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WO2009043588A2 - Films antibactériens de régulation de ph pour la cavité buccale ou vaginale - Google Patents

Films antibactériens de régulation de ph pour la cavité buccale ou vaginale Download PDF

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Publication number
WO2009043588A2
WO2009043588A2 PCT/EP2008/008391 EP2008008391W WO2009043588A2 WO 2009043588 A2 WO2009043588 A2 WO 2009043588A2 EP 2008008391 W EP2008008391 W EP 2008008391W WO 2009043588 A2 WO2009043588 A2 WO 2009043588A2
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WO
WIPO (PCT)
Prior art keywords
film
weight
amount
range
effective
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2008/008391
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English (en)
Other versions
WO2009043588A3 (fr
Inventor
Giorgio Reiner
Nadia Giarratana
Valentina Reiner
Ulrich Becker
Amin Breitenbach
Peter Klaffenbach
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APR Applied Pharma Research SA
Labtec Gesellschaft fuer Technologische Forschung und Entwicklung mbH
Labtec GmbH
Original Assignee
APR Applied Pharma Research SA
Labtec Gesellschaft fuer Technologische Forschung und Entwicklung mbH
Labtec GmbH
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Publication of WO2009043588A2 publication Critical patent/WO2009043588A2/fr
Anticipated expiration legal-status Critical
Publication of WO2009043588A3 publication Critical patent/WO2009043588A3/fr
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/0216—Solid or semisolid forms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/92—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof
    • A61K8/922—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof of vegetable origin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/005—Antimicrobial preparations
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • 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.
  • FIG. 1 is an illustration showing a normal tooth and a tooth with three types of cavities.
  • 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.
  • FIG. 3 is a graph showing the pH of dental plaque at various times after a rinse with sucrose solution.
  • 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.
  • FIG. 5 is a graph measuring the cariogenic challenge to a tooth after a rinse with sucrose solution.
  • FIG. 6 is a graph measuring a series of carogenic challenges over a typical 24 hour period.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Cavities 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • Fig. 2 shows the effect of tooth brushing on the pH reached by plaque after a second glucose mouth rinse.
  • the pH drops due to acid produced by bacteria fermenting the sucrose. Once the pH reaches 5.3, enamel begins to dissolve.
  • one side of the arch is brushed and the pH rises to a neutral value of 7.0.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • Fig. 3 illustrates the characteristics of Stephan's Curve.
  • 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.
  • 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.
  • 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 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.
  • 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 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • conditions in the vaginal environment may allow unwanted organisms to gain a foothold and multiply.
  • BV bacterial vaginosis
  • 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.
  • vaginal candidosis 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.
  • tea tree oil from, for example, Melaleuca alternifolia
  • tea-tree oil has been used to treat yeast infections and bacterial vaginosis.
  • 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.
  • the present invention relates to fast dissolving films for simultaneously adjusting pH and lowering the amount of bacteria in the oral or vaginal environments.
  • 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.
  • 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.
  • 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.
  • those familiar with the art of oral films are familiar with a large number of diverse film ingredients.
  • 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.
  • 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.
  • a pH adjusting ingredient in an amount effective to neutralize the pH of the oral cavity
  • 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.
  • 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.
  • 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.
  • the film further comprises a pharmaceutically active agent.
  • 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.
  • 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 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.
  • the film may be characterized by various physical characteristics, including its structure, size and shape.
  • the film is a single layer homogeneous film.
  • 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 cm 2 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
  • 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.
  • 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.
  • the pH adjusting ingredient comprises sodium bicarbonate.
  • 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.
  • 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.
  • the antimicrobial essential oil may comprise any essential oil that is effective to reduce the number of bacteria in the oral cavity.
  • suitable essential oils include eucalyptus oil, menthol, peppermint oil, crisp mint oil, spearmint oil, Pelargonium sidoides root extract, and combinations thereof.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the film comprises one or more polymers that act as water soluble binding agents and/or hydrophilic polymers.
  • 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.
  • 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.
  • the polyvinyl alcohol may be hydrolysed to a degree that allows the film to be rigid but not overly brittle.
  • the degree of hydrolysis of the polyvinyl alcohol is less than 90% so as to avoid brittleness.
  • the degree of hydrolysis of the polyvinyl alcohol is in the range of about 70%-90%, and even more desirably about 88%.
  • 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.
  • the polyethylene glycol in the polymer may have a molecular weight that allows the film to be more easily manufactured, packaged, and/or administered.
  • the polyethylene glycol may have a molecular weight that allows the film to be more flexible (i.e. more plasticized).
  • 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).
  • the film may comprise glycerol as an additional ingredient in the film.
  • the glycerol may soften the film and allow it additional flexibility.
  • 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 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.
  • 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.
  • 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.
  • water antimicrobial agents
  • water soluble diluents such as plasticizing agents, softeners and fillers
  • flavoring agents such as plasticizing agents, softeners and fillers
  • saliva stimulating agents such as 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.
  • 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.
  • 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).
  • the ondansetron may be present in the film in an amount in the range of about 10% to about 30% by weight.
  • the ondansetron comprises Form B ondansetron base.
  • 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.
  • the polyvinyl alcohol may be hydrolysed to a degree that allows the film to be rigid but not overly brittle.
  • the degree of hydrolysis of the polyvinyl alcohol is less than 90% so as to avoid brittleness.
  • the degree of hydrolysis of the polyvinyl alcohol is in the range of about 70%-90%, and even more desirably about 88%.
  • 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.
  • the polyethylene glycol in the polymer may have a molecular weight that allows the film to be more easily manufactured, packaged, and/or administered.
  • the polyethylene glycol may have a molecular weight that allows the film to be more flexible (i.e. more plasticized).
  • 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
  • the film may comprise glycerol as an additional ingredient in the film.
  • the glycerol may soften the film and allow it additional flexibility.
  • 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.
  • the film may contain further ingredients as noted in PCT Application No.
  • 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.
  • 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).
  • the donepezil may be present in the film in an amount in the range of about 5% to about 20% by weight.
  • the donepezil comprises an amorphous donepezil hydrochloride.
  • 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.
  • the polyvinyl alcohol may be hydrolysed to a degree that allows the film to be rigid but not overly brittle.
  • the degree of hydrolysis of the polyvinyl alcohol is less than 90% so as to avoid brittleness.
  • the degree of hydrolysis of the polyvinyl alcohol is in the range of about 70%-90%, and even more desirably about 88%.
  • 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.
  • the polyethylene glycol in the polymer may have a molecular weight that allows the film to be more easily manufactured, packaged, and/or administered.
  • the polyethylene glycol may have a molecular weight that allows the film to be more flexible (i.e. more plasticized).
  • 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).
  • the film may comprise glycerol as an additional ingredient in the film.
  • the glycerol may soften the film and allow it additional flexibility.
  • 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.
  • the film may further comprise citric acid, especially anhydrous citric acid, as a taste-improving agent in the film.
  • 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.
  • 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.
  • the aminoalkyl methacrylate copolymer coats the donepezil in the formulation.
  • 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).
  • 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.
  • 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.
  • the donepezil may be present in the film in an amount in the range of about 5% to about 20% by weight.
  • the donepezil comprises an amorphous donepezil hydrochloride.
  • 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 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.
  • the film does not comprise a systemically acting drug.
  • the film comprises a drug such as a contraceptive.
  • the film is non-mucoadhesive.
  • 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.
  • 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 cm 2 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.
  • 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).
  • the composition of the film may allow the film to disintegrate upon contact with fluids in the vaginal cavity within about sixty seconds.
  • the pH adjusting ingredient may comprise essentially any ingredient that is effective to acidify the pH of the vagina.
  • 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.
  • the pH adjusting ingredient comprises lactic acid.
  • 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.
  • the antimicrobial essential oil may comprise any essential oil that is effective to reduce the number of bacteria in the vagina.
  • the essential oil comprises tea tree oil.
  • 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.
  • the film comprises one or more polymers that act as water soluble binding agents and/or hydrophilic polymers.
  • 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.
  • 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.
  • 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.
  • 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.
  • the polyvinyl alcohol may be hydrolysed to a degree that allows the film to be rigid but not overly brittle.
  • the degree of hydrolysis of the polyvinyl alcohol is less than 90% so as to avoid brittleness.
  • the degree of hydrolysis of the polyvinyl alcohol is in the range of about 70%-90%, and even more desirably about 88%.
  • 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.
  • the polyethylene glycol in the polymer may have a molecular weight that allows the film to be more easily manufactured, packaged, and/or administered.
  • the polyethylene glycol may have a molecular weight that allows the film to be more flexible (i.e. more plasticized).
  • 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).
  • the film may comprise glycerol as an additional ingredient in the film.
  • the glycerol may soften the film and allow it additional flexibility.
  • 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 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.
  • 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.
  • 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%.
  • 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 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.
  • 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.
  • 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%.
  • 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.
  • 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.
  • Fig. 8 is a graph showing the average values of the bacterial counts obtained over the experiment. Table 7
  • 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
  • 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
  • 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 1 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.
  • 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.

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Abstract

La présente invention concerne des films antibactériens qui peuvent réguler le pH et lutter contre la croissance bactérienne dans l'environnement buccal ou vaginal et des procédés d'utilisation de ceux-ci. Les films peuvent comprendre un ingrédient d'ajustement du pH, une huile essentielle antimicrobienne, et un polymère. Le polymère peut comprendre un alcool polyvinylique, un polyéthylène glycol et de l'amidon de riz. Les films buccaux et les procédés d'utilisation de ceux-ci pourraient empêcher la création de carie dentaire, et les films vaginaux et les procédés d'utilisation de ceux-ci pourraient traiter des infections vaginales.
PCT/EP2008/008391 2007-10-02 2008-10-02 Films antibactériens de régulation de ph pour la cavité buccale ou vaginale Ceased WO2009043588A2 (fr)

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US60/976,819 2007-10-02

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WO2011117313A1 (fr) * 2010-03-23 2011-09-29 Bioalliance Pharma Systèmes d'administration de médicaments à dissolution rapide
EP2377526A1 (fr) * 2010-03-23 2011-10-19 BioAlliance Pharma Systèmes d'administration de médicaments à dissolution rapide
GB2481630A (en) * 2010-07-01 2012-01-04 Robert Taylor Composition for dental health
CN102579654A (zh) * 2012-03-26 2012-07-18 杨长辉 一种用于人体阴道抑菌、护阴、洁阴的药物及其制备方法
WO2012053006A3 (fr) * 2010-10-18 2012-08-02 Panacea Biotec Ltd Films à dissolution rapide améliorés pour l'administration par voie orale comprenant une combinaison de polymères, procédé de préparation de ces derniers
WO2013123487A1 (fr) * 2012-02-19 2013-08-22 Orahealth Corporation Adhésif à base de gomme arabique alcalinisée pour disques adhésifs oraux
WO2014182138A1 (fr) * 2013-05-10 2014-11-13 주식회사 씨티씨바이오 Préparation de film contenant une base exempte de donépézil et procédé de production correspondant
US9914848B1 (en) 2016-10-31 2018-03-13 Ppg Architectural Finishes, Inc. Refinish coating composition
US20210139688A1 (en) * 2018-07-30 2021-05-13 Mitsubishi Chemical Corporation Fused deposition modeling type additive manufacturing material
EP4210681A4 (fr) * 2020-09-08 2024-10-23 Thorne Healthtech, Inc. Matrices solubles

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US6596298B2 (en) * 1998-09-25 2003-07-22 Warner-Lambert Company Fast dissolving orally comsumable films
DE10224607B4 (de) * 2002-06-04 2008-03-13 Lts Lohmann Therapie-Systeme Ag Filmförmige, zerfallsfähige Zubereitungen zur Wirkstofffreisetzung und Verfahren zu deren Herstellung
WO2005009386A2 (fr) * 2003-07-24 2005-02-03 Smithkline Beecham Corporation Films a dissolution orale

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Publication number Priority date Publication date Assignee Title
EP2377526A1 (fr) * 2010-03-23 2011-10-19 BioAlliance Pharma Systèmes d'administration de médicaments à dissolution rapide
WO2011117313A1 (fr) * 2010-03-23 2011-09-29 Bioalliance Pharma Systèmes d'administration de médicaments à dissolution rapide
GB2481630A (en) * 2010-07-01 2012-01-04 Robert Taylor Composition for dental health
WO2012001337A1 (fr) * 2010-07-01 2012-01-05 Robert Peter Taylor Composition pour la santé dentaire
WO2012053006A3 (fr) * 2010-10-18 2012-08-02 Panacea Biotec Ltd Films à dissolution rapide améliorés pour l'administration par voie orale comprenant une combinaison de polymères, procédé de préparation de ces derniers
CN108904460A (zh) * 2012-02-19 2018-11-30 奥拉黑尔斯公司 用于口腔粘附圆片的碱化金合欢树胶粘合剂
WO2013123487A1 (fr) * 2012-02-19 2013-08-22 Orahealth Corporation Adhésif à base de gomme arabique alcalinisée pour disques adhésifs oraux
CN104136010A (zh) * 2012-02-19 2014-11-05 奥拉黑尔斯公司 用于口腔粘附圆片的碱化金合欢树胶粘合剂
CN102579654A (zh) * 2012-03-26 2012-07-18 杨长辉 一种用于人体阴道抑菌、护阴、洁阴的药物及其制备方法
WO2014182138A1 (fr) * 2013-05-10 2014-11-13 주식회사 씨티씨바이오 Préparation de film contenant une base exempte de donépézil et procédé de production correspondant
RU2671487C2 (ru) * 2013-05-10 2018-11-01 СиТиСи БАЙО, ИНК. Препарат в форме пленки, содержащий свободное основание донепезила, и способ его получения
US9914848B1 (en) 2016-10-31 2018-03-13 Ppg Architectural Finishes, Inc. Refinish coating composition
US10358573B2 (en) 2016-10-31 2019-07-23 Ppg Architectural Finishes, Inc. Refinish coating composition
US20210139688A1 (en) * 2018-07-30 2021-05-13 Mitsubishi Chemical Corporation Fused deposition modeling type additive manufacturing material
US12043730B2 (en) * 2018-07-30 2024-07-23 Mitsubishi Chemical Corporation Fused deposition modeling type additive manufacturing material
EP4210681A4 (fr) * 2020-09-08 2024-10-23 Thorne Healthtech, Inc. Matrices solubles

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