by weight, (2) approximately 10% polyethylene glycol by weight, and (3) approximately 20% rice starch by weight. The polymer composition of the film may allow the film to quickly dissolve in the mouth without adhereing to the mucosal surface of the oral cavity, so as to prevent the transbuccal absorption of the ondansetron in the film (i.e. less than 50, 25, 10 or 2% absorption).

[074] The ondansetron may be present in the film in an amount in the range of about 10% to about 30% by weight. In a particular embodiment, the ondansetron comprises Form B ondansetron base.

[075] The polyvinyl alcohol in the polymer may be hydrolysed to a degree that allows the film to be more easily manufactured, packaged, and/or administered. For example, the polyvinyl alcohol may be hydrolysed to a degree that allows the film to be rigid but not overly brittle. In one embodiment, the degree of hydrolysis of the polyvinyl alcohol is less than 90% so as to avoid brittleness. In a particular desirable embodiment, the degree of hydrolysis of the polyvinyl alcohol is in the range of about 70%-90%, and even more desirably about 88%. The use of polyvinyl alcohol with a degree of hydrolysis below 90% may provide the film with further advantageous properties such as increased solubility, increased flexibility, increased water sensitivity, increased adhesion to hydrophobic surfaces, and/or decreased adhesion to hydrophilic surfaces. [076] Additionally, the polyethylene glycol in the polymer may have a molecular weight that allows the film to be more easily manufactured, packaged, and/or administered. For example, the polyethylene glycol may have a molecular weight that allows the film to be more flexible (i.e. more plasticized). In one embodiment, the average molecular weight of the polyethylene glycol is in the range of about 500 to about 1500 daltons, and even more desirably about 1000 daltons (referred to herein as PEG

1000).

[077] The film may comprise glycerol as an additional ingredient in the film. The glycerol may soften the film and allow it additional flexibility. In one embodiment, the glycerol is present in the film in the range of about 0.5% to about 10% by weight, and even more desirably about 4% by weight.

[078] The film may contain further ingredients as noted in PCT Application No.

WO/2008/040534. That application is incorporated herein by reference.

Oral Films Comprising Donepezil

[079] In yet another embodiment, the orally dissolvable film comprises (a) a polymer, and (b) donepezil or a pharmaceutically acceptable salt thereof, wherein the polymer comprises (1) polyvinyl alcohol in an amount in the range of about 20% to about 40% by weight, (2) polyethylene glycol in an amount in the range of about 5% to about 15% by weight, and (3) cyclodextrin in an amount in the range of about 30% to about 50% by weight. In a particular desirable embodiment, the polymer comprises (1) approximately 30% polyvinyl alcohol by weight, (2) approximately 10% polyethylene glycol by weight, and (3) approximately 40% cyclodextrin by weight. The polymer composition of the film may allow the film to quickly dissolve in the mouth without adhering to the mucosal surface of the oral cavity, so as to prevent the transbuccal absorption of the donepezil in the film (i.e. less than 50, 25, 10 or 2% absorption).

[080] The donepezil may be present in the film in an amount in the range of about 5% to about 20% by weight. In a particular embodiment, the donepezil comprises an amorphous donepezil hydrochloride.

[081] The polyvinyl alcohol in the polymer may be hydrolysed to a degree that allows the film to be more easily manufactured, packaged, and/or administered. For example, the polyvinyl alcohol may be hydrolysed to a degree that allows the film to be rigid but not overly brittle. In one embodiment, the degree of hydrolysis of the polyvinyl alcohol is less than 90% so as to avoid brittleness. In a particular desirable embodiment, the degree of hydrolysis of the polyvinyl alcohol is in the range of about 70%-90%, and even more desirably about 88%. The use of polyvinyl alcohol with a degree of hydrolysis below 90% may provide the film with further advantageous properties such as increased solubility, increased flexibility, increased water sensitivity, increased adhesion to hydrophobic surfaces, and/or decreased adhesion to hydrophilic surfaces. [082] Additionally, the polyethylene glycol in the polymer may have a molecular weight that allows the film to be more easily manufactured, packaged, and/or administered. For example, the polyethylene glycol may have a molecular weight that allows the film to be more flexible (i.e. more plasticized). In one embodiment, the average molecular weight of the polyethylene glycol is in the range of about 500 to about 1500 daltons, and even more desirably about 1000 daltons (referred to herein as PEG 1000).

[083] The film may comprise glycerol as an additional ingredient in the film. The glycerol may soften the film and allow it additional flexibility. In embodiments where the film comprises polyvinyl alcohol, the glycerol is present in the film in the range of about 2% to about 10% by weight, and even more desirably about 5% by weight. [084] The film may further comprise citric acid, especially anhydrous citric acid, as a taste-improving agent in the film. In a preferred embodiment, the final product comprises from about 0.5 to about 2.0 wt% citric acid, or from about 0.75 to about 1.25 wt% citric acid.

[085] In yet another embodiment, the orally dissolvable film comprises (a) a polymer, and (b) donepezil or a pharmaceutically acceptable salt thereof, wherein the polymer comprises (1) polyvinyl alcohol in an amount in the range of about 30% to about 50% by weight, (2) polyethylene glycol in an amount in the range of about 5% to about 15% by weight, and (3) aminoalkyl methacrylate copolymer in an amount in the range of about 5% to about 15% by weight. In a preferred embodiment, the aminoalkyl methacrylate copolymer coats the donepezil in the formulation. In a particular desirable embodiment, the polymer comprises polyvinyl alcohol in an amount of about 40% by weight, and aminoalkyl methacrylate copolymer in an amount of about 15% by weight. The polymer composition of the film may allow the film to quickly dissolve in the mouth without adhering to the mucosal surface of the oral cavity, so as to prevent the transbuccal absorption of the donepezil in the film (i.e. less than 50, 25, 10 or 2% absorption). [086] The aminoalkyl methacrylate copolymer in the polymer may mask the taste of the donepezil, facilitate the dissolution of the donepezil, and/or help to maintain the amorphous state of the donepezil. In one embodiment, the aminoalkyl methacrylate copolymer comprises the copolymer marketed as Eudragit E PO. The aminoalkyl methacrylate copolymer preferably contains diethyaminoethyl residues, and preferably comprises from about 20 to about 26 wt.% of such groups in a dry substance basis. The average molecular weight of the copolymer preferably ranges from about 120,000 to about 180,000, or from about 140,000 to about 160,000, and most preferably about 150,000. Preferred methacrylic monomers include butyl methacrylate and methyl methacrylate. This agent is preferably present in the final film in an amount of from about 5 to about 25 wt.%, preferably from about 10 to about 20 wt.%, and more preferably from about 12 to about 18 wt.%. The copolymer is preferably micronized to an average particle size less than 100, 100, or 10 microns.

[087] The donepezil may be present in the film in an amount in the range of about 5% to about 20% by weight. In a particular embodiment, the donepezil comprises an amorphous donepezil hydrochloride.

[088] The film may contain further ingredients as noted in PCT Application No. WO/2008/040534. That application is incorporated herein by reference.

The Vaginally Dissolvable Film

[074] In one embodiment, the vaginally dissolvable film comprises a pH adjusting ingredient and an antimicrobial essential oil, wherein the pH adjusting ingredient is present in the film in an amount effective to acidify the pH of the vagina, and wherein the antimicrobial essential oil is present in the film in an amount effective to reduce the number of bacteria in the vagina. In a particular embodiment, the film does not comprise a systemically acting drug. In another embodiment, the film comprises a drug such as a contraceptive. In yet another embodiment, the film is non-mucoadhesive. [075] The film may be characterized by various physical characteristics, including its structure, size and shape. For example, in one embodiment, the film is a single layer homogeneous film. In another embodiment, the film is a multi-layer film. The film may have a weight of from about 50 to about 200 milligrams, preferably from about 60 to about 160 milligrams. The film may vary in thickness from about 20 to about 300 microns, and preferably does not exceed 7 or 8 cm² in surface area. The characteristics of film may allow the film to be quickly placed in the vagina for the convenient treatment of vaginal infections. The thickness of the film may allow the film to remain stable after being placed in vaginal cavity. Importantly, the composition of the film may insure that the ingredients of the film are minimally absorbed through the vaginal mucosa (i.e. less than 50, 25, 10 or 2% absorption). Furthermore, the composition of the film may allow the film to disintegrate upon contact with fluids in the vaginal cavity within about sixty seconds.

[076] The pH adjusting ingredient may comprise essentially any ingredient that is effective to acidify the pH of the vagina. Non-limiting examples of suitable pH adjusting ingredients include lactic acid, citric acid, potassium acid tartrate, benzoic acid, alginic acid, sorbic acid, fumaric acid, ascorbic acid, stearic acid, oleic acid, tartaric acid, edetic acid ethylenediaminetetracetic acid, acetic acid, malic acid, and combinations thereof. In a particularly desirable embodiment, the pH adjusting ingredient comprises lactic acid. [077] The pH adjusting ingredient may be present in the film in an amount in the range of about 0.1% to about 50% by weight. Desirably, the pH adjusting ingredient is present in the film in an amount of approximately 20-30% by weight.

[078] The antimicrobial essential oil may comprise any essential oil that is effective to reduce the number of bacteria in the vagina. In a particular embodiment, the essential oil comprises tea tree oil.

[079] The antimicrobial essential oil may be present in the film in an amount in the range of about 0.05% to about 3% by weight. Desirably, the essential oil is present in the film in an amount in the range of about 0.01% to about 2% by weight, and even more desirably in an amount of approximately 1% by weight. Importantly, the amount of essential oil is effective to reduce the number of bacteria in the vagina. [080] Desirably, the film comprises one or more polymers that act as water soluble binding agents and/or hydrophilic polymers. Non-limiting examples of suitable polymers include polyvinyl alcohol, polyethylene glycol (PEG), propylene glycol, polyethylene oxide, and starches, celluloses, gelatins and the like. The film preferably comprises from about 40 to about 80 wt.% of these ingredients, and more preferably from about 50 to about 75 wt.%. The formulation may be surfactant free, or it may contain one or more surfactants.

[081] In a particular embodiment, the polymer in the vaginally dissolvable film comprises (1) polyvinyl alcohol in an amount in the range of about 20% to about 40% by weight, (2) polyethylene glycol in an amount in the range of about 0.5% to about 5% by weight, and (3) rice starch in an amount in the range of about 25% to about 50% by weight. In a particularly preferable embodiment, the polymer comprises (1) approximately 28% polyvinyl alcohol by weight, (2) approximately 1.2% polyethylene glycol by weight, and (3) approximately 39% rice starch by weight. The polymer composition of the film may allow the film to quickly dissolve in the vagina without adhering to the mucosal surfaces of the vaginal cavity, so as to prevent the absorption of the ingredients in the film.

[082] The polyvinyl alcohol in the polymer may be hydrolysed to a degree that allows the film to be more easily manufactured, packaged, and/or administered. For example, the polyvinyl alcohol may be hydrolysed to a degree that allows the film to be rigid but not overly brittle. In one embodiment, the degree of hydrolysis of the polyvinyl alcohol is less than 90% so as to avoid brittleness. In a particular desirable embodiment, the degree of hydrolysis of the polyvinyl alcohol is in the range of about 70%-90%, and even more desirably about 88%. The use of polyvinyl alcohol with a degree of hydrolysis below 90% may provide the film with further advantageous properties such as increased solubility, increased flexibility, increased water sensitivity, increased adhesion to hydrophobic surfaces, and/or decreased adhesion to hydrophilic surfaces. [083] Additionally, the polyethylene glycol in the polymer may have a molecular weight that allows the film to be more easily manufactured, packaged, and/or administered. For example, the polyethylene glycol may have a molecular weight that allows the film to be more flexible (i.e. more plasticized). In one embodiment, the average molecular weight of the polyethylene glycol is in the range of about 500 to about 1500 daltons, and even more desirably about 1000 daltons (referred to herein as PEG 1000). [084] The film may comprise glycerol as an additional ingredient in the film. The glycerol may soften the film and allow it additional flexibility. In one embodiment, the glycerol is present in the film in the range of about 0.5% to about 5% by weight, and even more desirably about 2% by weight.

The Method of Preventing Tooth Decay

[082] In one embodiment, the method of preventing tooth decay comprises (a) providing a non-mucoadhesive film able to disintegrate upon contact with saliva, wherein the film comprises (1) a pH adjusting ingredient in an amount effective neutralize the pH of the oral cavity, and (2) an antimicrobial ingredient in an amount effective to reduce the number of bacteria in the oral cavity; and (b) applying the film to the oral cavity of a human patient.

[083] The step of applying the film may be effective to buffer the pH in the oral cavity to a value in the range of about 6.0 to about 9.0. More desirably, the step of applying the film is effective to buffer the pH in the oral cavity to a value in the range of about 6.5 to about 7.5, and even more desirably to a value of approximately 7.0. Importantly, the step of applying the film may buffer the pH so as to prevent the decay of teeth in the oral cavity, while not raising the pH of the mouth to undesirable alkaline levels that may result in transbuccal absorption of the ingredients in the film.

[084] Furthermore, the step of applying the film may be effective to reduce the number of bacteria in the oral cavity by at least 15%. More desirably, the step of applying the film is effective to reduce the number of bacteria in the oral cavity by at least 30%. [085] The step of applying the film may comprise placing the dosage form on the tongue. Alternatively, step of applying the film may comprise placing the dosage form under the tongue. The method of preventing tooth decay may further comprise swallowing the dosage form within ten, twenty, thirty, forty-five or sixty seconds, and/or swallowing the dosage form with or without water. The Method of Treating Infection in the Vagina

[085] In one embodiment, the method of treating infection in the vagina comprises (a) providing a non-mucoadhesive film able to disintegrate within the vagina, wherein the film comprises (1) a pH adjusting ingredient in an amount effective acidify the pH of the vagina, and (2) an antimicrobial ingredient in an amount effective to reduce the number of bacteria in the vagina; and (b) applying the film to the vagina of a human patient. [086] The step of applying the film may be effective to buffer the pH in the vagina to a value in the range of about 3.5 to about 5.5. More desirably, the step of applying the film may be effective to buffer the pH in the vagina to a value in the range of about 4 to about 5, and even more desirably about a value of approximately 4.5.

[087] Furthermore, the step of applying the film may be effective to reduce the number of bacteria in the vagina by at least 15%. More desirably, the step of applying the film is effective to reduce the number of bacteria in the vagina by at least 30%.

Example 1

[088] Film pieces for oral use with an area of 6 cm² were prepared as described below so that each piece of film contained the ingredients listed in Table 1 below.

Table 1

[089] PEG and PVA were dissolved in water under stirring at 9O⁰C to form a mixture. After cooling to room temperature the sodium hydrogen carbonate was added to the mixture.

[090] Next, a dispersion of rice starch in ethanol was added to the mixture. The remaining ingredients including the essential oils were then added. The resulting mixture was stirred with a high-speed homogenizer and cast onto a foil with a knife. After removal of the solvents (drying for 10 min at room temperature followed by 30 minutes at 4O⁰C), individual films were punched and sealed.

Example 2

[091] Film pieces for oral use with an area of 6 cm² were prepared as described in Example 1 so that each piece of film contained the ingredients listed in Table 2 below. Table 2

Example 3

[092] Film pieces for oral use with an area of 6 cm² were prepared as described in Example 1 so that each piece of film contained the ingredients listed in Table 3 below.

Table 3

Example 4

[093] Film pieces for vaginal use with an area of 6 cm² were prepared as described below so that each piece of film contained the ingredients listed in Table 4 below.

Table 4

[094] PEG and PVA were dissolved in water under stirring at 9O⁰C to form a mixture.

After cooling to room temperature the pH down-regulating agent was added to the mixture.

[095] The remaining ingredients including the essential oils were merged with the base polymer mixture. The resulting mixture was stirred until homogenous and cast onto a foil with a knife. After removal of the solvents (drying for 10 min at room temperature followed by about 120 minutes at 4O⁰C), individual films were punched and sealed. MICROBIOLOGICAL TESTS

[096] In-vitro studies have been carried out with the aim to investigate the pH adjusting effect and the antibacterial effect of the films of Examples 1 and 2.

Example 5

[097] Saliva samples were collected in duplicate from three healthy volunteers. One sample from each volunteer was kept as a control, and the other saliva sample was combined with one piece of film prepared as according to Example 1. [098] The bacterial counts of the saliva samples were measured at 0 seconds and then at 30, 60, 120, 300, and 450 seconds after the addition of the film as shown in Table 5 below. Fig. 7 is a graph showing the average values of the bacterial counts obtained over the experiment. As seen in Fig. 7, the bacterial counts of the treated saliva samples dropped with the first 30 seconds and reached its plateau at 120 seconds after addition of the device to the saliva sample.

Table 5

BACTERIAL COUNT

Sample: saliva + pH-Normallzer RapldFilm

Negative Control: saliva

[099] The values of the bacterial counts for each time-point were then statistically processed by the Randomized Complete Block Analysis of Variance after logarithmic transformation. The data, reproduced in Table 6 below, indicates that statistically significant differences between control and treated samples were obtained starting from about 120 sec. of contact. Table 6

[0100] In conclusion, the microbiological study demonstrated that the essential oils contained in the oral film of Example 1 have a statistically significant effect on the microbial flora of the saliva.

Example 6

[0101] A microbial test was performed as according to Example 5 above using the films of Example 2.

[0102] Once again, the bacterial counts of the saliva samples were measured at 0 seconds and then at 30, 60, 120, 300, and 450 seconds after the addition of the film as shown in Table 7 below. Fig. 8 is a graph showing the average values of the bacterial counts obtained over the experiment. Table 7

Sample: saliva + pH-Normalizer Rapidfilm

Negative Control: saliva

[0103] The values of the bacterial counts for each time-point were then statistically processed by the Randomized Complete Block Analysis of Variance after logarithmic transformation. The resulting data is reproduced in Table 8 below.

Table 8

[0104] In conclusion, the microbiological study demonstrated that the essential oils contained in the oral film of Example 2 have a statistically significant effect on the microbial flora of the saliva.

PH TESTS

Example 7

[0105] Citric acid was added to 7 mL of bi-distilled water to produce a solution with a pH of 5.5. One piece of film prepared according to Example 1 was then added to the solution and the pH of the solution was measured over a 15 minute period at 5, 15, 30, 45, 60, 90, 105, 120, 180, 240, 300, 450, 600, and 900 seconds. The experiment was carried out in triplicate for each time-point. The resulting data is reproduced in Table 9 below. Table 9

PH VALUES

[0106] Fig. 9 is a graph showing average pH of the solution from time 0 until 900 seconds. As shown in Fig. 9, the pH of the solution progressively increased over time, reaching a plateau at about 450 sec. The average increase of pH at 450 sec, in comparison with the starting value, was of 1.65 pH-unit (pH=5.57 at TO vs. pH=7.22 at T450).

[0107] In conclusion, the amount of bicarbonate contained in the film was proven to neutralize acidity in saliva, which may allow the pH of the mouth and of the plaque to be maintained near neutral for normal tooth maintenance.

Example 8

[0108] The results obtained in Example 7's in vitro experiment were confirmed with an in vivo test. Fig. 10 is a graph showing the average mouth pH level of 10 volunteers before drinking coffee, after drinking coffee, and after application of a piece of film prepared as according to Example 1. Example 9

[0109] The results obtained in Example 7's in vitro experiment were confirmed with an in vivo test. Fig. 11 is a graph showing the average mouth pH level of 10 volunteers ten minutes after eating an apple, and after application of a piece of film prepared as according to Example 1.

Example 10

[01 10] The film made according to Example 1 was subjected to a second pH-test as described in Example 7 above, but the citric acid solution was replaced by artificial saliva.

[01 1 1] Specifically, one piece of film of prepared according to Example 1 was placed into 7 mL of artificial saliva prepared according to UNI EN ISO 12868-00 2002 to which lactic acid had been added drop by drop to reach a pH of less than 5. The pH of the solution was measured over a period of 3 minutes at 5, 15, 30, 45, 60, 90, 120, and 180 seconds. The experiment was carried out in triplicate for each time-point. [0112] Fig. 12 is a graph showing average pH of the solution from time 0 until 180 seconds. As shown in Fig. 12, the pH progressively increased over time to a value around neutral. The average increase of pH at 180 sec, in comparison with the starting value, was of 2.50 pH-units.

Example 11

[01 13] Film pieces for oral use were prepared so that each piece of film contained the ingredients listed in Tables 10, 1 1, and 12 below:

Table 10 - Ondansetron Formulation

Table 1 1 - Donepezil HCl Formulation A

Table 12 - Donepezil HCl Formulation B Pre-Mix

*not part of the finished product

Table 13: Donepezil HCl Formulation B

*not part of the finished product

Claims

What is claimed is:

1) An orally dissolvable film, comprising: a) a pH adjusting ingredient; and b) an antimicrobial essential oil; wherein the pH adjusting ingredient is present in the film in an amount effective to neutralize the pH of the oral cavity, wherein the antimicrobial essential oil is present in the film in an amount effective to reduce the number of bacteria in the oral cavity, and wherein the film does not comprise a systemically acting drug.

2) The film of claim 1 , wherein the film is non-mucoadhesive.

3) The film of claim lor claim 2, wherein the pH adjusting ingredient is selected from the group consisting of alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkali earth metal carbonates, alkali earth metal bicarbonates, alkali earth metal hydroxides, and combinations thereof.

4) The film of one of the preceding claims, wherein the pH adjusting ingredient is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium phosphate dibasic, sodium phosphate tribasic, potassium phosphate dibasic, potassium phosphate tribasic, calcium carbonate, magnesium carbonate, sodium hydroxide, magnesium hydroxide, potassium hydroxide, aluminum hydroxide, and combinations thereof.

5) The film of one of the preceding claims, wherein the pH adjusting ingredient comprises sodium bicarbonate.

6) The film of one of the preceding claims, wherein the antimicrobial essential oil is selected from the group consisting of eucalyptus oil, menthol, peppermint oil, crisp mint oil, spearmint oil, Pelargonium sidoides root extract, and combinations thereof.

7) The film of one of the preceding claims, wherein the antimicrobial essential oil is present in the film in an amount in the range of about 0.1% to about 10% by weight. 8) The film of one of the preceding claims, wherein the antimicrobial essential oil is present in the film in an amount in the range of about 1% to about 8% by weight.

9) The film of one of the preceding claims, wherein the antimicrobial essential oil is present in the film in an amount in the range of about 2% to about 5% by weight.

10) The film of one of the preceding claims, wherein the pH adjusting ingredient is present in the film in an amount in the range of about 1% to about 15% by weight.

1 1) The film of one of the preceding claims, wherein the pH adjusting ingredient is present in the film in an amount in the range of about 3% to about 10% by weight.

12) The film of one of the preceding claims, wherein the pH adjusting ingredient is present in the film in an amount in the range of about 5% to about 8% by weight.

13) The film of one of the preceding claims, wherein the antimicrobial essential oil comprises eucalyptus oil in an amount in the range of about 0.1% to about 10% by weight.

14) The film of one of the preceding claims, wherein the pH adjusting ingredient comprises sodium bicarbonate in an amount in the range of about 5% to about 10% by weight.

15) An orally dissolvable film, comprising: a) a polymer; b) a pH adjusting ingredient; and c) an antimicrobial essential oil; wherein the polymer comprises (1) polyvinyl alcohol in an amount in the range of about 40% to about 60% by weight, (2) polyethylene glycol in an amount in the range of about 10% to about 20% by weight, and (3) rice starch in an amount in the range of about 15% to about 30% by weight, wherein the pH adjusting ingredient is present in the film in an amount effective to neutralize the pH of the oral cavity, and wherein the antimicrobial essential oil is present in the film in an amount effective to reduce the number of bacteria in the oral cavity.

16) The film of claim 15, wherein the polymer comprises (1 ) approximately 50% polyvinyl alcohol by weight, (2) approximately 15% polyethylene glycol by weight, and (3) approximately 20% rice starch by weight. 17) An orally dissolvable non-mucoadhesive film, comprising: a) from about 75 % to about 90 wt.% of a polymer; and b) from about 5 % to about 20 wt.% donepezil or a pharmaceutically acceptable salt thereof; wherein the polymer comprises (1) polyvinyl alcohol in an amount in the range of about 25% to about 45% by weight, (2) polyethylene glycol in an amount in the range of about 5% to about 15% by weight, (3) propylene glycol in an amount of about 4% to about 10% by weight, and (4) cyclodextrin in an amount in the range of about 20% to about 35% by weight, said weight percentages being based on the weight of the film.

18) The film of claim 17, wherein the polyvinyl alcohol has a degree of hydrolysis less than 90%.

19) The film of claim 17 or 18, further comprising citric acid.

20) The film of one of claims 17 to 19, wherein the donepezil comprises amorphous donepezil hydrochloride.

21) An orally dissolvable non-mucoadhesive film, comprising: a) from about 75 % to about 90 wt.% of a polymer; and b) from about 5 % to about 20 wt.% donepezil or a pharmaceutically acceptable salt thereof; wherein the polymer comprises (1) polyvinyl alcohol in an amount in the range of about 30% to about 50% by weight, (2) polyethylene glycol in an amount in the range of about 5% to about 15% by weight, (3) propylene glycol in an amount of from 5% to 10% by weight, (4) aminoalkyl methacrylate copolymer in an amount in the range of about 10% to about 20% by weight, said weight percentages being based on the weight of the film; and wherein said aminoalkylmethacrylate copolymer coats said donepezil or pharmaceutically acceptable salt thereof in said film.

22) The film of claim 21, wherein said polyvinyl alcohol has a degree of hydrolysis of less than 90%.

23) The film of claim 21 or 22, wherein the donepezil comprises amorphous donepezil hydrochloride. 24) The film of one of claims 21 to 23 wherein the aminoalkyl methacrylate copolymer has a molecular weight of from 140,000 to 160,000.

25) The film of one of claims 21 to 24 wherein the aminoalkyl methacrylate copolymer has a molecular weight of from 140,000 to 160,000, and said donepezil is amorphous donepezil hydrochloride.

26) An orally dissolvable non-mucoadhesive film, comprising: a) from about 70 % to about 90 wt.% of a polymer; and b) from about 10 % to about 25 wt.% ondansetron or a pharmaceutically acceptable salt thereof; wherein the polymer comprises (1) polyvinyl alcohol in an amount in the range of about 30% to about 50% by weight, (2) polyethylene glycol in an amount in the range of about 5% to about 15% by weight, and (3) rice starch in an amount in the range of about 10% to about 30% by weight, said weight percentages being based on the weight of the film.

27) The film of claim 26 wherein said polyvinyl alcohol has a degree of hydrolysis of less than 90%.

28) The film of one of claims 26 or 27 , further comprising from about 2 % to about 6 wt.% glycerol, and from about 1 % to about 3 wt.% polysorbate 80.

29) The film of one of claims 26 to 28, wherein the ondansetron comprises Form B ondansetron base.

30) A vaginally dissolvable film, comprising: a) a pH adjusting ingredient; and b) an antimicrobial essential oil; wherein the pH adjusting ingredient is present in the film in an amount effective to acidify the pH of the vagina, wherein the antimicrobial essential oil is present in the film in an amount effective to reduce the number of bacteria in the vagina.

31) The film of claim 30, wherein the film does not comprise a systemically acting drug.

32) The film of claim 30 or 31, wherein the film is non-mucoadhesive. 33) The film of one of claims 30 to 32, wherein the pH adjusting ingredient is selected from the group consisting of lactic acid, citric acid, potassium acid tartrate, benzoic acid, alginic acid, sorbic acid, fumaric acid, ascorbic acid, stearic acid, oleic acid, tartaric acid, edetic acid ethylenediaminetetracetic acid, acetic acid, malic acid, and combinations thereof.

34) The film of one of claims 30 to 33, wherein the pH adjusting ingredient comprises lactic acid.

35) The film of one of claims 30 to 34, wherein the antimicrobial essential oil is tea tree oil.

36) The film of one of claims 30 to 35, wherein the antimicrobial essential oil is present in the film in an amount in the range of about 0.05% to about 3% by weight.

37) The film of one of claims 30 to 36, wherein the antimicrobial essential oil is present in the film in an amount in the range of about 0.01% to about 2% by weight.

38) The film of one of claims 30 to 37, wherein the antimicrobial essential oil is present in the film in an amount of approximately 1% by weight.

39) The film of one of claims 30 to 38, wherein the pH adjusting ingredient is present in the film in an amount in the range of about 0.1% to about 40% by weight.

40) The film of one of claims 30 to 39, wherein the pH adjusting ingredient is present in the film in an amount in the range of approximately 28% by weight.

41) A vaginally dissolvable film, comprising: a) a polymer; b) a pH adjusting ingredient; and c) an antimicrobial essential oil; wherein the polymer comprises (1) polyvinyl alcohol in an amount in the range of about 20% to about 40% by weight, (2) polyethylene glycol in an amount in the range of about 0.5% to about 5% by weight, and (3) rice starch in an amount in the range of about 25% to about 50% by weight, wherein the pH adjusting ingredient is present in the film in an amount effective to acidify the pH of the vagina, and wherein the antimicrobial essential oil is present in the film in an amount effective to reduce the number of bacteria in the vagina.

42) The film of claim 41 , wherein the polymer comprises (1) approximately 30% polyvinyl alcohol by weight, (2) approximately 1.2% polyethylene glycol by weight, and (3) approximately 39% rice starch by weight.

43) A method of preventing tooth decay in the oral cavity, comprising: a) providing a non-mucoadhesive film able to disintegrate upon contact with saliva, wherein the film comprises (1) a pH adjusting ingredient in an amount effective neutralize the pH of the oral cavity, and (2) an antimicrobial ingredient in an amount effective to reduce the number of bacteria in the oral cavity; and b) applying the film to the oral cavity of a human patient.

44) The method of claim 43, wherein the step of applying the film is effective to buffer the pH in the oral cavity to a value in the range of about 6.0 to about 9.0.

45) The method of claim 43 or 44, wherein the step of applying the film is effective to buffer the pH in the oral cavity to a value in the range of about 6.5 to about 7.5.

46) The method of claim 45, wherein the step of applying the film is effective to buffer the pH in the oral cavity to a value of approximately 7.0.

47) The method of one of claims 43 to 46, wherein the step of applying the film is effective to reduce the number of bacteria in the oral cavity by at least 30%.

48) The method of one of claims 43 to 47, wherein the step of applying the film is effective to reduce the number of bacteria in the oral cavity by at least 15%.

49) A method of treating infection in the vagina, comprising: a) providing a non-mucoadhesive film able to disintegrate within the vagina, wherein the film comprises (1) a pH adjusting ingredient in an amount effective acidify the pH of the vagina, and (2) an antimicrobial ingredient in an amount effective to reduce the number of bacteria in the vagina; and b) applying the film to the vagina of a human patient.

50) The method of claim 49, wherein the step of applying the film is effective to buffer the pH in the vagina to a value in the range of about 3.5 to about 5.5. 51) The method of claim 49 or 50, wherein the step of applying the film is effective to buffer the pH in the vagina to a value in the range of about 4 to about 5.

52) The method of one of claims 49 to 51 , wherein the step of applying the film is effective to buffer the pH in the vagina to a value of approximately 4.5.

53) The method of one of claims 49 to 52, wherein the step of applying the film is effective to reduce the number of bacteria in the vagina by at least 30%.

54) The method of one of claims 49 to 53, wherein the step of applying the film is effective to reduce the number of bacteria in the vagina by at least 15%.