IN AQUEOUS SOLUTION AND

METHODS FOR PREPARING SAME

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention pertains to stabilized hexahydro-5-pyrimidinamine compounds in aqueous solution. More particularly, this invention pertains to antiseptic compositions comprising a therapeutically effective amount of an antiseptic hexahydro-5-pyrimidinamine compound, a sufficient amount of a buffer solution to maintain the pH of the composition between about 5 and about 7, and a nonionic surfactant. The stabilized antiseptic compositions may be utilized in a wide variety of topical antiseptic pharmaceutical products. This invention also relates to methods for preparing the stabilized antiseptic compositions and the topical antiseptic pharmaceutical products in which they may be used.

2. Description of the Prior Art

Hexahydro-5-pyrimidinamine compounds (5-amino- hexahydropyrimidine) , such as hexetidine (l,3-bis(2- ethylhexyl)hexahydro-5-methyl-5-pyrimidinamine) , are well known in the art for their broad spectrum antimicrobial activity. These hexahydro-5-pyrimidinamine compounds are used in aqueous-based compositions for topical application to treat skin and body cavity infections. For example, these antimicrobial compositions are used in the treatment of oral infections such as gingivitis, oral ulcers, periodontal disease, and for the control of mouth odor, and in the treatment of other topical infections such as cervical vaginal infections, ear infections, nasal pharyngitis, and epidermal phytoses.

Hexetidine is a highly substituted saturated pyrimidine derivative which is soluble in most organic solvents and practically insoluble in water. Surfactants are usually necessary to solubilize hexetidine compositions in water. Anionic surfactants, however, inactivate hexetidine and nonionic surfactants produce variable results. Hexetidine is compatible with cationic surfactants, but cationic surfactants are often irritating and can cause staining of hard and soft tissue.

Hexetidine is also not very stable. The hexahydro-5-pyrimidinamine ring system in hexetidine can be cleaved thermally and hydrolytically to produce the open-chain compound triamine and the condensed bicyclic heterocycle hexedine, see G. Satzinger et al. , Analytical Profiles of Drug Substances, 1_, pp. 277-295, Academic Press, 1978. Accordingly, substantial effort has been expended towards synthesizing hexetidine, and its organic salts, and overcoming undesirable solubility properties and degradative reactions.

United States patent no. 2,837,463, issued to

Fondick et al. and assigned to Warner-Lambert Company, discloses therapeutic compositions which comprise certain hexahydro-5-pyrimidinamine compounds and a pharmaceutical carrier. The hexahydro-5-pyrimidinamine compound may be hexetidine and the therapeutic compositions may contain optional additives such as menthol to add flavor.

United States patent no. 4,141,968, issued to Kunz et al. and assigned to Doll GmbH, West Germany, discloses the preparation of certain substituted benzoic acid salts of hexetidine, particularly the terephthalic acid and 4-sulfamylbenzoic acid salts. These salts are said to have useful bacteriostatic activity. The benzoic acid salt component may be monosubstituted or disubstituted. The substituent groups on benzoic acid are selected from the group consisting of -COOH, -OH, - NH ₂ , -Sθ ₃ H and -S0 ₂ NH. When the substituent group is - COOH or -OH, the group must be located in the 4-position (para) on the benzoic acid moiety. When the benzoic acid salt component is disubstituted, the substituent groups must be different from each other. Substituent groups located at the 4-position on the benzoic acid ring are particularly preferred. Examples of the preferred substituted benzoic acid salts of hexetidine include:

1,3-bis(2-ethylhexyl)hexahydro-5-methyl-5- pyrimidinamine terephthalate 1,3-bis(2-ethylhexyl)hexahydro-S-methyl-5- pyrimidinamine 4-sulfamylbenzoate

1,3-bis(2-ethylhexyl)hexahydro-5-methyl-5- pyrimidinamine 4-hydroxybenzoate 1,3-bis(2-ethylhexyl)hexahydro-5-methyl-5- pyrimidinamine 2-aminobenzoate 1,3-bis(2-ethylhexyl)hexahydro-5-methyl-5- pyrimidinamine 4-aminobenzoate 1,3-bis(2-ethylhexyl)hexahydro-5-methyl-5- pyrimidina ine 4-aminosalicylate

1,3-bis(2-ethylhexyl)hexahydro-5-methyl-5- pyrimidinamine 5-sulfosalicylate

United States patent no. 4,490,353, issued to Crawford et al. and assigned to Colgate-Palmolive Company, discloses an antiplaque dentifrice containing an antiplaque quaternary ammonium compound, a betaine surfactant to improve foaming, a humectant, a nonionic gelling agent, a fluoride containing compound, and glycerin in an aqueous vehicle containing a dental abrasive. The antiplaque compound may be hexetidine and the amount of betaine surfactant necessary for foaming must be in the range from about 1.5-2%, by weight.

United States patent no. 4,574,081, issued to

Shymon and assigned to Colgate-Palmolive Company, discloses an antiplaque dentifrice having an improved flavor comprising an antiplaque compound, which may be hexetidine, a flavoring agent which consists essentially of at least -15% anethole, up to 46% menthol, up to 39% peppermint, and a sweetening agent in a dental vehicle containing a dental abrasive. The dentifrice may optionally'contain a betaine surfactant in an amount from about 1.5-5%, by weight.

United States patent no. 4,206,198, issued to Schmolka and assigned to BASF Wyandotte Corporation, discloses a dentifrice composition which contains a foam producing amount of a nonionic surfactant and a cationic antidecay agent. The nonionic surfactant is an ethoxylated adduct of a C-15 or C-16 fatty alcohol. The cationic antidecay agent may be hexetidine and the dentifrice composition may contain optional flavoring additives such as eucalyptus and sodium methylsalicylate.

United States patent no. 4,323,552, issued to Schmolka and assigned to BASF Wyandotte Corporation, discloses a high foaming dentifrice gel composition said to be compatible with antimicrobial agents. The gel

composition comprises a nonionic surfactant and a cationic antidecay agent. The nonionic surfactant is a cogeneric mixture of conjugated polyoxybutylene- polyoxyethylene polymeric compounds with the polyoxybutylene polymers in the mixture having an average molecular weight of at least 500. The cationic antidecay agent may be hexetidine and optional flavoring additives such as eucalyptus and sodium methylsalicylate may be included in the high foaming dentifrice gel composition.

United States patent no. 4,343,785, issued to Schmolka and assigned to BASF Wyandotte Corporation, discloses a gel dentifrice composition said to retain its gel properties at low temperatures. The gel dentifrice contains about 15% of a cogeneric mixture of conjugated polyoxybutylene-polyoxyethylene block copolymers, an effective amount of an essential additive and less than about 85% water. The average molecular weight of the polyoxybutylene polymers in the mixture is at least 1200. Additional requirements relate the hydrophobic molecular weight of the polyoxybutylene-polyoxyethylene block copolymers to the minimum polyethylene content and the minimum block copolymer content. The essential additive in the gel dentifrice composition may be hexetidine and optional flavoring agents such as eucalyptus and sodium methylsalicylate may be included in the gel.

United States patent no. 4,522,806, issued to Muhlemann et al. and assigned to Lever Brothers Company, discloses an antiplaque composition which contains the combination of hexetidine, as the water-insoluble pyrimidine base, plus one or more zinc cationic salts. The antiplaque composition is said not to stain teeth.

United States patent no. 4,624,849, issued to

Tooqood and assigned to The Proctor & Gamble Company, discloses a noncariogenic therapeutic lozenge comprising a cationic antimicrobial agent and a nonionic lubricant in a pharmaceutically acceptable carrier. The

antimicrobial agent may be hexetidine and the lubricant is selected from the group consisting of polyethylene glycols, hydrogenated tallow and hydrogenated vegetable oil.

United States patent no. 4,666,517, issued to Bakar and assigned to Colgate-Palmolive Company, discloses an oral antiplaque and antigingivitis composition comprising a synergistic antiseptic combination of hexetidine and tridecanol-1, in the weight ratio of 1:1 to 5:1, respectively.

British patent no. 1,468,557, assigned to Societe Norσan. discloses a pharmaceutical composition said to prolong the antibacterial effect of hexetidine. The composition contains hexetidine, choline salicylate and chlorobutanol in a pharmaceutically acceptable solvent.

While the above hexetidine containing compositions show improved activity, none of the above compositions are entirely satisfactory. None of these compositions significantly inhibit the thermal and hydrolytic ring cleavage of the hexahydro-5- pyrimidinamine system which results in substantial loss of antiseptic activity. Thus it would be commercially advantageous to enhance the stability of hexahydro-5- pyrimidinamine compounds, such as hexetidine. The present invention provides such improved stabilized antiseptic compositions without the disadvantages characteristic of previously known products. The present invention also provides methods by which these improved stabilized antiseptic compositions may be prepared.

SUMMARY OF THE INVENTION

The present invention pertains to stabilized aqueous antiseptic compositions which comprise (a) a

therapeutically effective amount of an antiseptic hexahydro-5-pyrimidinamine compound, (b) a sufficient amount of an aqueous buffer solution to maintain the pH of the antiseptic composition between about 5 and about 7, and (c) a nonionic surfactant. The stabilized antiseptic compositions may be utilized in a wide variety of topical antiseptic pharmaceutical products. This invention also relates to methods for preparing these stabilized antiseptic compositions and the topical antiseptic pharmaceutical products in which the stabilized antiseptic compositions may be employed.

DETAILED DESCRIPTION OF THE INVENTION

Applicants have discovered that aqueous solutions of hexahydro-5-pyrimidine compounds can be stabilized in buffer solutions maintained in the pH range from about 5 to about 7 in the presence of a nonionic surfactant. Applicants believe that the disproportionation of hexahydro-5-pyrimidine compounds in aqueous solution to hexedine and triamine is pH dependent. At low pH, degradation proceeds rapidly. At high pH, hexahydro-5-pyrimidine compounds precipitate out of solution. By maintaining the pH of the aqueous solution of the hexahydro-5-pyrimidine compound in the range from about 5 to about 7 in the presence of a nonionic surfactant, applicants have found that the antiseptic compounds show improved stability for extended periods of time.

The antiseptic compounds in the present invention are hexahydro-5-pyrimidinamine compounds. Any non-toxic, antiseptic hexahydro-5-pyrimidinamine compound or pharmaceutically acceptable salt of a hexahydro-5- pyrimidinamine compound may be employed. Suitable non- toxic, antiseptic hexahydro-5-pyrimidinamine compounds and their pharmaceutically acceptable salts are disclosed

in United States patents nos. 2,83/,463 and 4,141,968, which disclosures are incorporated herein by reference.

The preferred antiseptic hexahydro-5- pyrimidinamine compound is hexetidine (l,3-bis(2- ethylhexyl)hexahydro-5-methyl-5-pyrimidinamine) , and its pharmaceutically acceptable acid addition salts. Hexetidine has an unusual affinity for tissue. When applied topically, hexetidine adheres to tissue and is not eliminated prematurely from the site of action either physiologically or by pathological secretions. Hexetidine has a broad antibacterial spectrum which makes it very useful in preparations for topical application to skin and body cavity infections.

The preferred pharmaceutically acceptable salts of hexetidine are the terephthalate, 4-sulfamylbenzoate, 4-hydroxybenzoate, 2-aminobenzoate, 4-aminobenzoate, 4-aminosalicylate, and 5-sulfosalicylate salts, other similar salts, and mixtures of these salts. Hexetidine has the chemical formula set forth below.

CH,

/ \ CH ₃ (CH ₂ ) ₃ CH(C ₂ H ₅ )CH ₂ -N N-CH ₂ CH(C ₂ H ₅ ) (CH ₂ ) ₃ CH3 H, H,

\ / C

/ \ H ₂ N CH ₃

The amount of antiseptic hexahydro-5- pyrimidinamine compound present in the stabilized antiseptic composition of the present invention is a therapeutically effective amount. In a preferred embodiment, the hexahydro-5-pyrimidinamine compound is present in the antiseptic composition in an amount from about 0.025% to about 1.0%, preferably from about 0.025% to about 0.5%, and more preferably from about 0.05% to

about 0.25%, by weight of the stabilized antiseptic composition.

Buffer solutions are solutions to which limited amounts of a strong acid or strong base may be added without causing a significant change in the pH value of the solution. Buffer solutions usually contain two components, such as a weak acid and a salt of a weak acid, a mixture of an acid salt with the normal salt, or a mixture of two acid salts.

The buffer solutions in the present invention are solutions which are capable of maintaining the pH value of the antiseptic compositions, which contain therapeutically effective amounts of the hexahydro-5- pyrimidine compound, between about 5 and about 7, and preferably about 6. The buffer solution must not induce degradation of the hexahydro-5-pyrimidine compound or otherwise adversely affect the antiseptic activity of the hexahydro-5-pyrimidine compound. Suitable buffer solutions in the present invention include citric acid- sodium citrate solution, phosphoric acid-sodium phosphate solution, and acetic acid-sodium acetate solution. The buffer solution is preferably selected from the group consisting of citric acid-sodium citrate solution, phosphoric acid-sodium phosphate solution, and mixtures thereof, and more preferably, the buffer solution is citric acid-sodium citrate solution. The exact ratio of components in the buffer solution to obtain a specific pH value is well known in the art and is not the subject of the present invention.

Surfactants (surface active agents) are compounds which reduce surface tension when dissolved in water or which reduce interfacial tension between two liquids or a liquid and a solid. Surfactants can aid in the dispersion of a composition over the skin and throughout the oral cavity.

The surfactants in the present invention are compounds which will solubilize therapeutically effective amounts of hexahydro-5-pyrimidine compounds in water such as the buffer solutions in the present invention. The surfactant must not induce degradation of the hexahydro-

5-pyrimidine compound or otherwise adversely affect the antiseptic activity of the hexahydro-5-pyrimidine compound. The surfactant is preferably a nonionic surfactant.

Nonionic surfactants useful in the present invention include polyoxyethylene sorbitan fatty acid esters (polysorbates, polyethylene oxide sorbitan esters) _r which are the condensates of sorbitol esters of fatty acids with ethylene oxide. Polysorbates are available commercially as "Tweens," a trademark of ICI

United States, Inc. Particularly preferred polysorbates are Polysorbate 20 (sorbitan, monododecanoate, poly(oxy-

1,2-ethanediyl derivative, polyoxyethylene 20 sorbitan monolaurate, Tween 20) and Polysorbate 80 (sorbitan, mono-9-octadecanoate, poly(oxy-l,2-ethanediyl derivative, polyoxyethylene 20 sorbitan monooleate, Tween 80) . Both

Polysorbate 20 and Polysorbate 80 are yellow oily liquids, and have a characteristic odor and a warm somewhat bitter taste. Polysorbates are stable to weak acids and weak bases and are well tolerated, practically non-irritating, and have very low toxicity.

Other suitable nonionic surfactants useful in the present invention include polyoxyethylene castor oil derivatives which are ethoxylated hydrogenated castor oils. These surfactants are prepared by hydrogenating castor oil and treating the hydrogenated product with from about 10 to about 200 moles of ethylene glycol. These ethoxylated hydrogenated castor oils are known by the non-proprietary name of Polyethylene glycol (PEG) hydrogenated castor oils, in accordance with the dictionary of the Cosmetics, Toiletries and Fragrance Association, 3rd Edition, which name is used in

conjunction with a numeric suffix to designate the degree of ethoxylation of the hydrogenated castor cil product, i.e., the number of moles of ethylene oxide added to the hydrogenated castor oil product. Suitable PEG hydrogenated castor oils include PEG 16, 20, 25, 30, 40,

50, 60, 80, 100, and 200. A preferred PEG hydrogenated castor oil surfactant is Cremophor RH 60, a commercially available product from BASF-Wyandotte, Parsippany, New

Jersey.

In a preferred embodiment, the nonionic surfactant is selected from the group consisting of polyethylene oxide sorbitan esters, polyethylene glycol hydrogenated castor oils, and mixtures thereof. In a more preferred embodiment, the nonionic surfactant is selected from the group consisting of polysorbate 80 (polyethylene oxide sorbitan ester 80, Tween 80) and PEG 60 (polyethylene glycol hydrogenated castor oil 60, Cremophore RH 60) , and mixtures thereof. In a most preferred embodiment, the nonionic surfactant is a polysorbate 80 (polyethylene oxide sorbitan ester 80) .

The amount of nonionic surfactant present in the stabilized antiseptic composition is an amount sufficient to solubilize a therapeutically effective amount of the antiseptic hexahydro-5-pyrimidinamine compound. In general, the nonionic surfactant will be present in the stabilized antiseptic composition in an amount from about 0.2% to about 2.0%, preferably from about 0.4% to about 1.5%, and more preferably about 0.5% to about 1%, by weight of the stabilized antiseptic composition.

The present invention includes a method for preparing the stabilized aqueous antiseptic compositions. In general, the stabilized antiseptic compositions are prepared by admixing (a) a therapeutically effective amount of an antiseptic hexahydro-5-pyrimidinamine compound, (b) a sufficient amount of an aqueous buffer

solution to maintain the pH of the antiseptic composition between about 5 and about 7, and (c) a nonionic surfactant.

Once prepared, the stabilized antiseptic aqueous composition may be stored for future use or may be formulated with pharmaceutically acceptable carriers such as topical vehicles (non-oral and oral) and ingestible vehicles to prepare a wide variety of topical and ingestible antiseptic pharmaceutical compositions to suit particular applications. Non-oral topical compositions employ non-oral topical vehicles, such as creams, gels, foams, ointments and sprays, which are intended to be applied to the skin or body cavity and are not intended to be taken by mouth. Oral topical compositions employ oral vehicles, such as mouthwashes, rinses, oral sprays, suspensions, and dental gels, which are intended to be taken by mouth but are not intended to be ingested. Ingestible compositions employ ingestible or partly ingestible vehicles such as confectionery bulking agents which include hard and soft confectionery such as lozenges, tablets, toffees, nougats, suspensions, chewy candies, and chewing gums.

In one form of the invention, the stabilized antiseptic composition is incorporated into a non-oral topical vehicle which may be in the form of a cream, gel, foam, ointment, spray, and the like. Typical non-toxic non-oral topical vehicles known in the pharmaceutical arts may be used in the present invention. The preferred non-oral topical vehicles are water and pharmaceutically acceptable water-miscible organic solvents such as ethyl alcohol, isopropyl alcohol, propylene glycol, glycerin, and the like, and mixtures of these solvents. Water- alcohol mixtures are particularly preferred and are generally employed in a weight ratio from about 1:1 to about 20:1, preferably from about 3:1 to about 20:1, and most preferably from about 3:1 to about 10:1, respectively.

The non-oral topical antiseptic compositions may also contain conventional additives normally employed in those products. Conventional additives include humectants, emollients, lubricants, stabilizers, dyes, and perfumes, providing the additives do not interfere with the antiseptic properties of the hexahydro-5- pyrimidinamine compound.

Suitable humectants useful in the non-oral topical antiseptic compositions include glycerin, propylene glycol, polyethylene glycol, sorbitan, fructose, and the like, and mixtures thereof. Humectants, when employed, may be present in amounts from about 10% to about 20%, by weight of the topical antiseptic composition.

The coloring agents (colors, colorants) useful in the non-oral topical antiseptic composition are used in amounts effective to produce the desired color. These coloring agents include pigments which may be incorporated in amounts up to about 6% by weight of the non-oral topical antiseptic composition. A preferred pigment, titanium dioxide, may be incorporated in amounts up to about 2%, and preferably less than about 1%, by weight of the non-oral topical antiseptic composition. The coloring agents may also include natural food colors and dyes suitable for food, drug and cosmetic applications. These coloring agents are known as F.D.& C. dyes and lakes. The materials acceptable for the foregoing uses are preferably water-soluble. Illustrative nonlimiting examples include the indigoid dye known as F.D.& C. Blue No.2, which is the disodium salt of 5,5-indigotindisulfonic acid. Similarly, the dye known as F.D.& C. Green No.l comprises a triphenylmethane dye and is the monosodium salt of 4-[4-(N-ethyl-E~ sulfoniumbenzylamino) diphenylmethylene]-[1-(N-ethyl-N-p- sulfoniumbenzyl)-delta-2,5-cyclohexadieneimine] . A full recitation of all F.D.& C. coloring agents and their

corresponding chemical structures may be found in the

Kirk-Othmer Encyclopedia of Chemical Technology, 3rd

Edition, in volume 5 at pages 857-884, which text is incorporated herein by reference.

In accordance with this invention, therapeutically effective amounts of the stabilized antiseptic compositions of the present invention may be admixed with a non-oral topical vehicle to form a topical antiseptic composition. These amounts are readily determined by those skilled in the art without the need for undue experimentation. In a preferred embodiment, the non-oral topical antiseptic compositions will comprise the stabilized antiseptic composition in an amount from about 0.025% to about 2% and a non-oral topical vehicle in a quantity sufficient to bring the total amount of composition to 100%, by weight of the non-oral topical antiseptic composition. In a more preferred embodiment, the non-oral topical antiseptic compositions will comprise the stabilized antiseptic composition in an amount from about 0.05% to about 1% and a non-oral topical vehicle in a quantity sufficient to bring the total amount of composition to 100%, by weight of the non-oral topical antiseptic composition.

The present invention extends to methods for preparing the non-oral topical antiseptic compositions.

In such a method, the non-oral topical antiseptic composition is prepared by admixing a therapeutically effective amount of the stabilized antiseptic composition of the present invention and a non-oral topical vehicle.

The final compositions are readily prepared using standard methods and apparatus generally known by those skilled in the pharmaceutical arts. The apparatus useful in accordance with the present invention comprises mixing apparatus well known in the pharmaceutical arts, and therefore the selection of the specific apparatus will be apparent to the artisan.

In another form of the invention, the stabilized antiseptic composition is incorporated into an oral topical vehicle which may be in the form of a mouthwash, rinse, oral spray, suspension, dental gel, and the like. Typical non-toxic oral vehicles known in the pharmaceutical arts may be used in the present invention.

The preferred oral vehicles are water, ethanol, and water-ethanol mixtures. The water-ethanol mixtures are generally employed in a weight ratio from about 1:1 to about 20:1, preferably from about 3:1 to about 20:1, and most preferably from about 3:1 to about 10:1, respectively. The pH value of the oral vehicle is generally from about 4 to about 7, and preferably from about 5 to about 6.5. An oral topical vehicle having a pH value below about 4 is generally irritating to the oral cavity and an oral vehicle having a pH value greater than about 7 generally results in an unpleasant mouth feel.

The oral topical antiseptic compositions may also contain conventional additives normally employed in those products. Conventional additives include a fluorine providing compound, a sweetening agent, a flavoring agent, a coloring agent, a humectant, a buffer, and an emulsifier, providing the additives do not interfere with the antiseptic properties of the hexahydro-5-pyrimidinamine compound.

The coloring agents and humectants, and the amounts of these additives to be employed, set out above as useful in the non-oral topical antiseptic composition may be used in the oral topical antiseptic composition.

Fluorine providing compounds may be fully or slightly water soluble and are characterized by their ability to release fluoride ions or fluoride containing ions in water and by their lack of reaction with other components in the composition. Typical fluorine providing compounds are inorganic fluoride salts such as

water-soluble alkali metal, alkaline earth metal, and heavy metal salts, for example, sodium fluoride, potassium fluoride, ammonium fluoride, cuprous fluoride, zinc fluoride, stannic fluoride, stannous fluoride, barium fluoride, sodium fluorosilicate, ammonium fluorosilicate, sodium fluorozirconate, sodium monofluorophosphate, aluminum mono- and di- fluorophosphates and fluorinated sodium calcium pyrophosphate. Alkali metal fluorides, tin fluoride and onofluorophosphates, such as sodium and stannous fluoride, sodium monofluorophosphate and mixtures thereof, are preferred.

The amount of fluorine providing compound present in the present oral topical antiseptic composition is dependent upon the type of fluorine providing compound employed, the solubility of the fluorine compound, and the nature of the final oral antiseptic composition. The amount of fluorine providing compound used must be a nontoxic amount. In general, the fluorine providing compound when used will be present in an amount up to about 1%, preferably from about 0.001% to about 0.1%, and most preferably from about 0.001% to about 0.05%, by weight of the oral topical antiseptic composition.

When sweetening agents (sweeteners) are used, those sweeteners well known in the art, including both natural and artificial sweeteners, may be employed. The sweetening agent used may be selected from a wide range of materials including water-soluble sweetening agents, water-soluble artificial sweetening agents, water-soluble sweetening agents derived from naturally occurring water- soluble sweetening agents, dipeptide based sweetening agents, and protein based sweetening agents, including mixtures thereof. Without being limited to particular sweetening agents, representative categories and examples include:

(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, monellin, steviosides, and glycyrrhizin, and mixtures thereof;

(b) water-soluble artificial sweeteners such as soluble saccharin salts, i.e., sodium or calcium saccharin salts, cyclamate salts, the sodium, ammonium or calcium salt of 3,4-dihydro-6-methyl-l,2,3-oxathiazine-4- one-2,2-dioxide, the potassium salt of 3,4-dihydro-6- methyl-l,2,3-oxathiazine-4-one-2,2-dioxide (Acesulfame- K) , the free acid form of 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 United States patent no. 3,492,131, L-alpha- aspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alanin- amide hydrate (Alitame) , methyl esters of L-aspartyl-L- phenylglycerine and L-aspartyl-L-2,5-dihydrophenyl- glycine, L-aspartyl-2,5-dihydro-L-phenylalanine; L- aspartyl-L-(l-cyclohexen)-alanine, and the like; (d) water-soluble sweeteners derived from naturally occurring water-soluble sweeteners, such as chlorinated derivatives of ordinary sugar (sucrose) , e.g., chlorodeoxysugar derivatives such as derivatives of chlorodeoxysucrose or chlorodeoxygalactosucrose, known, for example, under the product designation of Sucralose; examples of chlorodeoxysucrose and chlorodeoxygalacto¬ sucrose derivatives include but are not limited to: 1- chloro-l ^, -deoxysucrose; 4-chloro-4-deoxy-alpha-D-galacto- pyranosyl-alpha-D-fructofuranoside, or 4-chloro-4- deoxygalactosucrose; 4-chloro-4-deoxy-alpha-D-galacto- pyranosyl-1-σhloro-l-deoxy-beta-D-fructo-furanoside, or 4,1'-dichloro-4,1'-dideoxygalactosucrose; 1' ,6'-dichloro- 1' ,6'-dideoxysucrose; 4-chloro-4-deoxy-alpha-D-galacto- pyranosyl-1,6-dichloro-l,6-dideoxy-beta-D-fructo-

furanoside, or 4,l',6'-trichloro-4,l',6'-trideoxygalacto- sucrose; 4,6-dichloro-4,6-dideoxy-alpha-D-galacto- pyranosyl-6-chloro-6-deoxy-beta-D-fructofuranoside, or

4,6,6'-trichloro-4,6,6'-trideoxygalactosucrose; 6 ,1 ^r ,6'- trichloro-6,1 ' ,6'-trideoxysucrose; 4,6-dichloro-4,6- dideoxy-alpha-D-galacto-pyranosyl-1,6-dichloro-l,6-di- deoxy-beta-D-fructofuranoside, or 4,6,1',6'-tetrachloro-

4,6,l',6'-tetradeoxygalacto-sucrose; and 4,6,1',6'- tetraσhloro-4,6,1 ^Λ ,6'-tetradeoxy-sucrose; and (e) protein based sweeteners such as thaumaoccous danielli (Thaumatin I and II) .

In general, an effective amount of sweetening agent is utilized to provide the level of sweetness desired in the particular oral topical antiseptic composition, and this amount will vary with the sweetener selected and the final oral antiseptic product desired. The amount of sweetener normally present is in the range from about 0.0025% to about 90%, by weight of the oral topical antiseptic composition, depending upon the sweetener used. The exact range of amounts for each type of sweetener is well known in the art and is not the subject of the present invention.

The flavoring agents (flavors, flavorants) which may be used include those flavors known to the skilled artisan, such as natural and artificial flavors. Suitable flavoring agents include mints, such as peppermint, citrus flavors such as orange and lemon, artificial vanilla, cinnamon, various fruit flavors, both individual and mixed, and the like.

The amount of flavoring agent employed in the oral topical antiseptic composition is normally a matter of preference subject to such factors as the type of final oral antiseptic composition, the individual flavor employed, and the strength of flavor desired. Thus, the amount of flavoring may be varied in order to obtain the result desired in the final product and such variations

are within the capabilities of those skilled in the art without the need for undue experimentation. The flavoring agents, when used, are generally utilized in amounts that may, for example, range in amounts from about 0.05% to about 6%, by weight of the oral topical antiseptic composition.

Suitable buffer solutions useful in the non- oral topical antiseptic compositions include citric acid- sodium citrate solution, phosphoric acid-sodium phosphate solution, and acetic acid-sodium acetate solution in amounts up to about 1%, and preferably from about 0.05% to about 0.5% by weight of the oral topical antiseptic composition.

In accordance with this invention, therapeutically effective amounts of the stabilized antiseptic compositions of the present invention may be admixed with an oral topical vehicle to form a topical antiseptic composition. These amounts are readily determined by those skilled in the art without the need for undue experimentation. In a preferred embodiment, the oral topical antiseptic compositions will comprise the stabilized antiseptic composition in an amount from about 0.025% to about 2% and an oral topical vehicle in a quantity sufficient to bring the total amount of composition to 100%, by weight of the oral topical antiseptic composition. In a more preferred embodiment, the oral topical antiseptic compositions will comprise the stabilized antiseptic composition in an amount from about 0.05% to about 1% and an oral topical vehicle in a quantity sufficient to bring the total amount of composition to 100%, by we ght of the oral topical antiseptic composition.

The present invention extends to methods for preparing the oral topical antiseptic compositions. In such a method, the oral topical antiseptic composition is prepared by admixing a therapeutically effective amount

of the stabilized antiseptic composition of the present invention and an oral topical vehicle. The final compositions are readily prepared using standard methods and apparatus generally known by those skilled in the pharmaceutical arts. The apparatus useful in accordance with the present invention comprises mixing apparatus well known in the pharmaceutical arts, and therefore the selection of the specific apparatus will be apparent to the artisan.

In a preferred embodiment, an oral topical antiseptic composition is made by first dissolving coloring agents, sweetening agents, and similar additives in water. The stabilized antiseptic composition is then admixed with the aqueous solution. Then sufficient water or ethanol, or mixtures of water and ethanol, are added to the solution with mixing until the final solution volume is reached. In a more preferred embodiment, the stabilized antiseptic composition is added to the solution as the final ingredient. The final oral topical antiseptic compositions are readily prepared using methods generally known in the pharmaceutical arts.

The oral antiseptic composition may also be in the form of dental gel. As used herein, the term "gel" means a solid or semisolid colloid which contains considerable quantities of water. The colloid particles in a gel are linked together in a coherent meshwork which immobilizes the water contained inside the meshwork.

The dental gel compositions of the present invention may contain the conventional additives set out above for oral topical antiseptic compositions such as mouthwashes, rinses, oral sprays, and suspensions and, in addition, may contain additional additives such as a polishing agent, a desensitizing agent, and the like, providing the additional additives do not interfere with the antiseptic properties of the hexahydro-5- pyrimidinamine compound.

In a dental gel composition, the oral vehicle generally comprises water, typically in an amount from about 10% to about 90%, by weight of the dental gel composition. Polyethylene glycol, propylene glycol, glycerin, and mixtures thereof may also be present in the vehicle as humectants or binders in amounts from about 18% to about 30%, by weight of the dental gel composition. Particularly preferred oral vehicles comprise mixtures of water with polyethylene glycol or water with glycerin and polypropylene glycol.

The dental gels of the present invention include a gelling agent (thickening agent) such as a natural or synthetic gum or gelatin. Gelling agents such as hydroxyethyl cellulose, methyl cellulose, glycerin, carboxypolymethylene, and gelatin and the like, and mixtures thereof may be used. The preferred gelling agent is hydroxyethyl cellulose. Gelling agents may be used in amounts from about 0.5% to about 5%, and preferably from about 0.5% to about 2%, by weight of the dental gel composition.

The dental gel compositions of the present invention may also include a polishing agent. In clear gels, a polishing agent of colloidal silica and/or alkali metal aluminosilicate complexes is preferred since these materials have refractive indices close to the refractive indices of the gelling systems commonly used in dental gels. In non-clear gels, a polishing agent of calcium carbonate or calcium dihydrate may be used. These polishing agents may be used in amounts up to about 75%, and preferably in amounts up to about 50%, by weight of the dental gel composition.

The dental gel may also contain a desensitizing agent such as a combination of citric acid and sodium citrate. Citric acid may be used in an amount from about 0.1% to about 3%, and preferably from about 0.2% to about

1%, by weight, and sodium citrate may be used in an amount from about 0.3% to about 9%, and preferably from about 0.6% to about 3%, by weight of the dental gel composition.

In accordance with this invention, therapeutically effective amounts of the stabilized antiseptic compositions of the present invention may be admixed into the dental gel compositions. These amounts are readily determined by those skilled in the art without the need for undue experimentation. In a preferred embodiment, the dental gel compositions will comprise the stabilized antiseptic composition in an amount from about 0.025% to about 2% and an oral topical vehicle in a quantity sufficient to bring the total amount of composition to 100%, by weight of the dental gel composition. In a more preferred embodiment, the dental gel compositions will comprise the stabilized antiseptic composition in an amount from about 0.05% to about 1% and an oral topical vehicle in a quantity sufficient to bring the total amount of composition to 100%, by weight of the dental gel composition.

The present invention extends to methods for preparing the stabilized antiseptic dental gel compositions. In such a method, the dental gel composition is prepared by admixing a therapeutically effective amount of the stabilized antiseptic composition of the present invention and an oral topical vehicle. The final compositions are readily prepared using methods generally known by those skilled in the dental and pharmaceutical arts. The apparatus useful in accordance with the present invention comprises mixing apparatus well known in the pharmaceutical arts, and therefore the selection of the specific apparatus will be apparent to the artisan.

In a preferred embodiment, an antiseptic dental gel composition is made by first dispersing a gelling

agent in a humectant or water, or a mixture of both, then admixing to the dispersion an aqueous solution of the water-soluble additives such as the fluorine providing compound, sweeteners and the like, then adding the polishing agent, and lastly admixing the flavoring agent and the stabilized antiseptic composition. The final gel mixture is then tubed or otherwise packaged. The liquids and solids in a gel product are proportioned to form a creamy or gelled mass which is extrudable from a pressurized container or from a collapsible tube. The final antiseptic compositions are readily prepared using methods generally known in the pharmaceutical arts.

In yet another form of the invention, the stabilized antiseptic composition is incorporated into an ingestible vehicle. The ingestible vehicle may be a confectionery bulking agent in the form of lozenges, tablets, toffees, nougats, suspensions, chewy candies, chewing gums, and the like. The pharmaceutically acceptable carriers may be prepared from a wide range of materials including, but not limited to, diluents, binders and adhesives, lubricants, disintegrants, coloring agents, bulking agents, flavoring agents, sweetening agents and miscellaneous materials such as buffers and adsorbents that may be needed in order to prepare a particular antiseptic confection.

The preparation of confectionery formulations is historically well known and has changed little through the years. Confectionery items have been classified as either "hard" confectionery or "soft" confectionery. The stabilized antiseptic compositions of the present invention can be incorporated into confectionery compositions by admixing the inventive composition into conventional hard and soft confections.

As used herein, the term confectionery material means a product containing a bulking agent selected from a wide variety of materials such as sugar, corn syrup.

and in the case of sugarless bulking agents, sugar alcohols such as sorbitol and mannitol and mixtures thereof. Confectionery material may include such exemplary substances as lozenges, tablets, toffee, nougat, suspensions, chewy candy, chewing gum and the like. The bulking agent is present in a quantity sufficient to bring the total amount of composition to

100%. In general, the bulking agent will be present in amounts up to about 99.98%, preferably in amounts up to about 99.9%, and more preferably in amounts up to about

99%, by weight of the ingestible antiseptic composition.

Lozenges are flavored medicated dosage forms intended to be sucked and held in the mouth. Lozenges may be in the form of various shapes such as flat, circular, octagonal and biconvex forms. The lozenge bases are generally in two forms: hard boiled candy lozenges and compressed tablet lozenges.

Hard boiled candy lozenges may be processed and formulated by conventional means. In general, a hard boiled candy lozenge has a base composed of a mixture of sugar and other carbohydrate bulking agents kept in an amorphous or glassy condition. This amorphous or glassy form is considered a solid syrup of sugars generally having from about 0.5% to about 1.5% moisture. Such materials normally contain up to about 92% corn syrup, up to about 55% sugar and from about 0.1% to about 5% water, by weight of the final composition. The syrup component is generally prepared from corn syrups high in fructose, but may include other materials. Further ingredients such as flavoring agents, sweetening agents, acidulants, coloring agents and the like may also be added.

Boiled candy lozenges may also be prepared from non-fermentable sugars such as sorbitol, mannitol, and hydrogenated corn syrup. Typical hydrogenated corn syrups are Lycasin, a commercially available product manufactured by Roquette Corporation, and Hystar, a

commercially available product manufactured by Lonza,

Inc. The candy lozenges may contain up to about 95% sorbitol, a mixture of sorbitol and mannitol in a ratio from about 9.5:0.5 up to about 7.5:2.5, and hydrogenated corn syrup up to about 55%, by weight of the solid syrup component.

Boiled candy lozenges may be routinely prepared by conventional methods such as those involving fire cookers, vacuum cookers, and scraped-surface cookers also referred to as high speed atmospheric cookers.

Fire cookers involve the traditional method of making a boiled candy lozenge base. In this method, the desired quantity of carbohydrate bulking agent is dissolved in water by heating the agent in a kettle until the bulking agent dissolves. Additional bulking agent may then be added and cooking continued until a final temperature of 145° C. to 156° C. is achieved. The batch is then cooled and worked as a plastic-like mass to incorporate additives such as flavors, colorants and the like.

A high-speed atmospheric cooker uses a heat- exchanger surface which involves spreading a film of candy on a heat exchange surface, the candy is heated to 165° C. to 170° C. in a few minutes. The candy is then rapidly cooled to 100° C. to 120° C. and worked as a plastic-like mass enabling incorporation of the additives, such as flavors, colorants and the like.

In vacuum cookers, the carbohydrate bulking agent is boiled to 125° C. to 132° C. , vacuum is applied and additional water is boiled off without extra heating. When cooking is complete, the mass is a semi-solid and has a plastic-like consistency. At this point, flavors, colorants, and other additives are admixed in the mass by routine mechanical mixing operations.

The optimum mixing required to uniformly mix the flavoring agents, coloring agents and other additives during conventional manufacturing of boiled candy lozenges is determined by the time needed to obtain a uniform distribution of the materials. Normally, mixing times of from 4 to 10 minutes have been found to be acceptable.

Once the boiled candy lozenge has been properly tempered, it may be cut into workable portions or formed into desired shapes. A variety of forming techniques may be utilized depending upon the shape and size of the final product desired. A general discussion of the composition and preparation of hard confections may be found in H.A. Lieberman, Pharmaceutical Dosage Forms: Tablets, Volume 1 (1980) , Marcel Dekker, Inc. , New York, N.Y. at pages 339 to 469, which disclosure is incorporated herein by reference.

The apparatus useful in accordance with the present invention comprises cooking and mixing apparatus well known in the confectionery manufacturing arts, and therefore the selection of the specific apparatus will be apparent to the artisan.

In contrast, compressed tablet confections contain particulate materials and are formed into structures under pressure. These confections generally contain sugars in amounts up to about 95%, by weight of the composition, and typical tablet excipients such as binders and lubricants as well as flavoring agents, coloring agents and the like.

In addition to hard confectionery materials, the lozenges of the present invention may be made of soft confectionery materials such as those contained in nougat. The preparation of soft confections, such as nougat, involves conventional methods, such as the combination of two primary components, namely (1) a high

boiling syrup such as a corn syrup, hydrogenated starch hydrolysate or the like, and (2) a relatively light textured frappe, generally prepared from egg albumin, gelatin, vegetable proteins, such as soy derived compounds, sugarless milk derived compounds such as milk proteins, and mixtures thereof. The frappe is generally relatively light, and may, for example, range in density from about 0.5 to about 0.7 grams/cc.

The high boiling syrup, or "bob syrup" of the soft confectionery is relatively viscous and has a higher density than the frappe component, and frequently contains a substantial amount of carbohydrate bulking agent such as a hydrogenated starch hydrolysate. Conventionally, the final nougat composition is prepared by the addition of the "bob syrup" to the frappe under agitation, to form the basic nougat mixture. Further ingredients such as flavoring agents, additional carbohydrate bulking agent, coloring agents, preservatives, medicaments, mixtures thereof and the like may be added thereafter also under agitation. A general discussion of the composition and preparation of nougat confections may be found in B.W. Minifie, Chocolate. Cocoa and Confectionery: Science and Technology, 2nd edition, AVI Publishing Co., Inc., Westport, Conn. (1980) , at pages 424-425, which disclosure is incorporated herein by reference.

The procedure for preparing the soft confectionery involves known procedures. In general, the frappe component is prepared first and thereafter the syrup component is slowly added under agitation at a temperature of at least about 65° C, and preferably at least about 100° C. The mixture of components is continued to be mixed to form a uniform mixture, after which the mixture is cooled to a temperature below 80° C. , at which point, the flavoring agent may be added. The mixture is further mixed for an additional period

until it is ready to be removed and formed into suitable confectionery shapes.

The ingestible antiseptic compositions may also be in the form of a pharmaceutical suspension. Pharmaceutical suspensions of this invention may be prepared by conventional methods long established in the art of pharmaceutical compounding. Suspensions may contain adjunct materials employed in formulating the suspensions of the art. The suspensions of the present invention can comprise:

(a) preservatives such as butylated hydroxyanisole (BHA) , butylated hydroxytoluene (BHT) , benzoic acid, ascorbic acid, methyl paraben, propyl paraben, tocopherols, and the like, and mixtures thereof. Preservatives are generally present in amounts up to about 1%, and preferably from about 0.05% to about 0.5%, by weight of the suspension;

(b) buffers such as citric acid-sodium citrate, phosphoric acid-sodium phosphate, and acetic acid-sodium acetate in amounts up to about 1%, and preferably from about 0.05% to about 0.5%, by weight of the suspension;

(c) suspending agents or thickeners such as cellulosics like methylcellulose, carrageenans like alginic acid and its derivatives, xanthan gums, gelatin, acacis, and microcrystalline cellulose in amounts up to about 20%, and preferably from about 1% to about 15%, by weight of the suspension; (d) antifoaming agents such as dimethyl polysiloxane in amounts up to about 0.2%, and preferably from about 0.01% to about 0.1%, by weight of the suspension;

(e) sweetening agents such as those sweeteners well known in the art, including both natural and artificial sweeteners. 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, monellin, steviosides, glycyrrhizin, and sugar alcohols such as sorbitol, mannitol, maltitol, hydrogenated starch hydrolysates and mixtures thereof may be utilized in amounts up to about

60%, and preferably from about 20% to about 50%, by weight of the suspension. Water-soluble artificial sweeteners such as soluble saccharin salts, i.e., sodium or calcium saccharin salts, cyclamate salts, the sodium, ammonium or calcium salt of 3,4-dihydro-6-methyl-l,2,3- oxathiazine-4-one-2,2-dioxide, the potassium salt of 3,4- dihydro-6-methyl-l,2,3-oxathiazine-4-one-2,2-dioxide (Acesulfame-K) , the free acid form of saccharin, and the like may be utilized in amounts from about 0.001% to about 5%, by weight of the suspension;

(f) flavoring agents such as those flavors well known to the skilled artisan, such as natural and artificial flavors and mints, such as peppermint, menthol, citrus flavors such as orange and lemon, artificial vanilla, cinnamon, various fruit flavors, both individual and mixed and the like may be utilized in amounts from about 0.5% to about 5%, by weight of the suspension; (g) coloring agents such as pigments which may be incorporated in amounts up to about 6%, by weight of the suspension. A preferred pigment, titanium dioxide, may be incorporated in amounts up to about 2%, and preferably less than about 1%, by weight of the suspension. The coloring agents may also include natural food colors and dyes suitable for food, drug and cosmetic applications. These colorants are known as F.D.& C. dyes and lakes. The materials acceptable for the foregoing uses are preferably water-soluble. Such dyes are generally present in amounts up to about 0.25%, and preferably from about 0.05% to about 0.2%, by weight of the suspension;

(h) decolorizing agents such as sodium metabisulfite, ascorbic acid and the like may be

incorporated into the suspension to prevent color changes due to aging. In general, decolorizing agents may be used in amounts up to about 0.25%, and preferably from about 0.05% to about 0.2%, by weight of the suspension; and

(i) solubilizers such as alcohol, propylene glycol, polyethylene glycol, and the like may be used to solubilize the flavoring agents. In general, solubilizing agents may be used in amounts up to about 10%, and preferably from about 2% to about 5%, by weight of the suspension.

The pharmaceutical suspensions of the present invention may be prepared as follows: (A) admix the thickener with water heated from about 40° C. to about 95° C. , preferably from about 40° C. to about 70° C., to form a dispersion if the thickener is not water soluble or a solution if the thickener is water soluble; (B) admix the sweetening agent with water to form a solution;

(C) admix the stabilized antiseptic composition with the thickener-water admixture to form a uniform thickener-stabilized antiseptic composition; (D) combine the sweetener solution with the thickener-stabilized antiseptic composition and mix until uniform; and

(E) admix the optional adjunct materials such as coloring agents, flavoring agents, decolorants, solubilizers, antifoaming agents, buffers and additional water with the mixture of step (D) to form the suspension.

The ingestible antiseptic compositions of this invention may also be in chewable form. To achieve acceptable stability and quality as well as good taste and mouth feel in a chewable formulation several considerations are important. These considerations include the amount of active substance per tablet, the

flavoring agent employed, the degree of compressibility of the tablet and the organoleptic properties of the composition.

Chewable antiseptic candy is prepared by procedures similar to those used to make soft confectionery. In a typical procedure, a boiled sugar- corn syrup blend is formed to which is added a frappe mixture. The boiled sugar-corn syrup blend may be prepared from sugar and corn syrup blended in parts by weight ratio of about 90:10 to about 10:90. The sugar- corn syrup blend is heated to temperatures above about 120° C. to remove water and to form a molten mass. The frappe is generally prepared from gelatin, egg albumin, milk proteins such as casein, and vegetable proteins such as soy protein, and the like, which is added to a gelatin solution ^< d rapidly mixed at ambient temperature to form an aerated sponge like mass. The frappe is then added to the molten candy mass and mixed until homogeneous at temperatures between about 65° C. and about 120° C.

The ingestible antiseptic composition of the instant invention can then be added to the homogeneous mixture as the temperature is lowered to about 65° C- 95° C. whereupon additional ingredients can then be added such as flavoring agents and coloring agents. The formulation is further cooled and formed into pieces of desired dimensions.

A general discussion of the lozenge and chewable tablet forms of confectionery may be found in H.A. Lieberman and L. Lachman, Pharmaceutical Dosage Forms: Tablets Volume 1, Marcel Dekker, Inc. , New York, N.Y. at pages 289 to 466, which disclosure is incorporated herein by reference.

In accordance with this invention, therapeutically effective amounts of the stabilized antiseptic compositions of the present invention may be

admixed into the hard and soft confectionery products.

These amounts are readily determined by those skilled in the art without the need for undue experimentation. In a preferred embodiment, the ingestible antiseptic composition will comprise the stabilized antiseptic composition in an amount from about 0.25% to about 2% and an ingestible vehicle, that is a pharmaceutically acceptable carrier, in a quantity sufficient to bring the total amount of composition to 100%, by weight the ingestible antiseptic composition. In a more preferred embodiment, the ingestible composition will comprise the stabilized antiseptic composition in an amount from about 0.05% to about 1% and an ingestible vehicle in a quantity sufficient to bring the total amount of composition to 100%, by weight the ingestible antiseptic composition.

The present invention extends to methods of making the ingestible antiseptic compositions. In such methods, an ingestible antiseptic composition is prepared by admixing a therapeutically effective amount of the stabilized antiseptic composition with a phar aceutically-acceptable carrier. The apparatus useful in accordance with the present invention comprises mixing and heating apparatus well known in the confectionery arts, and therefore the selection of the specific apparatus will be apparent to the artisan. The final ingestible antiseptic compositions are readily prepared using methods generally known in the confectionery arts.

The stabilized antiseptic compositions may also be incorporated into chewing gums. In this form of the invention, the chewing gum composition contains a gum base, a bulking agent, the inventive stabilized antiseptic composition, and various additives.

The gum base employed will vary greatly depending upon various factors such as the type of base desired, the consistency of gum desired and the other

components used in the composition to make the final chewing gum product. The gum base may be any water- insoluble gum base known in the art, and includes those gum bases utilized for chewing gums and bubble gums. Illustrative examples of suitable polymers in gum bases include both natural and synthetic elastomers and rubbers. For example, those polymers which are suitable as gum bases include, without limitation, substances of vegetable origin such as chicle, crown gum, nispero, rosadinha, jelutong, perillo, niger gutta, tunu, balata, gutta-percha, lechi-capsi, sorva, gutta kay, mixtures thereof and the like. Synthetic elastomers such as butadiene-styrene copolymers, polyisobutylene, isobutylene-isoprene copolymers, polyethylene, mixtures thereof and the like are particularly useful.

The gum base may include a non-toxic vinyl polymer, such as polyvinyl acetate and its partial hydrolysate, polyvinyl alcohol, and mixtures thereof. When utilized, the molecular weight of the vinyl polymer may range from about 2,000 up to and including about 94,000.

The amount of gum base employed will vary greatly depending upon various factors such as the type of base used, the consistency of the gum desired and the other components used in the composition to make the final chewing gum product. In general, the gum base will be present in amounts from about 5% to about 94%, by weight of the final chewing gum composition, and preferably in amounts from about 15% to about 45%, and more preferably in amounts from about 15% to about 35%, and most preferably in amounts from about 20% to about 30%, by weight of the final chewing gum composition.

The gum base composition may contain conventional elastomer solvents to aid in softening the elastomer base component. Such elastomer solvents may comprise terpinene resins such as polymers of alpha-

pinene or beta-pinene, methyl, glycerol or pentaerythritol esters of rosins or modified rosins and gums, such as hydrogenated, dimerized or polymerized rosins or mixtures thereof. Examples of elastomer solvents suitable for use herein include the pentaerythritol ester of partially hydrogenated wood or gum rosin, the pentaerythritol ester of wood or gum rosin, the glycerol ester of wood rosin, the glycerol ester of partially dimerized wood or gum rosin, the glycerol ester of polymerized wood or gum rosin, the glycerol ester of tall oil rosin, the glycerol ester of wood or gum rosin and the partially hydrogenated wood or gum rosin and the partially hydrogenated methyl ester of wood or rosin, mixtures thereof, and the like. The elastomer solvent may be employed in amounts from about 5% to about 75%, by weight of the gum base, and preferably from about 45% to about 70%, by weight of the gum base.

A variety of traditional ingredients may be included in the gum base in effective amounts such as plasticizers or softeners such as lanolin, palmitic acid, oleic acid, stearic acid, sodium stearate, potassium stearate, glyceryl triacetate, glyceryl lecithin, glyceryl monostearate, propylene glycol monostearate, acetylated monoglyceride, glycerine, mixtures thereof, and the like may also be incorporated into the gum base to obtain a variety of desirable textures and consistency properties. Waxes, for example, natural and synthetic waxes, hydrogenated vegetable oils, petroleum waxes such as polyurethane waxes, polyethylene waxes, paraffin waxes, microcrystalline waxes, fatty waxes, sorbitan monostearate, tallow, propylene glycol, mixtures thereof, and the like may also be incorporated into the gum base to obtain a variety of desirable textures and consistency properties. These traditional additional materials are generally employed in amounts up to about 30%, by weight of the gum base, and preferably in amounts from about 3% to about 20%, by weight of the gum base.

The gum base may include effective amounts of mineral adjuvants such as calcium carbonate, magnesium carbonate, alumina, aluminum hydroxide, aluminum silicate, talc, tricalcium phosphate, dicalcium phosphate and the like as well as mixtures thereof. These mineral adjuvants may serve as fillers and textural agents. These fillers or adjuvants may be used in the gum base in various amounts. Preferably the amount of filler when used will be present in an amount up to about 60%, by weight of the chewing gum base.

The chewing gum base may additionally include the conventional additives of coloring agents, antioxidants, preservatives and the like. For example, titanium dioxide and other dyes suitable for food, drug and cosmetic applications, known as F.D. & C. dyes, may be utilized. An anti-oxidant such as butylated hydroxytoluene (BHT) , butylated hydroxyanisole (BHA) , propyl gallate, and mixtures thereof, may also be included. Other conventional chewing gum additives known to one having ordinary skill in the chewing gum art may also be used in the chewing gum base.

The gum composition may include effective amounts of conventional additives selected from the group consisting of sweetening agents (sweeteners) , plasticizers, softeners, emulsifiers, waxes, fillers, bulking agents, mineral adjuvants, flavoring agents (flavors, flavorings) , coloring agents (colorants, colorings), antioxidants, acidulants, thickeners, mixtures thereof and the like. Some of these additives may serve more than one purpose. For example, in sugarless gum compositions, the sweetener, e.g., sorbitol or other sugar alcohol or mixtures thereof, may also function as a bulking agent. Similarly, in sugar containing gum compositions, the sugar sweetener can also function as a bulking agent.

The plasticizers, softeners, mineral adjuvants, colorants, waxes and antioxidants discussed above as being suitable for use in the gum base may also be used in the gum composition. Examples of other conventional additives which may be used include emulsifiers, such as lecithin and glyceryl monostearate, thickeners, used alone or in combination with other softeners, such as methyl cellulose, alginates, carrageenan, xanthan gum, gelatin, carob, tragacanth, locust bean, and carboxy methyl cellulose, acidulants such as malic acid, adipic acid, citric acid, tartaric acid, fumaric acid, and mixtures thereof, and fillers, such as those discussed above under the category of mineral adjuvants. The fillers when used may be utilized in an amount up to about 60%, by weight of the gum composition.

Bulking agents (carriers, extenders) suitable for use in chewing gums include sweetening agents selected from the group consisting of monosaccharides, disaccharides, poly-saccharides, sugar alcohols, and mixtures thereof; polydextrose; maltodextrins; minerals, such as calcium carbonate, talc, titanium dioxide, dicalcium phosphate, and the like. Bulking agents may be used in amounts up to about 90%, by weight of the final gum composition, with amounts from about 40% to about 70%, by weight of the gum composition being preferred , with from about 50% to about 65%, by weight, being more preferred and from about 55% to about 60%, by weight of the chewing gum composition, being most preferred.

The sweetening agent used may be selected from a wide range of materials including water-soluble sweeteners, water-soluble artificial sweeteners, water- soluble sweeteners derived from naturally occurring water-soluble sweeteners, dipeptide based sweeteners, and protein based sweeteners, including mixtures thereof. Without being limited to particular sweeteners, representative categories and examples include:

(a) water-soluble sweetening agents such as monosaccharides, disaccharides and polysaccharides such as xylose, ribulose, 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, monellin, steviosides, glycyrrhizin, and sugar alcohols such as sorbitol, mannitol, maltitol, hydrogenated starch hydrolysates and mixtures thereof;

(b) water-soluble artificial sweeteners such as soluble saccharin salts, i.e., sodium or calcium saccharin salts, cyclamate salts, the sodium, ammonium or calcium salt of 3,4-dihydro-6-methyl-l,2,3-oxathiazine-4- one-2,2-dioxide, the potassium salt of 3,4-dihydro-6- methyl-1,2,3-oxathiazine-4-one-2,2-dioxide (Acesulfame- K) , the free acid form of 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 United States patent no. 3,492,131, L-alpha- aspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alanin- amide hydrate (Alitame) , methyl esters of L-aspartyl-L- phenylglycerine and L-aspartyl-L-2,5-dihydrophenyl- glycine, L-aspartyl-2,5-dihydro-L-phenylalanine; L- aspartyl-L-(l-cyclohexen)-alanine, and the like;

(d) water-soluble sweeteners derived from naturally occurring water-soluble sweeteners, such as chlorinated derivatives of ordinary sugar (sucrose) , known, for example, under the product designation of Sucralose; and

(e) protein based sweeteners such as thaumaoccous danielli (Thaumatin I and II) .

In general, an effective amount of sweetener is utilized to provide the level of bulk and/or sweetness desired, and this amount will vary with the sweetener selected. This amount of sweetener will normally be present in amounts from about 0.0025% to about 90%, by

weight of the gum composition, depending upon the sweetener used. The exact range of amounts for each type of sweetener is well known in the art and is not the subject of the present invention. The amount of sweetener ordinarily necessary to achieve the desired level of sweetness is independent from the flavor level achieved from flavor oils.

Preferred sugar based-sweeteners are sugar (sucrose) , corn syrup and mixtures thereof. Preferred sugarless sweeteners are the sugar alcohols, artificial sweeteners, dipeptide based sweeteners and mixtures thereof. Preferably, sugar alcohols are used in the sugarless compositions because these sweeteners can be used in amounts which are sufficient to provide bulk as well as the desired level of sweetness. Preferred sugar alcohols are selected from the group consisting of sorbitol, xylitol, maltitol, mannitol, and mixtures thereof. More preferably, sorbitol or a mixture of sorbitol and mannitol is utilized. The gamma form of sorbitol is preferred. An artificial sweetener or dipeptide based sweetener is preferably added to the gum compositions which contain sugar alcohols.

The coloring agents useful in the gum compositions are used in amounts effective to produce the desired color. These coloring agents include pigments which may be incorporated in amounts up to about 6% by weight of the gum composition. A preferred pigment, titanium dioxide, may be incorporated in amounts up to about 2%, and preferably less than about 1% by weight of the composition. The colorants may also include natural food colors and dyes suitable for food, drug and cosmetic applications. These colorants are known as F.D.& c. dyes and lakes. The materials acceptable for the foregoing uses are preferably water-soluble. Illustrative nonlimiting examples include the indigoid dye known as F.D.& C. Blue No.2, which is the disodium salt of 5,5-indigotindisulfonic acid. Similarly, the dye known

as F.D.& C. Green No.1 comprises a triphenylmethane dye and is the monosodium salt of 4-[4-(N-ethyl-p_- sulfoniumbenzylamino) diphenylmethylene]-[1-(N-ethyl-N-p- sulfoniumbenzyl)-delta-2,5-cyclohexadieneimine] . A full recitation of all F.D.& C. colorants and their corresponding chemical structures may be found in the

Kirk-Othmer Encyclopedia of Chemical Technology, 3rd

Edition, in volume 5 at pages 857-884, which text is incorporated herein by reference.

Suitable oils and fats usable in gum compositions include partially hydrogenated vegetable or animal fats, such as coconut oil, palm kernel oil, beef tallow, lard, and the like. These ingredients when used are generally present in amounts up to about 7%, by weight, and preferably up to about 3.5%, by weight of the gum composition.

In accordance with this invention, therapeutically effective amounts of the stabilized antiseptic compositions of the present invention may be admixed into a chewing gum. These amounts are readily determined by those skilled in the art without the need for undue experimentation. In a preferred embodiment, the final chewing gum composition will comprise the stabilized antiseptic composition in an amount from about 0.025% to about 2% and a chewing gum composition in a quantity sufficient to bring the total amount of composition to 100%, by weight of the chewing gum composition. In a more preferred embodiment, the final chewing gum composition will comprise the stabilized antiseptic composition in an amount from about 0.05% to about 1% and an oral vehicle in a quantity sufficient to bring the total amount of composition to 100%, by weight of the chewing gum composition.

The present invention extends to methods of making the antiseptic chewing gum compositions. The stabilized antiseptic compositions may be incorporated

into an otherwise conventional chewing gum composition using standard techniques and equipment known to those skilled in the art. The apparatus useful in accordance with the present invention comprises mixing and heating apparatus well known in the chewing gum manufacturing arts, and therefore the selection of the specific apparatus will be apparent to the artisan.

For example, a gum base is heated to a temperature sufficiently high enough to soften the base without adversely effecting the physical and chemical make up of the base. The optimum temperatures utilized may vary depending upon the composition of the gum base used, but such temperatures are readily determined by those skilled in the art without undue experimentation.

The gum base is conventionally melted at temperatures that range from about 60° C. to about 120° C. for a period of time sufficient to render the base molten. For example, the gum base may be heated under these conditions for a period of about thirty minutes just prior to being admixed incrementally with the remaining ingredients of the base such as the plasticizer, fillers, the bulking agent and/or sweeteners, the softener and coloring agents to plasticize the blend as well as to modulate the hardness, viscoelasticity and formability of the base. The chewing gum base is then blended with the stabilized antiseptic composition of the present invention which may have been previously blended with other traditional ingredients. Mixing is continued until a uniform mixture of gum composition is obtained. Thereafter the gum composition mixture may be formed into desirable chewing gum shapes.

Throughout this application, various publications have been referenced. The disclosures in these publications are incorporated herein by reference in order to more fully describe the state of the art.

The present invention is further illustrated by the following examples which are not intended to limit the effective scope of the claims. All parts and percentages in the examples and throughout the specification and claims are by weight of the final composition unless otherwise specified.

EXAMPLES 1-12

These examples demonstrate a comparison of the stability of aqueous hexetidine solutions at various pH levels with different buffer solutions using Tween 80 or Cremophore RH 60 as the nonionic surfactant.

Twelve stock solutions of hexetidine were prepared containing 0.1% of hexetidine, 10% ethanol, 0.7% of a nonionic surfactant, and a buffer solution. The compositions and the pH values of the solutions are set out in Table 1 as Examples 1-12.

TABLE

AQUEOUS HEXETIDINE COMPOSITIONS

Citrate buffer solution contained citric acid and sodium citrate. Phosphate buffer solution contained phosphoric acid and sodium phosphate.

**

Tween 80 is polysorbate 80 (sorbitan, mono-9-octadecanoate, poly(oxy-1,2-ethanediyl) derivative).

Cremophore RH 60 is PEG 60 (polyethylene glycol hydrogenated castor oil 60).

The solutions of Examples 1-12 were assayed by gas chromatography for initial hexetidine content. The solution of each example was then divided into three equal samples. The first sample was stored at room temperature, the second sample was stored at 37° C, and the third sample was stored at 45° C. The samples were observed for a period of six months and assayed monthly by gas chromatography to determine the amount of hexetidine undecomposed. The pH values of the samples were also tested for stability each month and were found to be stable.

The results of the stability studies of the hexetidine compositions of Examples 1-12 over a six month period, expressed as a decimal fraction of the hexetidine

detected by gas chromatography, are set out in

Tables 2-4. Table 2 shows the stability of the hexetidine compositions at room temperature. Table 3 shows the stability of the hexetidine compositions at

37° C, and Table 4 shows the stability of the hexetidine compositions at 45° C. The value of the initial hexetidine content (time zero) of each Example represents the control.

TABLE 2

STABILITY OF AQUEOUS HEXETIDINE COMPOSITIONS AT ROOM TEMPERATURE

TABLE 3

STABILITY OF AQUEOUS HEXETIDINE COMPOSITIONS AT 37° C.

MONTH

Example 3 4

0.94 0.92 0.92 0.93 0.90 0.85 0.88 0.95 0.94 0.89 0.82'

0.89 0.84 0.91 0.91 0.87 0.90 0.87 0.91 0.88''

Solution turned cloudy.

TABLE 4

STABILITY OF AQUEOUS HEXETIDINE COMPOSITIONS AT 45° C.

Solution turned cloudy.

Example 1, which contained 0.1% hexetidine, 0.7% Tween 80, and 10% alcohol in a citrate buffer solution having a pH value of 4, showed significant decomposition at 37° C. and at 45° C after one month. The composition of Example 1 was judged unacceptable and was not evaluated further.

Example 2, which contained 0.1% hexetidine, 0.7% Tween 80, and 10% alcohol in a citrate buffer solution having a pH value of 5, remained relatively stable at room temperature and at 37° C. for three months but showed significant decomposition at 45° C. after two months. The composition of Example 2 was judged acceptable to stabilize the antiseptic composition.

Example 3, which contained 0.1% hexetidine, 0.7% Tween 80, and 10% alcohol in a citrate buffer

solution having a pH value of 6, remained stable at room temperature, at 37° C, and at 45° C. , for four months.

The composition of Example 3 was judged acceptable to stabilize the antiseptic composition.

Example 4, which contained 0.1% hexetidine,

0.7% Tween 80, and 10% alcohol in a citrate buffer solution having a pH value of 7, remained stable at room temperature and at 37° C. for three months. At 45° C, Example 4 remained stable for two months, but showed decomposition after three months and turned cloudy. The composition of Example 4 was judged acceptable to stabilize the antiseptic composition, but not as satis actory as the composition of Example 3.

Example 5, which contained 0.1% hexetidine, 0.7% Tween 80, and 10% alcohol in a phosphate buffer solution having a pH value of 7, was prepared to compare a phosphate buffer solution (Example 5) with a citrate buffer solution (Example 4) . The composition of Example 5 became cloudy and showed significant decomposition at 37° C. and at 45° C. after two months. The composition of Example 5, containing a phosphate buffer solution, was judged to be less satisfactory than the composition of Example 4, containing a citrate buffer solution, for stabilizing the antiseptic composition.

Example 6, which contained 0.1% hexetidine, 0.7% Tween 80, and 10% alcohol in a citrate buffer solution having a pH value of 8, showed significant decomposition at 45° C. after one month. Consequently, the composition of Example 6 was judged unacceptable for stabilizing the antiseptic composition.

Example 7, which contained 0.1% hexetidine,

0.7% Cremophore RH 60, and 10% alcohol in a citrate buffer solution having a pH value of 4, showed significant decomposition at 45° C. after one month.

Consequently, Example 7 was judged unacceptable for stabilizing the antiseptic composition.

Example 8, which contained 0.1% hexetidine, 0.7% Cremophore RH 60, and 10% alcohol in a citrate buffer solution having a pH value of 5, remained stable at 37° C. after two months. At 45° C. , the composition of Example 8 showed significant decomposition after two months. Thus, the composition of Example 8 was judged acceptable for stabilizing the antiseptic composition, but not as satisfactory as the composition of Example 2 using the Tween 80 polysorbate nonionic surfactant.

Example 9, which contained 0.1% hexetidine, 0.7% Cremophore RH 60, and 10% alcohol in a citrate buffer solution having a pH value of 6, remained stable at room temperature for four months. At 37° C, the composition of Example 9 remained stable for three months and at 45° C. , the composition of Example 9 remained relatively stable for three months. The composition of

Example 9, containing Cremophore RH 60, was judged acceptable for stabilizing the antiseptic composition, but was not as satisfactory as the composition of

Example 3, containing the polysorbate nonionic surfactant, in the same buffer solution and at the same pH value.

Example 10, which contained 0.1% hexetidine, 0.7% Cremophore RH 60, and 10% alcohol in a citrate buffer solution having a pH value of 7, remained relatively stable at room temperature, at 37° C. and at 45° C. , after three months. Thus, the composition Example 10 was judged acceptable, but was not as satisfactory as the composition of Example 9 at pH 6 for stabilizing the antiseptic composition.

Example 11, which contained 0.1% hexetidine, 0.7% Cremophore RH 60, and 10% alcohol in a phosphate buffer solution having a pH value of 7, was prepared to

compare a phosphate buffer solution (Example 11) with a citrate buffer solution (Example 10) . Example 11 remained stable at room temperature and at 37° C. for three months. At 45° C, the composition of Example 11 showed decomposition after two months, and turned cloudy after three months. Thus, the composition of Example 11, containing the phosphate buffer solution, was judged not as satisfactory as the composition of Example 10, containing the citrate buffer solution, for stabilizing the antiseptic composition.

Example 12, which contained 0.1% hexetidine, 0.7% Cremophore RH 60, and 10% alcohol in a citrate buffer solution having a pH value of 8, showed significant decomposition at 45° C. and turned cloudy after two months. Consequently, the composition of Example 12 was judged unacceptable for stabilizing the antiseptic composition.

Examples 1-12 show that the antiseptic compositions comprising the hexahydro-5-pyrimidinamine compound hexetidine are stabilized in an aqueous buffer solution having a pH value from about 5 to about 7, and preferably at about 6. The buffer solution may be a phosphate buffer solution or a citrate buffer solution, and is preferably a citrate buffer solution. The non¬ ionic surfactant may be Tween 80 or Cremophore RH 60, and is preferably Tween 80.

EXAMPLES 13-18

These examples demonstrate a comparison of the stability of aqueous hexetidine solutions at various pH levels with different buffer solutions using Pluronic F-127 as the surfactant.

Six stock solutions of hexetidine were prepared containing 0.1% of hexetidine, 10% ethanol, 0.7% of Pluronic F-127, and a buffer solution. The compositions

and the pH values of the solutions are set out in Table 5 as Examples 13-18.

TABLE 5

AQUEOUS HEXETIDINE COMPOSITIONS

Pluronic F-127 is a poloxamer (Poloxamer 407) which has an HLB of about 22 and is a poly(oxyethylene)-poly(oxypropylene) block copolymer.

The solutions of Examples 13-18 were assayed by gas chromatography for initial hexetidine content. The solution of each example was then divided into three equal samples. The first sample was stored at room temperature, the second sample was stored at 37° C. , and the third sample was stored at 45° C. The samples were observed for a period of one month and assayed by gas chromatography to determine the amount of hexetidine undecomposed.

The stability of the hexetidine compositions of Examples 13-18 after a one month period, expressed as a decimal fraction of the hexetidine detected by gas chromatography, are set out in Table 6. Table 6 shows the stability of the hexetidine compositions at room temperature (R.T.), at 37° C. , and at 45° C. The value of the initial hexetidine content (time zero) of each Example represents the control.

TABLE 6

STABILITY OF AQUEOUS HEXETIDINE COMPOSITIONS

Examples 13-18, which contained 0.1% hexetidine, 0.7% Pluronic F-127, and 10% alcohol in a buffer solution having a pH value of 4-8, showed significant decomposition at 37° C. and at 45° C after one month. The compositions of Example 13-18 were judged unacceptable to stabilize the antiseptic composition and were not evaluated further.

EXAMPLES 19-20

These examples demonstrate a comparison of the stability of a control aqueous hexetidine solution, Example 19, and a preferred aqueous hexetidine solution. Example 20.

The compositions of Examples 19 and 20 are set out in Table 7. Example 19 (control) did not contain a buffer solution. Example 20 (preferred composition) contained a citric acid/sodium citrate buffer solution to maintain the pH value of the solution at 6.

TABLE

AQUEOUS HEXETIDINE COMPOSITIONS

The solutions of Examples 19-20 were assayed by gas chromatography for initial hexetidine content. The solution of each example was then divided into three equal samples. The first sample was stored at room temperature, the second sample was stored at 37° C. , and the third sample was stored at 45° C. The samples were observed for a period of three months and assayed monthly by gas chromatography to determine the amount of hexetidine undecomposed.

The stability of the hexetidine compositions of Examples 19-20 over a three month period, expressed as a decimal fraction of the hexetidine detected by gas chromatography, and as the percentage improvement in stability of the experimental formulation (Example 20) over the control formulation (Example 19) , are set out in Table 8. Table 8 shows the stability of the hexetidine compositions at room temperature, at 37° C. , and at 45° C. The value of the initial hexetidine content (time zero) of each Example represents the control.

TABLE 8

STABILITY OF AQUEOUS HEXETIDINE COMPOSITIONS

Percentage improvement was calculated according to the formula: (experimental - control) X 100X = percentage improvement control

Table 8 shows that the preferred hexetidine composition of Example 20 had a percentage improvement in hexetidine stability of 38% over the control hexetidine composition of Example 19 after storage at 45° C. for three months. Examples 19 and 20 show the stabilizing effect on hexetidine of a citric acid-sodium citrate buffer solution at pH 6 with Tween 80 surfactant.

The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention and all such

modifications are intended to be included within the scope of the following claims.