WO2003075661A1

WO2003075661A1 - Oral formulations containing nucleotides that inhibit perception of unpleasant taste

Info

Publication number: WO2003075661A1
Application number: PCT/US2003/006485
Authority: WO
Inventors: Richard Alexander Mcgregor; Harvey Donald Homan
Original assignee: Linguagen Corp
Current assignee: Linguagen Corp
Priority date: 2002-03-08
Filing date: 2003-03-03
Publication date: 2003-09-18
Anticipated expiration: 2004-09-08
Also published as: AU2003230588A1

Abstract

An oral formulation which contains as an active ingredient, a effective amount of a nucleotide compound which contains a purine or pyrimidine group or derivative thereof which is bonded to a ribose or deoxyribose sugar moiety, or a derivative of ribose or 1 deoxyribose and an ionizable phosphate or similar anionic -organic group in combination with a non-toxic orally acceptable carrier base and methods for the use of the nucleotides with or without a carrier.

Description

ORAL FORMULATIONS CONTAINING NUCLEOTIDES THAT INHIBIT

PERCEPTION OF UNPLEASANT TASTE

INTRODUCTION

The present invention relates to methods and compositions for inhibiting the sensory perception of unpleasant taste. The invention is directed to the use of an active ingredient that can be added to . oral formulations such as mouthwash, mouthrinse and dentifrice in order to decrease the unpleasant taste left in the mouth after eating or as a result of bacterial metabolism.

The unpleasant taste can be decreased without the active ingredient having to impart a taste of its own. The active ingredient of the invention also decreases the perception of the bitter taste invoked by other active components of foods and other formulations that are placed in the oral cavity. The active ingredient may also be formulated in combination with other ingredients such as water alcohol, humectant, phenolic flavor, dental polishing agent, thickener and water. RACKCROITNU OF THE INVENTION

Previous inventions have focused on decreasing breath malodor by the addition of various ingredients to mouthwash, mouthrinse and dentifrice. The approach to addressing unpleasant taste in the oral cavity has been to overpower it with compounds that have a strong taste such as menthol. The applicant is not aware of any disclosure or suggestion in the art of using a compound that does not impart a strong taste to abrogate unpleasant taste in the oral cavity. The active ingredient whose use is herein claimed has been disclosed as having the property of decreasing the perception of the bitter taste of various foods and pharmaceuticals when they are mixed with and administered contemporaneously with such foods and pharmaceuticals (U S Serial Nos 60/113,562, 09/865,346 The effect of these active ingredients on the bitter taste perception that has previously imparted by bitter taste moieties, has not been reported and could npot have been predicted, based on the prior art As used herein the term "unpleasant taste" means a taste that a majority of a taste test panel of six randomly selected individuals will agree is a taste that lingers for 30 to 60 minutes after the mgestion of a food or beverage and is unacceptable

Mouthwashes, mouthrmses, dentifrices and denture adhesives can elicit unpleasant taste m the oral cavity

For example, a mouthwash or mouthrinse containing 0 35% eucalyptus oil can be perceived as having a bitter or medicinal taste Hussam and Barcelon (1991) proposed the use of 0 0025% fenchone, borneol or lsoborneol to significantly suppress this off-taste These, and other mentholated compositions appear to decrease perception of bitterness due to their cooling effect on the mouth Other mentholated compositions used to reduce bitter taste in mouthwash or mouthrinse are menthol, di-D- frυctofuranose 1,2' 2,3' -dianhydride, anethole and menthofuran (Kondo and Nishimura, 1991, Ueki et al . , 1993) Polygodial from plant extracts suppresses bitterness by a similar method of cooling (Ishikawa et al . , 1995) Peppermint oil has been used as a bitterness blocker in mouthwash, mouthrinse and dentifrice to reduce the required amount of menthol (Hussein et aJ . , 1994, Carlm et al , 1994) Sweeteners are also used to reduce bitterness of oral compositions (Peterson et al . , 1994)

Accordingly it is an object of the invention to provide a formulation comprising an active ingredient that is capable of decreasing the perception of unpleasant taste in the oral cavity, which has been caused by foods, pharmaceuticals or other compositions.

It is also an object of the invention to provide the active ingredient in an oral formulation which may be used as a mouthwash, mouthrinse, dentifrice or dental adhesive composition.

It is also an object of the invention to provide gums, tablets, lozenges, tooth powders, tooth hardeners, antitartar compositions and anticalculus compositions which contain the active ingredient in an amount that is effective to control unpleasant tastes in the oral cavity.

It is also an object of the invention to provide an active ingredient to control an unpleasant taste in the oral cavity wherein the active ingredient inherently has no significant taste.

These and other objects of the invention will become apparent from a review of the appended specification.

SUMMARY OF THE TNVENTTON The present invention relates to oral formulations which contain as an active ingredient, a effective amount of a nucleotide compound which contains a purine or pyrimidine group or derivative thereof which is bonded to a ribose or deoxyribose sugar moiety, or a derivative of ribose or deoxyribose and an ionizable phosphate. The term effective amount is used to describe the amount of the nucleotide compound which is effective to reduce unpleasant tastes in the oral cavity. The nucleotide compound may be incorporated as a component of a mouthwash, mouthrinse or dentifrice composition. These compositions may contain suitable vehicles and other conventional ingredients such as water, ethanol, humectants, flavors, dental polishing agents, thickeners, surfactants, biocides, fluorides etc. which are employed in such compositions in amounts which provide the desired form of a composition. The nucleotide compound is used at a concentration that is effective to decrease the perception of an unpleasant taste in the oral cavity

The amount of the nucleotide compound employed in the invention may comprise about 0 0001% to 10% by weight and preferably between about 0 0025% and 0 5% by weight is used based on the total weight of the particular composition m which it is employed

The present invention also provides for a method of decreasing unpleasant taste present m the oral cavity comprising administering a mouthwash, mouthrinse or dentifrice containing an effective amount of the nucleotide compounds according to the invention

DETAILED DESCRIPTION OF THE TNVFNTTON

Without being bound by any theory by which the present invention operates, it is believed that the nucleotide compounds described herein operate by blocking unpleasant tastes which may be present m the oral cavity of a human subjects

The preferred nucleotides are soluble in water and may be prepared in water or water/alcohol mixtures The unpleasant taste can be derived from recently eaten food or beverage products or from byproducts of bacterial metabolism in the oral cavity

The oral formulation can be a simple aqueous solution of solvent and nucleotide Alternatively, the oral formulation that the ingredient of the invention is added to may optionally include an anticaries agent such as sodium fluoride, potassium fluoride, stannous fluoride, sodium monofluorophosphate and sodium hexafluoride , antibacterial agent such as chlorhexidme, benzthonium chloride, cetyl pyridmium chloride and lupulones, alcohol such as ethanol and isopropanol, humectants such as glycerol, sorbitol, manmtol, polyethylene glycol and propylene glycol, surfactant such as sodium lauryl sulfate, sodium dodecyl benzene sulfonate, sodium N-coco, N-methyl taurate and N-lauroyl sarcosine; antitartar agents such as tetrasodium pyrophosphate and sodium triphosphate,- potassium chloride, potassium citrate and potassium nitrate to decrease teeth sensitivity; flavorings such as peppermint oil, wintergreen oil and eucalyptus oil; sweeteners such as sucrose, aspartyl phenyl alanine methyl ester and saccharin; preservatives such as benzoate; polishing agents such as calcium carbonate, dicalcium phosphate and tricalcium phosphate; tooth hardeners; tooth whiteners; buffers; anticalculus agents such as azacycloalkane diphosphonic acid; thickening agents such as carrageenan and hydroxymethyl cellulose; vitamins; coloring agents. The orally acceptable vehicle for the compositions of the present invention when such compositions are mouthwashes or mouthrinses will normally be any which is employed in such compositions that do not contain the ingredient of the invention and wilj typically have a solvent base that is aqueous or aqueous alcoholic with the preferred alcohol being ethanol.

In preferred oral compositions that are in the form of mouthwashes or mouthrinses, there will also be present about 0-20wt% of alcohol, preferably ethanol, about 10- 50wt% of humectant, phenolic flavor in the range of about 0-lwt%, with the balance of the formulation comprising water at levels of up to about 90wt%.

The orally acceptable vehicle for the compositions of the present invention when such compositions are gums, tablets, lozenges, tooth powders, tooth hardeners, antitartar compositions, dental adhesives or anticalculus compositions will normally be any which is employed in such compositions that do not contain the nucleotide compound of the invention. These formulations are exemplified in Remington 20th Ed., Mack Pub. Co. (2000).

In preferred oral compositions that are in the form of gums, tablets, lozenges, tooth powders, tooth hardeners, antitartar compositions, dental adhesives or anticalculus compositions, there will also be present about 0-40wt% or l-30wt% dental polishing agent, preferably finely divided silica, about 0-45wt% or 1- 35wt.% humectant, about 0.5-10wt% thickener, about 0-20wt% or 1-20 of a sugar such as sucrose or lactose about 0-5wt% surfactant, and up to 90wt% water.

The ingredients, including the ingredient of the invention, are mixed and packaged by methods known to persons skilled in the art.

The nucleotide compounds are well known and comprise adenosine, guanine, cytosine, thymine, inosine and uracyl in chemical combination with a sugar and a phosphate. The preferred nucleotide compounds include, but are not limited to, adenosine 5 ' -monophosphate, inosine 5'- monophosphate, adenosine 3':5'-cyclic monophosphate, guanosine 2' :3' -cyclic monophosphate, guanosine 3':5'- cyclic monophosphate, cytidine 5 ' -monophosphate, guanosine 2 ' -monophosphate, guanosine 3 ' -monophosphate , guanosine 5 ' -monophosphate, uridine 5 ' -monophosphate , 2'- deoxyadenosine 5 ' -monophosphate, 2 ' -deoxyadenosine 5'- triphosphate, 2 ' -deoxycytidine 5 ' -monophosphate , and 2¹- deoxyguanosine 5 ' -monophosphate . In specific, non-limiting embodiments, where adenosine 5 ' -monophosphate, inosine 5 ' -monophosphate, adenosine 3' :5' -cyclic monophosphate, uridine 5'- monophosphate, 2 ' -deoxyadenosine 5 ' monophosphate, 2 ' - deoxyadenosine 5 ' -triphosphate or 2 ' -deoxyguanosine 5'- monophosphate is used to decrease unpleasant taste in the mouth an oral formulation comprising a concentration of the nucleotide of between about 0.0001% and 10% by weight, preferably between about 0.0025% and 0.5% is used . In specific, non-limiting embodiments, where guanosine 2' :3' -cyclic monophosphate, guanosine 3':5'- cyclic monophosphate, cytidme 5' -monophosphate, guanosine 2' -monophosphate, guanosine 5 ' -monophosphate, 2'- deoxycytidme 5 ' -monophosphate or guanosine 3'- monophosphate is used to decrease unpleasant taste in the mouth an oral formulation comprising a concentration of the nucleotide of between about 0 001% and 10% by weight, preferably between about 0 025% and 0 5% by weight based on the total weight of composition is used

The preferred embodiment of the invention is such that the compounds claimed to decrease unpleasant taste are nucleosides m the form of adenosine, inosine, guanosine, cytosme, thymme, uracyl , 5-methylcytosme, thiouracil, bromothymine, azaadenmes, azaguanosme, xanthme, hypoxanthme , 8-bromoguanme, 8-chloroguanme, 8-aminoguanme , 8-hydrazmoguanιne, 8-hydroxyguanιne, δmethylguanme , 8- thioguanme , 2 -ammopurine, 2,6- diaminopurme , 5-ethylcytosme , 5-methylcytosme, 5- bromouracil, 5 - lodouracil , 5-ethyluracιl , 5-propyluracιl , 5-vmyluracιl , and 5-bromovmyluracιl combined with ribose or deoxyribose sugar, or derivative thereof, and contain an ionizable phosphate or similar anionic organic molecule The compositions containing the nucleotide are in a pharmaceutically acceptable matrix m which the matrix has a composition such that the pH range is between 3 0 and 11 0 when placed in a suitable aqueous environment at a concentration of 1% by weight The expression "pharmaceutically acceptable matrix" includes liquid carriers, liquid sprays, gels, solid tablets, chewable matrices such as gums, fast dissolving matrices and semi solid granules These matrices are prepared by utilizing any one of a wide variety of different prior art methods well known to one of ordinary skill in the art The compositions as described above are sufficient to block unpleasant tastes present m the mouth of human subjects as determined by subjective determination of the taste intensity DESCRIPTION OF THE PREFERRED EMBODIMENTS

EXAMPLE 1 A mouth wash formulation is prepared as follows: adenosine 5' -monophosphate 2. Og ethanol 1.5g glycerin 2. Og purified water qs 100. Og

EXAMPLE 2

A mouthwash formulation is prepared as follows:

Adenosine 5' -monophosphate 2. Og

Sorbitol lOg Glycerine lOg

Betaine 0.5g

Ethanol lOg

Propylene glycol 7. Og

Phenolic flavors 0.15g purified water qε lOOg

EXAMPLE 3

A dentifrice formulation is prepared as follows: Adenosine 5 ' -monophosphate 2. Og

Glycerine lOg

Glycine 0.2g

Sodium fluoride 0.25g

Xanthum gum 0.5g Sodium lauryl sarcosinate lg

Silica 20g purified water qs lOOg

EXAMPLE 4

A dent i f ri ce f ormu l at ion i s prepared as f ol l ows : Adenosine 5' -monophosphate 2. Og

Sodium fluoride 0.25g

Hydrated silica 25g

Xanthum gum 0.6g Sodium alkyl sulfate 1. Og

Titanium dioxide 1. Og

Sodium saccharin 0.13g purified water qs lOOg

EXAMPLE 5 A gum formulation is prepared as follows:

Adenosine 5 ' -monophosphate 2. Og

Estergum lOg Coumorone resin 15g

Dry latex 5g

Sucrose 50g

Glycine 0.02g

Flavor 1.5g Corn Syrup qs lOOg

EXAMPLE 6

A sugar-free gum formulation is prepared as follows Adenosine 5 ' -monophosphate 2. Og

Estergum lOg

Coumorone resin 15g

Dry latex 5g

Sorbitol 49.75g Saccharin 0.25g

Glycine 0.02g

Flavor 1.5g

Corn syrup qs lOOg

EXAMPLE 7 A lozenge formulation is prepared as follows Adenosine 5 ' -monophosphate 2. Og

Sorbitol 17.5g

Mannitol 17.5g

Starch 15g

Glycine 0.02g

Saccharin 0.2g

Flavor 1.5g

Corn syrup qs lOOg

EXAMPLE 8 A dental adhesive formulation is prepared by adding Adenosine 5' -monophosphate 2. Og to any commertcially available denture adhesive

EXAMPLE 9 A tablet formulation is prepared which has Adenosine 5 ' -monophosphate 2. Og with or without suitable excipients.

EXAMPLE 10

The m vivo assay may be carried out as follows: 4 Subjects consumed 10 grams of onion. After 10 minutes, the unpleasant taste is graded on a scale from 1 to 10 (10 being the most unpleasant) Each subject then rinsed with 15 mL of a 10 mM AMP solution Forty-five minutes after consumption of the onions, each subject rinsed with 15 mL of a 20 mM AMP solution

Claims

WK CT .AT M :

I. An, oral formulations which contains as an active ingredient, a effective amount of one or more nucleotide compounds which contains a purme or pyrimidine group or derivative thereof which is bonded to a ribose or deoxyribose sugar moiety, or a derivative of ribose or deoxyribose and an ionizable phosphate in combination with a non-toxic orally acceptable carrier base .

2. An oral formulation as defined in claim 1 which contains adenosine 5' -monophosphate .

3. An oral formulation as defined in claim 1 which contains inosine 5 ' -monophosphate

4. An oral formulation as defined m claim 1 which contains adenosine 3 ',5 '-cyclic monophosphate.

5. An oral formulation as defined in claim 1 which contains guanosine 2' :3' -cyclic monophosphate.

6. An oral formulation as defined m claim 1 which contains guanosine 3 ',5 '-cyclic monophosphate.

7 An oral formulation as defined m claim 1 which contains cytidme 5 ' -monophosphate .

8. An oral formulation as defined in claim 1 which contains guanosine 2 ' -monophosphate .

9. An oral formulation as defined in claim 1 which contains guanosine 3 ' -monophosphate .

10. An oral formulation as defined in claim 1 which contains guanosine 5 ' -monophosphate .

II. An oral formulation as defined in claim 1 which contains uridine 5 ' -monophosphate .

12. An oral formulation as defined m claim 1 which contains 2 ' -deoxyadenosine 5 ' -monophosphate .

13. An oral formulation as defined in claim 1 which contains 2 ' -deoxycytidme 5 ' -monophosphate .

14 An oral formulation as defined in claim 1 which contains 2 ' -deoxyguanosme 5 ' -monophosphate .

15 An oral formulation as defined in claim 1 which contains 2 ' -deoxyadenosine 5 ' -triphosphate .

16. A method of decreasing the sensation of an unpleasant taste, said method comprising contacting the oral cavity of a subject having said unpleasant taste with an effective amount of a compound consisting of a nucleotide compound as defined in claim 1.