IIIHIII III US005453284A United States Patent (19) 11 Patent Number: 5,453,284 Pelico (45) Date of Patent: * Sep. 26, 1995 (54. STABILIZED ENZYMATIC DENTIFRICE 4,178,362. 12/1979 Hoogendoorn ............................ 424/48 4,269,822 5/1981 Pellico ........ ... 424/50 (76 Inventor: Michael A. Pelico, 3024 Military Ave., 4,537,764 8/1985 Pellico ... ... 424/50 Los Angeles, Calif. 90272 4,564,519 1/1986 Pellico ........ ... 424/48 4,576,817 3/1986 Montgomery ... 424/94. *ck Notice:- - - S. t s s 4,617,1904,578.265 10/19863/1986 PellicoMontgomery ........ ... ... 426/61424/50 subsequent to Aug. 9, aSOeel C1S- 5,176,899 1/1993 Montgomery ............................. 424/50 claimed. Primary Examiner-Phelan, D. Gabrielle (21 Appl. No.: 283,816 Attorney, Agent, or Firm-Donald Diamond 22 Filed: Aug. 1, 1994 (57 ABSTRACT Related U.S. Application Data Hydro-activated and/or oxygen activated aqueous, enzy matic, antimicrobial dentifrices are stabilized against enzy 63 Continuation-in-part of Ser. No. 10,841, Jan. 29, 1993, Pat. matic activation prior to oral application of the dentifrice by No. 5,336,494. incorporating a thickener into the dentifrice formulation so I51) int. Cl. ....................... A61K 128 as to provide the formulation with an enzyme immobilizing 52) U.S. Cl 424/94. 4:424/49: 424/50: viscosity which inhibits enzymatic action during processing 424/94.1: 424/94.2 and in the dentifrice package. An illustrative, thickened, - A enzymatic dentifrice with this enhancement contains glu 58 Field of Search ................................... 424/94.1-94.4, cose oxidase, glucose, lactoperoxidase and potassium thio 424/49, 50 cyanate together with carboxymethylcellulose in an amount 56) References Cited tO provide the dentifrice with a viscosity of at least about 800 centipoises. U.S. PATENT DOCUMENTS 4,150,113 4/1979 Hoogendoorn ............................ 424/50 16 Claims, No Drawings 5,453,284 1. 2 STABLIZED ENZYMATIC DENTIFRICE tains a thiocyanate salt and lactoperoxidase for interacting with hydrogen peroxide to produce a hypothiocyanate (sic) REFERENCE TO RELATED APPLICATION bacterial inhibitor, with pre-application stability being main tained by limiting any unbound water in the chewable This application is a continuation-in-part of U.S. patent dentifrice to an amount not more than about 1.0 wt.% and application Ser. No. 08/010,841 filed Jan. 29, 1993, now limiting the total water, bound and unbound, to not more U.S. Pat. No. 5,336,494, and entitled Pet Chewable Products than about 10 wt.%. With Enzymatic Coating, the disclosure of which is incor U.S. Pat. No. 5,176,899 (Montgomery, 1993) discloses an porated herein by reference. aqueous enzymatic dentifrice which contains, for example, 10 Beta-D-Glucose and glucose oxidase for producing hydro BACKGROUND OF THE INVENTION gen peroxide upon oral application of the dentifrice and, 1. Field of the Invention optionally, contains a thiocyanate salt and lactoperoxidase This invention relates to enzymatic dentiffice composi for interacting with hydrogen peroxide to produce a tions and, more particularly, to stabilized, aqueous, enzy hypothiocyanite (OSCN-) bacteriostatic agent, with pre matic dentifrices which, upon oral application, produce an 15 application stability being maintained by processing and anti-bacterial and bacteriostatic effect in the oral cavity by packaging the dentifrice under vacuum conditions or in an activation of the enzyme system within the dentifrice. inert gas environment so as to limit the level of dissolved 2. Related Art oxygen in the dentifrice. The enzymatic dentifrice compositions described in U.S. It is disclosed in the prior art that enzymatic anti-bacterial 20 Pat. Nos. 4,564,519 and 4,578,265 comprise an enzyme systems, predicated on oxidoreductase enzymes such as system containing an oxidizable substrate and an oxi glucose oxidase, can be incorporated into oral care products doreductase enzyme specific to such substrate for producing and other products such as powder milk (U.S. Pat. No. hydrogen peroxide upon oral application of the dentifrice 4,617,190) and bandages (U.S. Pat. No. 4,576,817) for with the chemical environment of the oral cavity providing producing an anti-bacterial effect in a defined environment. 25 the source of the additional reactant (oxygen) or reactants U.S. Pat. No. 4,150,113 (Hoogendoorn et al., 1979) and (oxygen, water) to effect the enzymatic reaction. It is dis U.S. Pat. No. 4,178,362 (Hoogendoornet al., 1979) disclose, closed in these patents that it is essential to limit any water respectively, an enzymatic toothpaste and an enzymatic present in the described dentifrices to an amount not more chewable dentifrice containing glucose oxidase which acts than about 10 wt.% in order to impart maximum stability on glucose present in saliva and tooth plaque to produce 30 and shelf life to the compositions since water promotes the hydrogen peroxide. The patentees note that oral bacterial, oxidation/reduction reaction and is also a reactant in certain through enzyme systems having SH-GROUPS, effect gly enzymatic reactions. colysis of food products containing sugars and point out that lactoperoxidase, which is present in saliva, provides the It would, of course, be advantageous to increase the water 35 concentration of the aforesaid enzymatic dentifrice compo means for transferring oxygen from hydrogen peroxide to sitions to an amount in excess of 10 wt.% in order to the oral bacteria resulting in the oxidation of the SH improve the oral application characteristics of the dentifrice, containing enzymes into inactive disulfide enzymes. It is without initiating the enzymatic reaction within the denti further disclosed that the dentifrice may be formulated with frice package and thereby preserve the package integrity of potassium thiocyanate. the product. U.S. Pat. No. 4,269,822 (Pellico et al., 1981) discloses an 40 antiseptic dentifrice containing an oxidizable amino acid SUMMARY OF THE INVENTION substrate and an oxidoreductase enzyme specific to such substrate for producing hydrogen peroxide and ammonia In accordance with this invention, there is provided an upon oral application of the dentifrice, with pre-application aqueous enzymatic dentifrice having a water content in stability being maintained by limiting the quantity of any 45 excess of 10 wt.% and containing, per gram of dentifrice, water present in the dentifrice. from about 0.015 to about 0.6 millimole of oxidizable U.S. Pat. No. 4,537,764 (Pellico et al., 1985) discloses an substrate and from about 0.5 to about 5,000 International enzymatic dentifrice containing Beta-D-Glucose and glu Units of oxidoreductase enzyme specific to such substrate cose oxidase for producing hydrogen peroxide upon oral for producing hydrogen peroxide upon oral application of application of the dentifrice, with pre-application stability 50 the dentifrice, and further containing non-toxic, ambient, being maintained by limiting any water in the dentifrice to water soluble thickener in an amount to provide the denti frice with a viscosity from about 800 to about 75,000 not more than about 10 wt.% based on the weight of the centipoises to thereby stabilize the dentifrice against the dentiffice. production of hydrogen peroxide prior to oral application of U.S. Pat. No. 4,578,365 (Pellico et al., 1986) discloses a 55 di-enzymatic dentifrice which contains, for example, glu the dentifrice. cose and glucose oxidase for producing hydrogen peroxide upon oral application of the dentifrice and further contains DETAL LED DESCRIPTION a thiocyanate salt and lactoperoxidase for interacting with The invention described herein is directed to the use of hydrogen peroxide to produce a hypothiocyanate (sic) with 60 thickener in aqueous dentifrice compositions containing a pre-application stability being maintained by limiting any hydro-activated and/or oxygen activated enzyme system to water in the dentifrice to not more than about 10 wt.% based thereby provide a viscosity which inhibits the enzymatic on the weight of the dentifrice. reaction prior to oral application of the dentifrice. U.S. Pat. No. 4,564,519 (Pellico et al., 1986) discloses a The thickeners which can be used in the practice of this di-enzymatic chewable dentifrice which contains, for 65 invention comprise non-toxic, ambient, water soluble hydro example, glucose and glucose oxidase for producing hydro colloids such as carboxymethylcellulose (sodium carboxym gen peroxide upon chewing the dentifrice and further con ethylcellulose),hydroxymethylcellulose, high-viscosity 5,453,284 3 4 starch, hydrogenated starch, Xanthan gun and mixture and an alkali metal salt of an oxygen accepting anion for thereof as well as equivalents thereof. The thickener is interacting with hydrogen peroxide to produce an oxidized generally present in an amount to provide the enzymatic anionic bacterial inhibitor. dentifrice with a viscosity from about 800 to about 75,000 Peroxidases which can be used in the practice of this centipoises, with an intermediate amount being so selected invention include lactoperoxidase, horse radish peroxidase, as to provide the dentifice with a viscosity from about 2,000 iodide peroxidase, chloride peroxidase and myeloperoxi to about 60,000 centipoises, and a preferred amount being so selected as to provide the dentifrice with a viscosity from dase. Oxidizable salts which can be used in the practice of about 15,000 to about 50,000 centipoises. Viscosity deter this invention include, for example, the thiocyanate, chloride minations