BR9917782B1 - method for the preparation of a physiologically compatible film. - Google Patents

Description

Report of the Invention Patent for "METHOD FOR PREPARING A PHYSIOLOGICALLY COMPATIBLE FILM".

Divided from Pl 9914064-0, filed September 23, 1999.

Field of the Invention

This invention relates to orally consumable rapid dissolving films. The films are used for the release of breath deodorizing agents, antimicrobial agents and salivary stimulants into the oral cavity. The films may also be used for the release of active pharmaceutical agents.

Background of the Invention

In a more perfect world, people should thoroughly clean their mouths after every meal as part of their routine oral hygienic practices. Unfortunately, several factors conspire to prevent the widespread agreement of such a basic need for a good oral cleansing regimen.

Oral cleaning should be difficult or inconvenient at certain times, depending on the nature of the cleaning and the situation in which cleaning should occur. Brushing, flossing, cleaning your tongue, and gargling with a variety of devices and compositions that are well-suited to someone's home privacy are common oral care practices. However, the devices and compositions used in oral cleaning practices are less convenient for use away from home, where bathing facilities may be scarce, unavailable or non-sanitary.

Since brushing, flossing, cleaning your mouth and gargling in public are not considered to be socially acceptable behaviors in many, if not all cultures, a variety of less indiscreet oral cleansing products have been developed. These products include chewing gum and breath-fresh diamonds. Although chewing gum and diamonds have been formulated to achieve a variety of beneficial effects, they are not always socially acceptable. For example chewing gum is expressly banned from certain institutions such as schools as well as in certain countries such as Singapore. Chewing gum and mint are used for extended periods of time and they require a lot of sucking and chewing action from the consumable, which can be disturbing, tedious and undesirable.

Another portable oral cleanser is a mouth spray. Similar to an oral disinfectant, an oral spray can provide the rapid-jet consumable of a strong breath freshener, which may be irresistible from a prolonged consumer product such as chewing gum or diamonds. On the other hand, oral sprays are indiscreet. Spraying an oral spray typically generates a noise that undesirably draws public attention to the consumable. In addition, oral sprays are packaged in relatively expensive and complex metal containers that may become clogged in use and are not environmentally friendly. In addition, if the sprayer is misdirected not only wastes the product, it can result in eye irritation, a sticky face and / or stained clothing.

It has been proposed to use an edible film as a vehicle for non-indiscreetly supplying breath-freshening agents. See JP 5-236885. This Japanese Patent Application, however, does not disclose the inclusion of antimicrobial agents in the film, using the film to reduce the amount of undesirable bacteria within the oral cavity, or by stimulating saliva. Moreover, this patent application does not describe the use of the film for purposes other than breath freshening or inside cavities other than the mouth.

US Patent No. 5,518,902 to Ozaki et al (Hayashibara) describes high pullulan products such as edible films, dentifrices and pharmaceuticals (column 3, lines 44 to 56 and Example B-8 ). Products may include a variety of ingredients other than pullulan, such as other polysaccharides, polyhydric alcohols, antiseptics and flavoring agents (column 4, line 58 to column 5 line 11). None of the essential oils such as thymol, eucalyptol, methyl salicylate or menthol are mentioned as suitable ingredients.

U.S. Patent No. 5,411,945 to Ozaki et al (Hayashibara) describes a pullulan binder and products produced therewith, including edible films (Example B-2). Products may include a variety of ingredients other than pullulan, such as other polysaccharides, antibacterial agents, flavoring agents and pharmaceutically active substances (column 4, lines 5 to 15). None of the essential oils are mentioned as suitable ingredients.

U.S. Patent No. 4,851,394 to Kubodera describes edible glycomanane / polyhydric alcohol films, which may comprise pullulan (column 3, line 59 to column 4, line 21). The films are contrasted with existing pullulan-based films, which are considered to have no water resistance (column 1, lines 40 to 44). None of the essential oils are mentioned as suitable ingredients.

U.S. Patent No. 3,784,390 to Hijiya et al. Describes pullulan films and their use in coating and packaging materials for food, pharmaceuticals and other oxygen-sensitive materials. All examples of this patent describe the mixture of pullulan in hot water.

U.S. Patent No. 4,623,394 to Nakamura et al. Discloses a gradually disintegrating molded article which may be a pullulan film. The articles contained a specific hetero mannan, either carob gum.

U.S. Patent No. 4,562,020 to Hijiya et al. Describes a process for producing a self-sustaining glycan film, which may be pullulan.

Japanese Patent Document JP5-1198 describes films made of a polyvinyl alcohol and at least one of carrageenan, water soluble cellulose alpha starch and water soluble polysaccharides.

WO 99/17753 describes fast dissolving films for the supply of drugs to be absorbed in the digestive tract.

WO 98/26780 describes a flat, sheet, paper or puff type presentation for the application and release of active substances in the buccal cavity. The specific active ingredient described in WO 98/26780 is buprenorphine.

WO 98/20862 describes a film for use in the oral cavity which may contain a cosmetic or an active pharmaceutical substance.

WO 98/26763 discloses a flat, sheet, paper or puff type presentation for the release of active substances into the oral cavity. The specific asset described is apomorphine.

Despite the existence of rapidly dissolving films for oral consumption in the prior art, there is still room for improvement in such films and in the processes for their manufacture.

All references cited in this report are incorporated by reference in their entirety.

Summary of the Invention

The invention provides a physiologically acceptable film which is specially adapted to adhere and dissolve rapidly in the mouth of a consumable. In a first embodiment of the invention, the film provides at least one oral health agent, such as antimicrobial agents and salivary stimulants. Antimicrobial agents are effective against germs that cause breath, dental plaque and gingivitis. Salivary stimulants are effective against the condition known as xerostomia or dry mouth. In addition, oral health films are an effective breath freshener against bad oral odor. The film formerly used for the manufacture of films according to the present invention retains oral health care agents in the oral cavity to provide prolonged efficacy.

In a second embodiment of the invention, the rapid dissolving film acts as a vehicle for the administration of an orally active pharmaceutical agent through a mucous membrane or an open wound of a patient. The invention is also directed to a method for producing a soft, non-sticky film suitable for oral supply. The method comprises mixing a film forming agent and at least one stabilizing agent to provide a film forming mixture; dissolving water-soluble ingredients to provide an aqueous solution that combines the film-forming mixture and the aqueous solution to provide a hydrated polymer gel; mixing oils to form an oily mixture; adding the oily mixture to the hydrated polymer gel and mixing them to provide a uniform emulsified gel; shaping the uniform gel onto a substrate and drying the shaped gel to provide a film.

Brief Description of the Drawings

Figure 1 is a photograph of an agar plate covered with a thin layer of Streptococcus mutans, ATCC 25175, and exposed to a film according to the present invention containing 0.391 mg of essential oils.

Figure 2 is a photograph of an agar plate covered with a thin layer of Streptococcus mutans, ATCC 25175, and dripped from an essential oil mixture containing 0.391 mg of essential oils per drop.

Detailed Description of Preference Modes Description of Oral Care Film Compositions.

The first embodiment of the invention is a physiologically acceptable film which is specially adapted to adhere to and dissolve in a consumable mouth to provide an antimicrobial agent that kills the germs that cause breath, dental plaque and gingivitis. . Thus, the film can be an effective tool for the prevention and treatment of breath, dental plaque accumulation, dental tartar accumulation and gingivitis. Such a film preferably comprises pullulan, thymol, methyl salicylate, eucalyptol and menthol.

LISTERINE® brand mouthwash is perhaps the best-known example of oral antiseptic composition that has been shown to be effective in killing microbes in the oral cavity, which are responsible for plaque, gingivitis and bad breath. LISTERINE® brand mouthwash achieves its antimicrobial effect through a combination of essential oils that penetrate and kill microorganisms. These essential oils include precisely balanced amounts of thymol, methyl salicylate, menthol and eucalyptol (hereinafter "essential oils") in a hydroalcoholic solution. Many bad breath bacteria live in cavities or cracks in the surface of the tongue. LISTERINE® mouthwash reduces bad breath due to high concentrations of antimicrobial agents in a liquid medium that can easily penetrate into such cavities and fissures. This would not be possible with a solid dosage form containing low amounts of these antimicrobial ingredients. However, the preferred consumable film of the invention captures a significant portion of the hygiene benefits and appeal to consumable of the LISTERINE® brand mouthwash in a more portable and non-indiscreetly consumed form.

It was a significant challenge to maintain the interaction of the essential oil and the relatively high oil content of the LISTERIN® ® mouthwash in one film. However, the inventors have overcome this challenge by providing the inventive film.

Another aspect of this invention is that while the amounts of essential oils in LISTERINE ® are relatively high for incorporation into a film, the film according to the present invention still provides a lower total amount of essential oils per unit. dose when compared with that of the LISTERINE ® oral disinfectant. Nevertheless the film surprisingly provides antimicrobial efficacy in the oral cavity. The inventors theorize that the preferred film-forming ingredients, pullulan, form a thin layer on oral surfaces retaining the small amount of essential oils that are able to penetrate cavity cavities and cracks. to provide sustained antimicrobial efficacy. Although the inventors are presently unaware of another breath-taking, breath-taking film that provides antimicrobial efficacy, they are aware of a breath-taking film described in JP 5-236885, which is considered to have breath-cooling activity. but is not described as having any ingredients that have significant antimicrobial activity. In addition, JP 5-236885 discloses that its films must contain flavor and extract in amounts of 5 to 7% by weight, with the flavor being added as an oil (essential oils are not described), whereas The film of the invention preferably has an oil content of at least about 10 wt.%, more preferably from about 15 wt.% to about 30 wt.% and more preferably about 15 wt.%. about 25% by weight. Except, as otherwise noted in the examples, the amounts of oils and other ingredients in the film are by weight percent after the film formulation has been dried to create the film.

The amounts of the specific essential oils used in the film compositions may vary as long as they are in sufficient amounts to provide antimicrobial efficacy. In general, the amount of thymol, methyl salicylate and eucalyptol is from about 0.01 to about 4 weight percent of the film composition, preferably from about 0.50 to about 3 percent. .0 percent by weight and more preferably from about 0.70 to about 2.0 percent by weight of the film. Menthol may be added from about 0.01 to about 25 to 15% by weight of the composition, preferably from about 2.0 to about percent by weight and even more preferably from about 3 to about 25%. 9 percent of the film. The amounts added can be easily determined for those skilled in the art and may exceed these as long as the total oil content does not create stickiness or other processing problems. In certain embodiments, essential oils are combined in synergistically effective amounts to kill the germs that produce the plaques that cause dental plaque, gingivitis, and bad breath.

A major difficulty in formulating a film having such a relatively high oil content is that simply increasing the amount of oil in the film without determining the precise proportions of many other ingredients typically results in a film that is very wet and thus difficult to manipulate or process. The inventors have discovered how to provide a high oil film that is moist enough so that it does not break, but is not so moist that it feels sticky or significantly adherent to adjacent films. . Thus, a non-stick film according to the invention may be stored in contact with other such films (such as in a stack), or may be wrapped around themselves (e.g. around without having to place an anti-sticking agent (such as a plastic film, paper or other support) between adjacent parts of the film.

The film-forming agent used in the films according to the present invention may be selected from the group consisting of pullulan, hydroxy propyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol. - la, sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl polymer, amylose, high amylose starch, propylated hydroxy amylose high starch, dextrin, pectin, chitin, chitosan, levane, elsinane, collagen, gelatin, zein, gluten, soy protein isolate, whey protein isolate, casein and mixtures of the same. A film former is preferably pullulan, in amounts ranging from about 0.01 to about 99% by weight, preferably from about 30 to about 80% by weight, more preferably from about 0.01 to about 80% by weight. from about 45 to about 70 wt% of the film and even more preferably from about 60 to about 65 wt% of the film. The film of the invention is preferably composed of pullulan as a film-forming agent and essential oils as antimicrobial and flavoring agents, and may further comprise water, additional antimicrobial agents, additional film-forming agents, plasticizers, additional flavoring agents, sulfur precipitating agents, saliva stimulating agents, cooling agents, surfactants, stabilizing agents, emulsifying agents, thickening agents, agglutinating agents, coloring agents, sweeteners, fragrances and the like.

Due to the relatively high oil content in the oral health care film, it is preferable to avoid substantial amounts of humectants in the film (and more preferably have no humectant in the film) so as to prevent the production of a super-wet film. and self-adherent. Specifically, it is preferable to formulate the film with a plasticizer other than glycerin, which is also a humectant, and with a sweetener other than sorbitol, which is a mild humectant.

Sulfur precipitating agents that reduce oral odor can also be added to the oral health care films of the present invention. These agents bind with and inactivate volatile sulfur compounds that cause a large percentage of oral bad odor. Sulfur precipitating agents useful in the present invention include metal salts such as copper salts and zinc salts. Preferred salts include copper glyconate, zinc glyconate, zinc citrate and zinc glyconate. The amount of the sulfur precipitating agent is from about 0.01 to about 2 wt.%, Preferably from about 0.15 wt.% To about 1.5 wt.%. most preferably from about 0.25 weight percent to about 1.0 weight percent of the film.

Saliva stimulating agents may also be added to the oral health care films of the present invention. Useful saliva stimulating agents are those described in U.S. Patent No. 4,820,506, which is incorporated by reference in this report in its entirety. Saliva stimulating agents include food acids such as citric, lactic, malic, succinic, ascorbic, adipic, fumaric and tartaric acids. Preferably the food acids are citric, malic and ascorbic acids. The amount of saliva stimulating agents in the film is from about 0.01 to about 12 wt%, preferably from about 1 wt% to about 10 wt%, and most preferably from about 0.01 to about 12 wt%. about 2.5 wt% to about 6 wt%.

Plasticizers preferably include triacetin in amounts ranging from about 0 to about 20% by weight, preferably from about 0 to about 2% by weight. Other suitable plasticizing agents include mono acetin and diacetin.

Cooling agents preferably include monomethyl succinate, in amounts ranging from about 0.001 to 2.0% by weight, preferably from about 0.2 to about 0.4% by weight. Monomethyl succinate containing a cooling agent is available from Mane Inc. Other suitable cooling agents include WS3, WS23, Ultracool II and the like.

Preferred surfactants include fatty acid mono- and diglycerides and polyethylene sorbitol esters such as Atmos 300 and Polysorbate 80. The surfactant may be added in amounts ranging from about 0.5 to 15%. by weight, preferably from about 1 to about 5% by weight of the film. Other suitable surfactants include pluronic acid, sodium lauryl sulfate and the like.

Preferably the stabilizing agents include xanthan gum, locust bean gum and carrageenan in amounts ranging from about 0 to about 10% by weight, preferably from about 0.1 to about 2%. by weight of the film. Other suitable stabilizing agents include guar gum and the like.

Emulsifying agents preferably include triethanolamine stearate, quaternary ammonium compounds, acacia, gelatin, lecithin, bentonite, veegum and the like, in amounts ranging from about 0 to about 5% by weight. preferably from about 0.01 to about 0.7% by weight of the film.

Preferably the thickening agents include methyl cellulose, carboxyl methyl cellulose, and the like, in amounts ranging from about 0 to about 20% by weight, preferably from about 0.01 to about 5% by weight.

Binding agents preferably include starch, in amounts ranging from about 0 to about 10% by weight, preferably from about 0.01 to about 2% by weight.

Suitable sweeteners that may be included are those well known in the art, including both natural and artificial sweeteners. Suitable sweeteners include, for example:

A) Water-soluble sweetening agents such as monosaccharides, disaccharides and polysaccharides such as xylose, ribose, glucose (dextrose), mannose, galactose, fructose (levulose), sucrose (sugar), maltose, invert sugar ( a mixture of fructose and glucose derived from sucrose), partially hydrolyzed starch, corn syrup solids, dihydrochalcones, monelin, steviosides and glycyrizine;

B) water-soluble artificial sweeteners such as soluble saccharin salts, i.e. saccharin sodium or calcium salts, cyclamate salts, 3,4-dihydroxy sodium, ammonium or calcium salt 6-methyl-1,2,3-oxythiazine-4-one-2,2 dioxide, the potassium salt of 3,4-dihydro-6-methyl-1,2,3-oxythiazine-4-one -2, 2 dioxide (acesulfame K), the free acid form of the saccharin, and the like;

C) dipeptide-based sweeteners such as L-aspartic acid-derived sweeteners such as L-aspartyl-L-phenylalanine methyl ester (aspartame) and materials described in US Patent No. 3,492,131, L-alpha-aspartyl-N- (2,2,4,4-tetramethyl-3-thietanyl) -D-alaninamide hydrate, L-aspartyl-L-phenyl glycerine and L-aspartyl-L-methyl esters 2,5-dihydrophenyl glycine, L-aspartyl-2,5-dihydro-L-phenyl alanine, L-aspartyl-L- (1-cyclohexenyl) -alanine and the like;

D) Water soluble sweeteners derived from natural water soluble sweeteners, such as chlorinated derivatives of common sugar (sucrose), known, for example under the description of sucralose product; and

E) protein-based sweeteners such as thaumatococcous danielli (Thaumatin I and II).

An effective amount of an auxiliary sweetener is generally employed to provide the desired sweetness level for a specific composition, and that amount will vary with the selected sweetener. This amount will usually be from 0.01% to about 10% by weight of the composition when an easily extractable sweetener is used. The water soluble sweeteners described in category A above are commonly used in amounts from about 0.01 to about 10% by weight, and preferably in amounts from about 2 to about 5% by weight. Some of the sweeteners in category A (such as glycyrizine) may be used in the amounts defined for categories B to E below due to the sweetener's known sweetening capacity. In contrast, sweeteners described in categories B through E are generally used in amounts of from about 0.01 to about 10 wt%, with from about 2 to about 8 percent by weight being preferably from about 3 to about 6 percent by weight, most preferably. These amounts may be used to achieve a desired level of sweetness independent of the taste level achieved from any flavor flavors used. Of course, sweeteners do not need to be added to films intended for non-oral administration.

Flavorings that may be used include those known to those skilled in the art, such as natural and artificial flavors. Such flavorings may be chosen from synthetic flavoring oils and / or oils, resins and extracts derived from vegetables, leaves, flowers, fruits and so on, and combinations thereof. Representative aroma oils include: green peppermint oil, cinnamon oil, peppermint oil, clove oil, bay leaf oil, tannin oil, cedar leaf oil, nutmeg oil, sage oil and bitter almond oil. Artificial, natural or synthetic fruit flavors such as vanilla, chocolate, coffee, cocoa and citrus oils, including the essences of lemon, orange, grape, lime, grapefruit and fruit, are also useful. including apple, pear, peach, strawberry, gooseberry, cherry, plum, pineapple, apricot, and so on. These flavorings may be used individually or in admixture. Commonly used flavors include mint such as peppermint, artificial vanilla, cinnamon derivatives and various fruit flavors, whether employed individually or in mixtures. Flavorings such as aldehydes and esters including cinnamyl acetate, cinnamyl aldehyde, citral, diethylacetal, dihydrocarbyl acetate, eugenyl formate, p-methyl anisole and so on may also be used. Generally, any food flavoring or additive, such as those described in Chemicals Used in Food Processing, publication 1274 by the National Academy of Sciences, pages 63 to 258, may be used. Other examples of aldehyde flavorants include but are not limited to acetaldehyde (apple); benzaldehyde (cherry, almond); cinnamic aldehyde (cinnamon), citral, that is, alpha citral (lemon, lime); neral, ie beta citral (lemon, lime); decanal (orange, lemon); ethyl vanillin (vanilla, cream); heliotropin, ie piperonal (vanilla, cream); vanillin (vanilla, cream); alpha amyl cinnamaldehyde (spicy fruit flavors); butyraldehyde (butter, cheese); valeraldehyde (butter, cheese); citronellal (modify, many types); decanal (citrus fruits); C-9 aldehyde (citrus) C-8 aldehyde (citrus); C-12 aldehyde (citrus fruits); 2-ethyl butyraldehyde (berry type fruits); tolyl aldehyde (cherry, almond); veratraldehyde (vanilla); 2-6-dimethyl-5-heptenal, that is melonal (melon); 2-6-dimethyl octane (green fruit); and 2-dodecenal (citrus, mandarin); cherry; grape; mixtures thereof and the like.

The amount of flavoring employed is usually a matter preferably subject to such factors as flavor type, individual flavor and desired strength. Thus, the amount may be varied to obtain the desired result in the final product. These variations are within the capabilities of those skilled in the art without the need for undue experimentation. In general, amounts of from about 0.1 to about 30 weight percent may be used in amounts of from about 2 to about 25 weight percent, and preferably from about 8 to about 30 weight percent. 0 percent by weight, most preferred.

The compositions of this invention may also contain coloring or coloring agents. Coloring agents are used in amounts effective to produce the desired color. Coloring agents useful in the present invention include pigments such as titanium dioxide, which may be incorporated in amounts of up to 5 weight percent, and preferably less than about 1 weight percent. Dyes may also include natural food colors and dyes suitable for food, drug and cosmetic applications. These dyes are known as FD&C dyes and pigments. Acceptable materials for the preceding use spectrum are preferably water soluble and include FD&C Blue NO 2 which is the disodium salt 5,5-indigotindisulfonic acid. Similarly, the dye known as Green NO3 comprises a triphenyl methane dye and is the 4- [4-N-ethyl-p-sulfobenzylamino) diphenylmethylene] - [1-N-ethyl] N-sulfonyl benzyl) -2,5-cyclohexadienimine]. A list of all FD&C and D&C dyes and their corresponding chemical structures can be found in Kirk-Otmer Encyclopedia of Chemical Technology, Volume 5, pages 857 to 884, the text of which is incorporated in this report. by reference.

Anti-Microbial Effectiveness of Oral Protection Films

The preferred embodiment of the oral protection film composition according to the present invention contains the essential oils used in the LISTERINE ® mouthwash to provide antimicrobial efficacy. The films are of the proper shape and size to be placed in the oral cavity. The film adheres to a surface in the mouth, usually in the roof of the mouth or tongue and dissolves rapidly. The amount of essential oils in an individual film that is of a preferred size to be placed in the mouth is significantly lower than the recommended 20 ml amount of LISTERINE ® oral disinfectant.

In a formula preferably according to the present invention, the amount of thymol and eucalyptol in the film is about 70 times lower than in the mouthwash. The amount of methyl salicylate in the film is about 46 times lower than in the mouthwash. The amount of menthol in the film is about 2.8 times lower than in the mouthwash. These numbers are based on comparing the 20 ml dose of the mouthwash with a 0.0358 gram film.

The inventors unexpectedly found that the film provides continued antimicrobial efficacy in these lower amounts of oils. The inventors believe that the effectiveness of essential oils is increased by creating a pullulan layer in the oral cavity that holds essential oils. This is unexpected because the pulp is water soluble and the film dissolves very quickly.

Prolonged antimicrobial activity is shown in the following experiments.

The purpose of these experiments was to determine the antibacterial efficacy of applying a breath film on the tongue odor odor microorganisms thirty, sixty or ninety minutes after use. The thirty-minute study also tested the effectiveness of using two films. The baseline of recoverable foul-smelling microbial counts in the subjects was determined by plating the recovered microorganisms from a mouth swab onto a selective agar medium. The test product was dispensed and subjects dissolved one or two films over their tongues. Subjects remained in the vicinity and returned for a second tongue smear thirty, sixty or ninety minutes after the product was tested in their language. After a forty-eight hour washout period, subjects returned to a control without treatment. The 30-minute isolated film use group showed a reduction in the microbial count of bad odor in medium Yog compared with the control group. Data were statistically significant at the limit (p = 0.052). The difference between the one film group and the untreated control group represented a 42.7 percent reduction in the colony count of bad odor microbes.

A statistically significant reduction in bad odor microbes was also observed with the two-film use group. A 79.6% reduction in the colony count of bad odor microbes was obtained (P <0.001).

A statistically significant reduction in bad odor microbes was observed sixty minutes after the use of a single breath film. A 69.8% reduction in the colony count of bad odor microbes was obtained (p = 0.002).

A significant reduction in bad odor was also observed ninety minutes after the use of a single breath film. A 69.1% reduction in the colony count of bad odor microbes was obtained (p = 0.006).

The data from these studies support the following conclusions: (1) Pullulan polymer-based breath-based film containing essential oils is an antibacterial composition effective against oral odor-causing bacteria and (2) significant bacterial reductions have been achieved. in vivo within thirty, sixty and ninety minutes after use.

Experimental Procedures

The procedures used in these antimicrobial studies were as follows. Subjects were required to refrain from all oral hygiene procedures (eg tooth brushing, oral washing), to eat or drink any food, drink or confectionery from midnight before the study and until that the study was completed on each of the test days. Subjects abstained from smoking the mornings prior to odor assessments. Germs Death Test in vivo.

1. Materials

Vials containing 10 ml of 0.01% sterile peptone

Sterile smears

Forty-four grams of base columbia blood agar was suspended and boiled until completely dissolved. The medium was sterilized at 121 - 124 ° C for 15 minutes.

0.2 grams of lead acetate dissolved in 1 ml of filter sterilized distilled water. Added after the base medium has been autoclaved.

b 50 mg of hemine dissolved in 1 ml 1N NaOH, made up to 100 ml with distilled water. Sterilized filter. Added 2 ml per liter of OOPS III after the base medium was autoclaved. c 1.2 grams of Glutaciona dissolved in 10 ml of distilled water. Filter sterilized.

2. Procedure

a) All media were previously reduced in an anaerobic chamber overnight. The plates were loosely wrapped in plastic bags to prevent over drying.

(b) The panelists abstained from oral hygiene, food and drink from midnight before the trial until the trial was completed. Twelve panelists were used for the sixty-ninety minute experiments. Eighteen panelists were used for the 30-minute experiments.

c) Each panelist rubbed the right side of his tongue by placing the smear at the midpoint of the tongue and sliding to the tip. The smear was placed in a peptone tube.

d) The panelist received a film treatment, both a single film and two films. Panellists placed the breath film on the left side of their tongues, covering the tongue from its midpoint to the tip and allowing the film to dissolve with its mouth slightly open for thirty seconds to prevent the film from sticking to the palate.

e) After thirty or sixty minutes the panelists rubbed the left side of the tongue by placing the smear at the midpoint of the tongue and sliding forward to the tip. The smear was placed in a peptone tube.

f) The peptone tubes were vortexed vigorously for 10 seconds and serial dilutions were made. The 10 4 dilution was plated in duplicate on OOPS III agar using a Spiral Biotech Autoplate 4000 (Bethesda, MD). All plates were identified with panelist's initials, date of analysis, season sampling time, and replication number.

g) The plates were incubated in an anaerobic chamber at 35 ° C to 37 ° C for 7 days to allow full growth of the colonies without overgrowth.

h) After a 48-hour washout period the panelists returned to control without treatment. No films were applied and steps from (e) to (g) were followed as described.

i. After a 48-hour no-wash period, the sixty-minute panelists returned for another single-film application. Steps from (a) to (h) were followed, except that the panelists returned within 90 minutes of step (e).

j. Dark pigmented colonies (H2S producing organisms) were counted either with total plate counts either manually under appropriate magnification or by segment counting using a standard Spiral Biotech counting plate. The appropriate code was entered in the data sheet to allow interpretation of the counts. The CFU counted were converted to CFU / ml by dividing the appropriate exponential volume constant listed in Table A and multiplying by 1000. This value was then multiplied by the plate dilution factor (10 "4). Table A. Constants Exponential Volume for Pairs of Segments.

<table> table see original document page 20 </column> </row> <table>

The film used for in vivo germ killing tests was Example 19 as described in Table 2. The films used in the study were approximately 22 mm χ 32 mm, between about 33 and 38 μm (0.0013 and 0.0015 inch) thick and weighed from about 35 to about 37 mg.

The increased activity of the pullulan film containing the essential oil is also shown in Figures 1 and 2. Figure 1 is a photograph of one of an Streptpcoccus mutans, ATCC No. 25175 scattered agar plate, which a piece of an essential oil pullulan film according to the invention was added. The film piece supplied approximately 0.391 mg of essential oil using the Example described below.

Figure 2 is a photograph of a streptococcus mutans-spread ATCC No. 25175 agar plate to which drops of essential oils were added. The drops were 148 µl in volume and contained 0.391 mg of essential oils. The percentages of each of the essential oils in the drop were 2.200% menthol, 0.186% eucalyptol, 0.186% methyl salicylate and 0.1300% thymol in a hydroalcohol solution.

The area or zone of inhibition around the film in figure 1 is much larger than the film dimensions. This is due to the presence of pullulan because the oils in the pullulan film were spread over the pullulan, diffused forward and were not removed by washing after repeated rinsing. In contrast, the essential oils in figure 2 did not spread beyond the droplet, remaining in a circle and were easily washed off after 1 or 2 rinses. This shows that the antimicrobial efficiency of essential oils is increased by the presence of pullulan.

Methods For Preparing Films Containing Essential Oils.

The methods for preparing films according to the invention are capable of encapsulating the oil ingredients within the film forming matrix and maintaining the integrity of the film even when the film contains oils in amounts of 10% by weight or more. .

In certain methods for the preparation of films according to the invention, the film-forming ingredients are mixed and hydrated with water separately from the water-soluble ingredients, which are mixed in aqueous solution separately from the organic ingredients. of surfactants. In these methods the final formulation is preferably produced by mixing the film-forming phase with the aqueous phase, and then introducing into the mixture the organic phase, which includes surfactants such as Polysorbate 80 and Atmos 300. Such a mixture of - sa is mixed until emulsified. In other embodiments, the aqueous phase and the film-forming phase are combined in one step by dissolving the water-soluble ingredients in water and then adding the gum to hydrate. The organic phase is then added to that single aqueous phase.

The resulting formulation is molded onto a suitable substrate and dried to form a film. The film is preferably air dried or dried under warm air and cut to a desired size, packaged and stored. The film may contain from about 0.1% to about 10 weight percent moisture, preferably from about 3% to about 8 weight percent unit, and even more preferably from about 10%. from about 4 to about 7 weight percent moisture.

The film forming phase may include pullulan and stabilizing agents such as xanthan gum, locust bean gum and carrageenan. These ingredients are mixed and then hydrated in water for about 30 to about 48 hours to form a gel. The water is preferably heated to a temperature of about 25 to about 45 ° C to promote hydration. The amount of water is from about 40 to about 80% of the gel. The resulting hydrated gel is cooled to a temperature of about 20 to about 30 ° C for about 1 to about 48 hours. The water is preferably deionized.

The aqueous phase may include ingredients such as coloring agent (s), copper glyconate and sweetener. The water is preferably deionized and the amount of water used is from about 5 to about 80 weight percent of the final gel mixture.

If sodium saccharin and copper glyconate were both ingredients of the formulation, it is preferable to dissolve them separately in solution to prevent precipitation.

In a preferred method for producing the films containing the essential oils according to the invention, it is possible to hydrate the film-forming ingredients and combine all the ingredients without heating. The method preferably for the production of films comprises dissolving the water-soluble ingredients in water to form an aqueous mixture; mixing the powder forming film ingredients to form a powder mixture; adding the powder mixture to the aqueous mixture to form a hydrated polymer gel; stirring the hydrated polymer at room temperature from about 30 minutes to about 48 hours; mixing the cooling agent, thymol and menthol in the flavoring oil to form an oil mixture; adding methyl salicylate, eucalyptol and surfactant to the oil mixture; adding the oil mixture to the hydrated polymer gel and mixing until uniform; deaerate the film until air bubbles are removed, mold the uniform mixture onto a suitable substrate; and drying the molded mixture to form a film.

Preferably the method of making a film containing an essential oil hydrates the film-forming ingredients without heating the water. Heating ingredients increases energy costs in the manufacturing process. In addition, heating results in undesirable loss of volatile ingredients due to evaporation, which also affects the germ-killing activity of the composition due to the loss of essential oils. In addition, mixing oils in two tapas minimizes the amount of aroma lost.

While not wishing to be bound by theories, it is believed that the film-forming ingredients can be hydrated and mixed without heating due to the ionic effect known as the Donnan equilibrium. Hydration of film-forming agents in the presence of electrolytes in solution effectively lowers the viscosity of the polymer gel being formed, thereby increasing the effectiveness of the hydration process. The water-soluble ingredients of the formulation provide the electrolytes, which are dissolved in the hydration solution prior to the addition of the film-forming ingredients. High shear mixing also accelerates hydration, which crumbles the dust clusters, providing a larger surface area for contact with water. In addition, the effects of local heating generated on the shear regions provide energy for hydration without substantially increasing the mass temperature.

It is preferable to avoid the addition of both copper glyconate and saccharin at the same time in the aqueous solution as a precipitate may form. Thus, it is preferably the combination of a sweetener other than saccharin and copper glyconate.

Description of Film Compositions Providing Pharmaceutical Agents.

A second embodiment of the invention is a rapid dissolving film comprising at least one pharmaceutically active and physiologically acceptable agent. The term "physiologically acceptable" as used in this report is intended to encompass compounds, which upon administration to a patient are adequately tolerated without causing undue negative side effects. The term encompasses edible compounds. The term "pharmaceutically active agents" as used herein is intended to include non-food agents that promote structural and / or functional change in or on bodies to which they have been administered. These agents are not specifically limited; however they must be physiologically acceptable and compatible with the film. Pharmaceutically acceptable active agents include, but are not limited to:

A) antimicrobial agents such as triclosane, cetyl pyridium chloride, domiphene bromide, quaternary ammonium salts, compounds of zinc, sanguinarine, fluorides, alexidine, octonidine, EDTA, and the like,

B) non-steroidal antiinflammatory drugs such as aspirin, acetaminophen, ibuprofen, ketoprofen, diflunisal, phenoprofen calcium, na- proxene, sodium tolmetim, indomethacin and the like,

C) antitussives such as benzonate, caramifene edisylate, menthol, dextromethorphan hydrobromide, clofedianol hydrochloride, and the like,

D) decongestants such as pseudoephedrine hydrochloride, phenylephrine, phenyl propanolamine, pseudoephedrine sulfate, and the like,

E) antihistamines such as bronpheniramine maleate, chlorpheniramine maleate, carbonoxamine maleate, clemastine fumarate, dexchlorpheniramine maleate, diphenyldramine hydrochloride, azatadine maleate, diphenyldramine citrate, doxylamine, promethazine hydrochloride, pyrilamine maleate, tryptamine citrate, tripolidine hydrochloride, acrivastine, loratadine, bronfniramine, dexbrompheniramine, and the like,

F) expectorants such as guaifesine, ipecac, potassium iodide, terpine hydrate and the like,

G) antidiarrheals, such as loperamide, and the like.

H) H2 antagonists such as famotidine, ranitidine and the like,

I) proton pump inhibitors such as omeprazole, lanzoprazole, and the like,

J) non-selective general CNS depressants, such as aliphatic alcohols, barbiturates and the like,

K) non-selective general CNS stimulants such as caffeine, nicotine, strychnine, picrotoxin, pentylenetetrazole and the like,

L) drugs that selectively modify CNS function such as phenyldantoin, phenobarbital, primidone, carbamazepine, etosuximide, metsuximide, fensuximide, trimetadione, diazepan, benzodiazepines, fenacetamide, feneturide, acetazolamide, sultiamo, bromide, bromide, bromide, similar,

M) Parkinson's anti-disease drugs such as levodopa, amantadine and the like,

N) narcotics - analgesics such as morphine, heroin, hydro-mosphone, metopone, oxymorphone, levorphanol, codeine, hydrocodone, xicodone, nalorphine, naxolone, nalxetrone and the like,

O) analgesics and antipyretics such as salicylates, phenylbutazone, indomethacin, phenacetin and the like,

P) psychopharmacological drugs such as chlorpromazine, meth trimimeprazine, haloperidol, clozapine, imipramine, tranylcypromine, phenelzine, lithium and the like.

The amount of medicaments that may be used in the rapidly dissolving films of the present invention is dependent upon the dose required to provide an effective amount of the medicament. Examples of specific drug doses that can be provided by a rapidly dissolving oral film strip are given in Table 1.

Table 1

<table> table see original document page 25 </column> </row> <table> <table> table see original document page 26 </column> </row> <table>

The ingredients used for the manufacture of pharmaceutical containing films are similar to those used for the manufacture of oral protection films. Specifically the plasticizing agents, cooling agents, surfactants, stabilizing agents, emulsifiers, thickening agents, binding agents, film formers, sweeteners, flavorings and colors described above may also be used in all films according to the present invention.

Films supplying a pharmaceutical agent may also include a triglyceride. Examples of triglycerides include vegetable oils such as corn oil, sunflower seed oil, peanut oil, olive oil, canola oil, soybean oil and mixtures thereof. A preferred triglyceride is olive oil. Triglyceride is added to the film in amounts from about 0.1 weight percent to about 12 weight percent, preferably in a range from about 0.5 weight percent to 9 weight percent, of the product. film.

Films containing the pharmaceutical agent may also include a preservative. The preservative is added in amounts from about 0.001 wt% to about 5 wt%, preferably from about 0.01 wt% to 1 wt% of the film. Preferred preservatives include sodium benzoate and potassium sorbate.

The pharmaceutical agent-containing films may also include a polyethylene oxide compound. The molecular weight of the polyethylene oxide compound ranges from about 50,000 to about 6,000,000. A polyethylene oxide compound preferably is N-10 available from Union Carbide Corporation. The polyethylene oxide compound is added in amounts from about 0.1 wt% to about 10 to 5 wt%, preferably from about 0.2 wt% to about 4, 0% by weight of the film.

Films containing the pharmaceutical agent may also include propylene glycol. Propylene glycol is added in amounts from about 1 wt% to about 20 wt%, preferably from about 5 wt% to about 15 wt% of the film.

The active ingredient used in the film may be coated to mask the taste of the active ingredient or prevent the active ingredient from numbing the tongue or other surfaces of the oral cavity. Coatings that may be used are known to those skilled in the art. These include polymers such as Eudragit® E, cellulosics as well as ethylcellulose, and the like.

An additional way to mask the taste of the active ingredient is by using an ion exchange resin, such as Amberlite RP-69, obtained from Rohn and Haas, and 10 w XYS-40010.00 available from Dow Chemical Co.

Examples

The invention will be illustrated in more detail with reference to the following examples, but it should be understood that the present invention is not considered to be limited thereto.

Preparation Method I

The following method was used for preparing the films of Examples 1 through 13. A) Film-forming ingredients (such as xanthan gum, locust bean gum, carrageenan and pullulan) other than Po - lysorbate 80 and Atmos 300 are mixed and hydrated in purified hot water for gel formation and stored in a refrigerator overnight at an approximate temperature of 4 ° C for preparation A.

B) The coloring agent (s), copper gluconate and sweetener are added to and dissolved in purified water to form preparation B.

C) Preparation B is added to preparation A and is well mixed to form preparation C.

D) The flavoring agent and the oils (for example the cooling agent, thymol, methyl salicylate, eucalyptol and menthol) are mixed to form preparation D.

Ε) Polysorbate 80 and Atmos 300 are added to preparation D and well mixed to form preparation E.

F) Preparation E is added to preparation C and well mixed to form preparation F.

Preparation F is poured into a mold and molded to form a desired thickness film at room temperature. The film is dried under warm air and cut to a desired size, packaged and stored;

Preparation Method II

Examples 14 to 18 were prepared using a preferred method comprising the following steps:

A) dissolving copper gluconate, acesulfame K, aspartame, glycerin, sorbitol and the dye in purified water to form an aqueous mixture;

B) mixtures pullulan, xanthan gum, locust bean gum and carcinogen together in powder form to form a powder mixture;

C) adding the powder mixture from step B to the aqueous mixture from step A to form a hydrated polymer gel; D) stirring the hydrated polymer from step C at low speed (about 50 to 100 RPM) overnight at room temperature;

E) mixing and dissolving the cooling agent, thymol and menthol in the flavoring oil;

F) adding methyl salicylate, eucalyptol, Polysorbate 80 and Atmos 300 to the oil mixture of step E;

G) adding the oil mixture from step F to the hydrated polymer gel from step D and mixing until uniform;

H) shaping the uniform mixture from step G onto a suitable substrate; and

I) drying the molded mixture to form a film.

Example 1

Example 1 produced a film according to the invention that had a blue-green color, a mint odor and a refreshing mint taste.

Examples 2 to 4

Examples 2 to 4 contain sorbitol, glycerin or both. These examples produced products that broke easily into pieces, or were very moist and / or self-adhering. However, they produced films that rapidly dissolved in the oral cavity with a refreshing mint taste.

Examples 5 and 6

Examples 5 and 6 removed glycerin and sorbitol. The resulting films did not stick together during processing and packaging and were stable to moisture over a long time frame.

Examples 7 to 9

Examples 7 through 9 were produced to determine the effect of Avicel® on germ killing activity. While examples 7 through 9 produced more acceptable films from a processing and handling perspective, they had decreased antimicrobial activity over non-Avicel® films, such as those in example 8. Examples 10 through 15

Examples 10 to 15 varied the amounts of aspartame and menthol to change the sweetness and freshness of the film.

Example 16

Example 16 was prepared by replacing sorbitol, which was replaced with maltitol having less wetting properties. The resulting film was less sticky during processing and long term storage.

Example 17

Example 17 was prepared in which pullulan was replaced with another film former, polyvinyl pyrrolidone, for the production of films according to the invention.

Example 18

Example 18 was prepared in which pullulan was partially replaced by another film former, konjac gum, for the production of films according to the invention.

Example 19

Example 19 represents a film containing a saliva stimulant, citric acid.

Example 20

Example 20 is the film composition used in the antimicrobial efficacy studies described above.

The formulas for examples 1 to 20 were summarized in Table 2. The amounts in these examples are presented as actual weight (grams) or weight percent by weight. These formulas create the solution / gel that is molded and dried on a film. The actual amount of each ingredient in the finished dry film depends on the amount of relative humidity removed during drying. Table 2 - 1st part

<table> table see original document page 31 </column> </row> <table> <table> table see original document page 32 </column> </row> <table> <table> table see original document page 33 < / column> </row> <table> <table> table see original document page 34 </column> </row> <table> <table> table see original document page 35 </column> </row> <table> <table> table see original document page 36 </column> </row> <table> The following examples are films according to the second embodiment of the present invention in which the fast dissolving film contains a pharmaceutical agent. . The examples 21A through 21E listed in Table 3 are medicament-containing rapid dissolving oral film formulas. The amounts in Table 3 are in milligrams.

Table 3

<table> table see original document page 37 </column> </row> <table>

* calculated assuming complete evaporation of water from the films after drying.

Table 4 summarizes the additional films according to the invention. The amounts in table 4 are in weight by weight percentages prior to drying.

Table 4

<table> table see original document page 38 </column> </row> <table>

Example 22A was used for the manufacture of films containing: a) 7.5 mg dextromethorphan hydrobromide, b) 2.5 mg tripolydine, c) 4.0 mg chlorpheniramine maleate and d) 12.5 mg diphenyldramine hydrochloride.

Example 22B was used for the manufacture of a film containing 10 mg dextromethorphan hydrobromide.

Example 22C was used for the manufacture of a film containing 10 mg dextromethorphan hydrobromide.

Example 22D was used for the manufacture of a film containing a) 10 mg phenylephrine hydrochloride, b) 10 mg phenylphrine hydrochloride, and 4 mg chlorpheniramine maleate and c) 10 mg dextromethorphan hydrobromide.

Example 22E was used for the manufacture of a film containing 7.5 mg dextromethorphan hydrobromide.

Example 22F was used to manufacture a film containing 20 mg of coated dextromethorphan hydrobromide to provide a dose of 7.5 mg.

Example 22G was used to make a film containing a) 7.5 mg dextromethorphan hydrobromide, b) 10 mg phenylephrine hydrochloride, and c) 10 mg phenylephrine hydrochloride and 4 mg chlorpheniramine maleate.

Example 22H was used to manufacture a film containing 15 mg dextromethorphan hydrobromide.

Example 22I was used for the manufacture of a film containing 15 mg dextromethorphan hydrobromide.

Process for the manufacture of films containing pharmaceutical products.

Example 22A was manufactured using the following procedure:

1. Add sodium benzoate and sweetener to the water.

2. Mix carob gum, xanthan gum and carrageenan together.

3. Add the gum mixture to the mixture from step 1 and mix until dissolved.

4. Mix the active ingredient with both water and propylene glycol. Warm up if necessary. 5. Add the remaining ingredients to the mixture from step 4 or mix the remaining ingredients in a separate mixture.

6. Add the mixtures from step 4 and step 5 to the mixture from step 3. Mold and dry to make a film and cut to a size to achieve the desired dose.

Examples 22B through 22E were manufactured using the following procedure.

1. Add sodium benzoate to water heated to 50 ° C. Mix to dissolve.

2. Separately add Peg 1450, titanium dioxide and the active ingredient to the mixture from step 1, mixing in each addition.

3. Mix the locust bean gum, the xanthan gum and the carrageenan together.

4. Add the gums to the mixture from step 2 and mix until dissolved.

5. Add remaining ingredients together with heat if necessary.

6. Add the mixture from steps 4 and 5 together. Mold and dry to make a film and cut to a size to achieve the desired dose.

Examples 22F to 22I were manufactured in the same manner as examples 20B to 20E, except that the active agent was dispersed immediately before the film was molded.

Although the invention has been described in detail and with reference to specific examples thereof, it will become apparent to one skilled in the art that various changes and modifications may be made thereto without departing from the spirit and scope of the invention.

Claims (13)

Method for the preparation of a physiologically compatible film, characterized in that it comprises: mixing at least one water soluble film former and at least one stabilizing agent to provide a film forming mixture; dissolving the water soluble ingredients to provide an aqueous solution; combining said film-forming mixture and said aqueous solution to provide a hydrated polymer gel; mixing the oils to form a mixture of oils; adding said oil mixture to said hydrated polymer gel and mixing to provide a uniform gel; shaping the uniform gel onto a substrate; and drying the molded gel to provide said film. Method according to claim 1, characterized in that at least one surfactant is mixed in said oil mixture. A method according to claim 1, characterized in that the total amount of said oils in said oil mixture is at least about 5% by weight of the total weight of the ingredients in said method. Method according to claim 3, characterized in that said total amount of oils is at least about 15% by weight. A method according to claim 1, characterized in that said drying is performed until said film has a moisture content of from about 3 wt% to about 8 wt%. Method according to claim 1, characterized in that before being combined with said aqueous solution, said film-forming mixture is hydrated with water at a temperature of about 25 ° C to about 25 ° C. 50 ° C and then cooled to a temperature of about 4 to about 30 ° C for about 2 to 48 hours. Method according to claim 1, characterized in that said film-forming mixture is a powder which is directly combined with said aqueous solution. A method according to claim 7, characterized in that said hydrated gel polymer is formed without heating. A method according to claim 8, characterized in that said hydrated gel polymer is stirred at room temperature for about 2 to about 48 hours. Method according to claim 9, characterized in that said oil mixture is prepared by mixing thymol and menthol in a flavoring oil, and then adding methyl salicylate and eucalyptol. Self-adhering film, characterized in that it is producible by the method as defined in claim 1. The method according to claim 1, characterized in that the water-soluble film former is selected from the group consisting of pullulan, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose. , polyvinyl alcohol, sodium alginate, polyethylene glycol, tragacanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl polymer, amylose, high amylose starch high hydroxypropylated amylose, dextrin pectin, chitin, chitosan, levanoelsinane, collagen, gelatin, zein, gluten, soy protein isolate, whey protein isolate, casein, and mixtures thereof. A method according to claim 12, characterized in that said water-soluble polymer is pullulan.