Topical composition

Abstract: A composition and method for the topical application of a water dispersible active ingredient to a surface of a warm blooded animal is provided. Specifically, such composition is provided to have the properties of being readily flowable at room temperature upon filling a container therewith, maintaining such flowable condition after storage for a substantial length of time and being readily flowable upon application to the desired animal situs. Uniquely, upon contact with the warm surface of the animal then, and only then, does the composition quickly form into a non-flowable relatively substantive gel. Specifically such composition comprises: (a) a water soluble nonionic block copolymer of ethylene oxide and propylene oxide of the formula HO(C₂H₄O) a (C₃H₆O) b (C₂H₄O) c H; (b) the active ingredient to be topically delivered; and (c) water.

Description: This invention relates to the provision of anti-microbial mouthwashes for the topical application of water soluble antimicrobial ingredients to the internal surface of the mouth of a warm blooded animal including humans. In particular, this invention relates to such a composition which can be applied as a relatively low viscosity flowable liquid and which will quickly, upon contact with the warm surface of such animal, turn into a relatively high viscosity, essentially non-flowable, gel. The problem of providing such a composition has been addressed in CA-A-1 072 413 and US-A-4 188 373: CA-A-1 072 413 discloses a composition, formulated with appropriate amounts of gelling agents, the primary component of which is poloxamer (e.g. Pluronic F-127), which is liquid at room temperature and gel forming upon warming to a temperature above 26°C. The concentration of the polymer is adjusted to give the desired sol-gel transition temperature. One type of application is the formulation of non-toxic compositions for therapeutic, prophylactic or cosmetic treatment of humans or animals for application to the body or body cavities. US-A-4 188 373 discloses a pharmaceutical composition for medicinally treating a mucous membrane or eye condition, comprising from 10-26% by weight of a polyoxyethylene-polyoxypropylene block copolymer (e.g. Pluronic F-127), which has a gel transition temperature of 25-40°C. The present invention comprises the use in the preparation of an antimicrobial mouthrinse of 10 to 17% by weight of the said composition of a single water soluble, nonionic block copolymer of ethyleneoxide and propylene oxide of the formula HO(C₂H₄O) a (C₃H₆O) b (C₂H₄O) c H, wherein the ethylene oxide units comprise from 65 to 75% by weight of the said copolymer and the said copolymer has an average molecular weight of from 11,000 to 13,000; the said copolymer being provided in such quantity such that the said composition is flowable at temperatures below 80°F (26.7°C) and forms a gel upon contact with the surface of the oral cavity. Preferably, the weight percent of the copolymer in the composition should be from twelve to seventeen percent. The ethylene oxide/propylene oxide block copolymer of the composition of the present invention is selected from a group of water soluble polyalkylene glycol block copolymers known generically as poloxamers. The copolymer preferably has an average molecular weight of from 12,000 to 13,000. The poloxamer of choice is designated poloxamer 407 and has an average molecular weight of about 12,500. The poly(ethylene oxide) blocks average 67 moles, i.e. about 69%, by weight. Poloxamer 407 as described by the manufacturer is nontoxic, exhibiting in rat studies an LD₅₀ of 15.4 g/kg and in studies with rabbits, an acute dermal toxicity greater than 2 g/kg. An aqueous solution of 20% by weight of Poloxamer 407 was found by the manufacturer to be non-irritating in a Draize Rabbit Eye irritation study. Table 1 sets out some of the physical properties of this preferred poloxamer 407 as sold by the BASF Wyandotte Corporation of Parsippany, New Jersey under the trademark PLURONIC (Registered Trade Mark) F127. Poloxamer 407 is virtually tasteless and odourless and hence has found use in solubilization of aromatics in oral hygiene products such as aqueous alcoholic mouthwashes. As usual in these compositions, the concentration is quite low (less than 10% by weight and generally less than 1% by weight) and hence such compositions do not exhibit the self gelling properties described herein. The poloxamer compounds are indeed known to be useful in forming gels and, in fact are so described in a brochure of the aforementioned BASF Corporation entitled Pluronic & Tetronic Block Copolymers Surfactant pp. 16-17 (1987). In a further publication of BASF entitled Technical Data of Pluronic Polyols, the recommended procedure is described for forming gels from Pluronic F127 solutions. It is said that gels will be formed with concentrations having a minimum of 20% by weight of such compound and may be formed by dissolving the Pluronic F127 at 80°C into the solution and cooling to room temperatures to form the gel. Alternatively, the Pluronic F127 may be dissolved into a water solution at 5 to 10°C and then brought to room temperature whereupon it forms a ringing gel. As is apparent, these teachings would not lead one skilled in the art to employ Pluronic F127 to meet the objects of this invention in that such teachings are totally inimical to the objects of this invention; it is taught that the result is a gelled solution at room temperature i.e. one that cannot be filled, stored or dispensed as a flowable liquid. Instead, it has now been discovered that by employing poloxamer 407, in concentrations untaught by the prior art namely, greater than ten percent and less than seventeen percent and preferably from twelve to seventeen percent an aqueous single phase solution is produced which is liquid and flowable at room temperature and will gel in only a few seconds when elevated to about 80°F (26.7°C). While the mechanism for the phenomenon of gelling at the desired temperature is not completely clear, it is believed that such behaviour is totally dependent on the choice of a specific narrow range of defining parameters for the polymer e.g. molecular weight and proportions of ethylene oxide to propylene oxide units together with the choice of a narrow band of concentrations of the polymer in the composition. In addition to anti-microbial active ingredients mouthwashes in accordance with the present invention may also contain antibiotic agents e.g. triclosan, chlorhexidene, alexidine, cetylpyridinium chloride or sanguinarine as well as essential oils, fluorides providing anticaries properties, and astringents such as zinc compounds. Some typical anti-microbial agents are set out with greater particularity in commonly assigned copending British Patent Application 8801773, published as GB 2200551A on August 10, 1988. Such active ingredients may also include astringent salts which form a thin protective film on the surface of body cells and hence lessen the cells sensitivity to external stimuli such as might be caused by mechanical, thermal or chemical action. Examples of astringent compounds utilized in orally applied compositions include zinc salts such as zinc chloride and zinc citrate which are soluble in water. Such active ingredient may also include certain compounds for the purpose of topical deodorization such as, for example, chlorophyllins. Additionally, such active ingredient may include fluorides as anticaries agents such as sodium fluoride, stannous fluoride and sodium monofluorophosphate. In addition to such active ingredients, additional components are typically employed in oral aqueous compositions including such additional components as alcohol, flavour, humectants and surfactants. Alcohols are employed, in denatured form, in concentrations of 5 to 30% for the various purposes of enhancing the impact of a flavour ingredient, enhancing antimicrobial efficacy or for facilitating the solubility of other ingredients. Suitable alcohols are for example ethanol or isopropanol. Flavours utilized in mouth washes for example, include such ingredients as eucalyptol, menthol, thymol, methyl salicylate together with flavour modifiers. Additionally, certain mint-type flavours and cinnamon type flavours have been employed including for example peppermint, spearmint or clove. Frequently, sweeteners such as saccharin compounds are also included. Humectants are employed primarily to prevent crystallization around closures. Glycerin sorbitol, polyethylene glycol, and polypropylene glycol are generally the humectants of choice. Additionally, as has been described above, surfactants have been employed, primarily to aid in the solubilization of some of the other ingredients and to provide a foaming action if desired. In addition to the poloxamer compounds described above, such surfactants may include other nonionics such as polyethylene fatty acid esters, and sorbitan monostearate as well as cationics such as cetylpyridinium chloride or anionics such as sodium lauryl sulphate. Description of Certain Embodiments The following examples are further illustrative of the nature of the present invention. All amounts and proportions referred to herein are by weight. Example 1 An antimicrobial mouthrinse is prepared comprising chlorhexidine digluconate as the active antimicrobial agent. This composition is a flowable liquid at temperatures below 82°F (27.8°C), and when heated to 82°F gels in less than one minute. The sample gels upon contact with the oral surface. Example 2 An antimicrobial mouthrinse is prepared comprising cetylpyridinium chloride as the active antimicrobial agent. Again, this composition is a flowable liquid below 82°F and when heated to 82°F (27.6°C), gels in less than one minute. The sample gels upon contact with the oral surface. Accordingly, the use of alternative antimicrobial agents does not effect the desired gelling phenomenon.

Claims: The use in the preparation of an antimicrobial mouthrinse of 10 to 17% by weight of the said mouthrinse of a single water soluble, nonionic block copolymer of ethyleneoxide and propylene oxide of the formula HO(C₂H₄O) a (C₃H₆O) b (C₂H₄O) c H, wherein the ethylene oxide units comprise from 65 to 75% by weight of the said copolymer and the said copolymer has an average molecular weight of from 11,000 to 13,000; the said copolymer being provided in such quantity that the said composition is flowable at temperatures below 80°F (26.7°C) and forms a gel upon contact with the surface of the oral cavity.

Inventors: PIECHOTA STANLEY E JR, PIECHOTA, STANLEY E., JR.
Applicants: COLGATE PALMOLIVE CO, COLGATE-PALMOLIVE COMPANY
Application year: 1991
Main classification: A61K7
IPC codes: A61K9, A61K8, A61K47, A61Q11, A61K31