Indian Patents. 211634:ORAL PREPARATIONS

Title of Invention	ORAL PREPARATIONS
Abstract	1. A synergistic oral preparation having an anti-caries activity comprising a selective combination of pyruvic acid or an orally-acceptable salt thereof and urea or a derivative thereof and/or arginine or a derivative thereof

Full Text	FORM-2 THE PATENTS ACT,1970 (39 of 1970) PROVISIONAL / COMPLETE SPECIFICATION SECTION 10 15-11-2000 TITLE "A SYNERGISITIC ORAL PREPARATION HAVING ANTI -CARIES ACTIVITIES" APPLICANT HINDUSTAN LEVER LIMITED, A Company Incorporatol aobor the Indian Companies Act, 1913, of Hindustan Lever Houoe, 165/165 BackbayReciamation , Bombay 400020, Maharashtra, India . GRANTED 1 5 NOV 2000 The following specification particularly describes the nature of the invention and the manner in which it is to be performed This invention relates to oral preparations and in particular to oral preparations having an anti-caries activity. It is well-known that various water-soluble fluorine-containing compounds are useful for combating dental caries. Examples are sodium monofluorophosphate, sodium fluoride and stannous fluoride. There have been proposals to combat dental caries through the use in oral compositions of agents which do not contain fluorine. One of the ways to combat dental caries is to induce a pH-rise in the plaque, or to buffer the plaque-pH. For that purpose; urea has been suggested and used in oral preparations. (J. Am. -Dent. Assoc. 42, (1954), pages 185-190). Similarly, arginine has been proposed to buffer plaque-pH and to produce a pH-rise effect (US-A-4,154,813). In our quest for other agents that induce a pH-rise in the plaque, we discovered that pyruvic acid or a salt thereof has a pH-rise effect when mixed with S.mutans FA-1 and Lactobacillus acidophilus and salivary sediment-systems containing mixtures of oral bacteria. Pyruvic-acid has been proposed, amongst a variety of other agents, as an anti-caries agent in JP-A-59/029618. According to this reference, the pyruvic acid has an anti¬microbial activity against S.mutans in the oral cavity. A pH-rise effect is not disclosed. We have now surprisingly found, that the combination of pyruvic acid or an orally acceptable salt thereof with urea and/or arginine produces an additive pH-buffering effect. Consequently, the present invention relates to oral preparations having an anti-caries activity, comprising pyruvic acid or an orally-acceptable salt thereof, characterised in that it further comprises urea and/or arginine. The orally-acceptable salts of pyruvic acid are the alkali metal salts such as the sodium and potassium salts. Other suitable salts are litium, magnesium, calcium, strontium, copper, zinc, stannous, lanthanium, yterbium, scandium, europium. The amount of the pyruvic acid or salt thereof, used in the present invention, ranges from 1 to 50 % by weight, preferably from 2 to 25 % by weight, and most preferably 5-10 % by weight. The-argimr«, used-in-the-pr«sent~invcntion7 is-norrnally preserrrin an amount of 1 to 50 % by weight, preferably 2 to 25 % by weight, and particularly preferably 5-10 % by weight. The urea is normally present in an amount of 1-20 % by weight, preferably 1-10 % by weight. Derivatives of urea and arginine may also be used, e.g. sialin, small peptides with 2-4 amino acids, one of which is arginine of the type AA-arg and arg-AA, wherein AA is glycine, leucine, isoleucine, tyrosine, serine, as described in US-A-4,154,813, and compounds according to US-A-4,477,429 of the formula: CH3(CH2)yNH-CH(COOH)-(CH2),-NH-C-(:NH)-NH2 where y = 6-29. such as N-alpha-octylarginine and N-alpha-decylarginine. Together with the pyruvic acid or salt thereof and urea and/or arginine, the oral product of the invention will contain other conventional ingredients wetT-lcnown to those skilled in art depending on the form of the oral product. For instance, in the case of an oral product in the form of a dentifrice cream or paste, the product will comprise an humectant-containing liquid phase and a binder or thickener which acts to maintain the particulate solid abrasive in stable-suspension in the liquid phase. A surfactant and a flavouring agent are also usual regredients of commercially acceptable dentifrices. Humectants commonly used are glycerol and sorbitol syrup (usually comprising an approximately 70 % solution). However, other humectants are known to those in the art including propylene glycol, lactitol and hydrogenated com syrup. The amount of humectant will generally range from about 10 to 85 % by weight of the dentifrice. The remainder of the liquid phase will consist substantially of water. Likewise, numerous binding or thickening agents have been indicated for use in dentifrices, preferred ones being sodium carboxymethylcellulose and xanthan gum. Others include natural gum binders such as gum tragacanth, gum karaya and gum arabic, Irish moss, alginates and carrageenans. Silica thickening agents include the silica aerogels and various precipitated silicas. Mixtures of binding and thickening agents may be used. The amount of binder and thickening agent included in a dentifrice is generally between 0.1 and 10 % by weight. It is usual to include a surfactant in a dentifrice and again the literature discloses a wide variety of suitable materials. Surfactants which have found wide use in practice are sodium lauryl sulphate, sodium dodecylbenzene sulphonate and sodium lauroylsarcosinate. Other anionic surfactants are usually present in an amount of from 0.5 to 5 % by weight of the dentifrice. Flavours that are usually used in dentifrices are those based on oUs of spearmint and peppermint. Examples of other flavouring materials used are menthol, clove, wihiergreen, eucalyptus and aniseed. An amount of from 0.1 % to 5 % by weight is a suitable amount of flavour to incorporate in a dentifrice. The oral compositions of the invention may also comprise an abrasive agent such as silica, alumina, hydrated alumina, calcium carbonate, anhydrous dicalcium phosphate, dicalcium phosphate dihydrate, water-insoluble sodium metaphosphate, calcium pyrophosphate, hydroxy apatites etc. in an amount of up to 60 % by weight. The oral composition of the invention may include a wide variety of optional ingredients. These include an anti-plaque agent such as an anti-microbial compound for example chlorhexidine or 2,4,4,-trichloro-2'-hydroxy-diphenyl ether, or a zinc compound (see EP-A-161,898); an anti-tartar ingredient such as a condensed phosphate, e.g. an alkali metal pyrophosphate, hexametaphosphate or polyphosphate, (see US-A-4,515,772 and US-A-4,627,977) br zinc citrate (see US-A-4,100,269); sweetening agent, such as saccharin;_an_opacif-ying_agent, such-as titanium dioxide; a preservative, such as formalin; a colouring agent; or pH-controlling agent such as an acid, base or buffer, such as benzoic acid. Biomolecules such as enzymes, bacteriocins, anti-bodies etc. may also be included, as well as bleaching and whitening agents such as peroxy compounds. The compositions of the present invention may also contain additional anti-caries agents, such as sodium fluoride, sodium monofluorophosphate, stannous fluoride, calcium glycerophophate, sodium trimetaphosphate, casein and casein derivatives etc.. For a fuller discussion of the formulation of oral compositions, reference is made to Harry's Cosmeticology, Seventh Edition, 1982, Edited by J.B. Wilkinson and £.J. Moore, pages 609 to 617. The following Examples illustrate the invention. Percentages and parts are by weight. The combination of the anti-caries agents of the invention may also be included in foodstuffs -for-caries-reduction/prevention. Example 1 Salivary sediment experiments were carried out similar to those reported by Weinberg in Arch. Oral Biol., Vol. 28, 11, (1983), page 1007. Two panellists fasted and refrained from oral hygiene for 12 hours before the experiment. Fifteen miUilitres of stimulated saliva were then collected and placed in weighed centrifuge tubes. The sediment was centrifuged and washed twice with KCl solution. It was diluted with the same weight of KCl solution and incubated at 37°C for three hours. Amounts of solutions added : All the solutions were taken to pH 7 and mixed together. The sediment was then also set to pH 7 and this was then added to. the mixture of solutions. The pH of the solutions were then measured at 0, 15, 30,'!45, 60 90, 120, 150, 180 and 210 minutes. The data was then plotted on a pH v time graph. Final concentrations of solutions: KCl 135mM Glucose 2.8mM Pyruvate 33mM Arginine 33mM Urea 1.5mM Glucose 20M1 Test 100M! Sediment 500al KCl 2.48ml, 2.38ml or 2.28ml (Dependant on the amount of test solution added) For the solutions containing pyruvate and another agent 100/xl of each solution were added so the final concentrations were the same. a If required to ensure a large pH drop extra glucose was added after 30 minutes. The following results were obtained: Time (mins) Water Pyruvate Arginine Urea Pyr + Arg Pyr + Urea 0 7.32 7.32 7.40 7.33 7.44 7.36 15 6.75 6.67 6.88 7.12 6.77 6.99 30 6.6! 6.67 6.79 6.95 6.72 6.99 45 6.42 6.58 6.71 6.91 6.68 6.97 60 6.40 6.67 6.65 6.88 6.73 6.91 90 5.72 6.39 6.39 6.56 6.59 6.78 120 5.36 6.30 6.28 6.40 6.63 6.70 150 5.25 6.23 6.30 6.50 6.57 6.72 180 5J3 6.22 6.59 6.58 6.62 6.68 210 5.35 6.14 6.83 6.71 6.73 6.71 Fig. 1 and 2 these data. We claim: 1. A synergistic oral preparation having an anti-caries activity comprising a selective combination of pyruvic acid or an orally-acceptable salt thereof and urea or a derivative thereof and/or arginine or a derivative thereof. 2. A synergistic oral preparation as claimed in claim 1, comprising 1-50% by weight of pyruvic acid or an orally acceptable salt thereof, and 1-20% by weight of urea or a derivative thereof and/or 1-50% by weight of arginine or a derivative thereof. 3. A synergistic oral preparation as claimed in claim 2, wherein the weight percentages are 5-10%, 5-10% and 1-10% respectively. Dated this 13th day of November, 2000 Anjan Sen Of Anjan Sen & Associates (Applicants Agent)

Full Text

FORM-2
THE PATENTS ACT,1970
(39 of 1970)
PROVISIONAL / COMPLETE
SPECIFICATION SECTION 10

15-11-2000

TITLE
"A SYNERGISITIC ORAL PREPARATION
HAVING ANTI -CARIES ACTIVITIES"
APPLICANT
HINDUSTAN LEVER LIMITED, A Company Incorporatol aobor the Indian Companies Act, 1913, of Hindustan Lever Houoe, 165/165 BackbayReciamation , Bombay 400020, Maharashtra, India .
GRANTED

1 5 NOV 2000
The following specification particularly describes the nature of the invention and the manner in which it is to be performed

This invention relates to oral preparations and in particular to oral preparations having an anti-caries activity.
It is well-known that various water-soluble fluorine-containing compounds are useful for combating dental caries. Examples are sodium monofluorophosphate, sodium fluoride and stannous fluoride.
There have been proposals to combat dental caries through the use in oral compositions of agents which do not contain fluorine. One of the ways to combat dental caries is to induce a pH-rise in the plaque, or to buffer the plaque-pH. For that purpose; urea has been suggested and used in oral preparations. (J. Am. -Dent. Assoc. 42, (1954), pages 185-190). Similarly, arginine has been proposed to buffer plaque-pH and to produce a pH-rise effect (US-A-4,154,813).
In our quest for other agents that induce a pH-rise in the plaque, we discovered that pyruvic acid or a salt thereof has a pH-rise effect when mixed with S.mutans FA-1 and Lactobacillus acidophilus and salivary sediment-systems containing mixtures of oral bacteria.
Pyruvic-acid has been proposed, amongst a variety of other agents, as an anti-caries agent in JP-A-59/029618. According to this reference, the pyruvic acid has an anti¬microbial activity against S.mutans in the oral cavity. A pH-rise effect is not disclosed. We have now surprisingly found, that the combination of pyruvic acid or an orally acceptable salt thereof with urea and/or arginine produces an additive pH-buffering effect.

Consequently, the present invention relates to oral preparations having an anti-caries activity, comprising pyruvic acid or an orally-acceptable salt thereof, characterised in that it further comprises urea and/or arginine.
The orally-acceptable salts of pyruvic acid are the alkali metal salts such as the sodium and potassium salts. Other suitable salts are litium, magnesium, calcium, strontium, copper, zinc, stannous, lanthanium, yterbium, scandium, europium.
The amount of the pyruvic acid or salt thereof, used in the present invention,
ranges from 1 to 50 % by weight, preferably from 2 to 25 % by weight, and most
preferably 5-10 % by weight.
The-argimr«, used-in-the-pr«sent~invcntion7 is-norrnally preserrrin an amount of 1 to 50 % by weight, preferably 2 to 25 % by weight, and particularly preferably 5-10 % by weight. The urea is normally present in an amount of 1-20 % by weight, preferably 1-10 % by weight. Derivatives of urea and arginine may also be used, e.g. sialin, small peptides with 2-4 amino acids, one of which is arginine of the type AA-arg and arg-AA, wherein AA is glycine, leucine, isoleucine, tyrosine, serine, as described in US-A-4,154,813, and compounds according to US-A-4,477,429 of the formula:
CH3(CH2)yNH-CH(COOH)-(CH2),-NH-C-(:NH)-NH2 where y = 6-29.
such as N-alpha-octylarginine and N-alpha-decylarginine.
Together with the pyruvic acid or salt thereof and urea and/or arginine, the oral product of the invention will contain other conventional ingredients wetT-lcnown to those skilled in art depending on the form of the oral product. For instance, in the case of an oral product in the form of a dentifrice cream or paste, the product will comprise an humectant-containing liquid phase and a binder or thickener which acts

to maintain the particulate solid abrasive in stable-suspension in the liquid phase. A surfactant and a flavouring agent are also usual regredients of commercially acceptable dentifrices.
Humectants commonly used are glycerol and sorbitol syrup (usually comprising an approximately 70 % solution). However, other humectants are known to those in the art including propylene glycol, lactitol and hydrogenated com syrup. The amount of humectant will generally range from about 10 to 85 % by weight of the dentifrice. The remainder of the liquid phase will consist substantially of water.
Likewise, numerous binding or thickening agents have been indicated for use in
dentifrices, preferred ones being sodium carboxymethylcellulose and xanthan gum.
Others include natural gum binders such as gum tragacanth, gum karaya and gum
arabic, Irish moss, alginates and carrageenans. Silica thickening agents include the
silica aerogels and various precipitated silicas. Mixtures of binding and thickening
agents may be used. The amount of binder and thickening agent included in a
dentifrice is generally between 0.1 and 10 % by weight.
It is usual to include a surfactant in a dentifrice and again the literature discloses a wide variety of suitable materials. Surfactants which have found wide use in practice are sodium lauryl sulphate, sodium dodecylbenzene sulphonate and sodium lauroylsarcosinate. Other anionic surfactants are usually present in an amount of from 0.5 to 5 % by weight of the dentifrice.
Flavours that are usually used in dentifrices are those based on oUs of spearmint and peppermint. Examples of other flavouring materials used are menthol, clove, wihiergreen, eucalyptus and aniseed. An amount of from 0.1 % to 5 % by weight is a suitable amount of flavour to incorporate in a dentifrice.

The oral compositions of the invention may also comprise an abrasive agent such as silica, alumina, hydrated alumina, calcium carbonate, anhydrous dicalcium phosphate, dicalcium phosphate dihydrate, water-insoluble sodium metaphosphate, calcium pyrophosphate, hydroxy apatites etc. in an amount of up to 60 % by weight.
The oral composition of the invention may include a wide variety of optional ingredients. These include an anti-plaque agent such as an anti-microbial compound for example chlorhexidine or 2,4,4,-trichloro-2'-hydroxy-diphenyl ether, or a zinc compound (see EP-A-161,898); an anti-tartar ingredient such as a condensed phosphate, e.g. an alkali metal pyrophosphate, hexametaphosphate or polyphosphate, (see US-A-4,515,772 and US-A-4,627,977) br zinc citrate (see US-A-4,100,269); sweetening agent, such as saccharin;_an_opacif-ying_agent, such-as titanium dioxide; a preservative, such as formalin; a colouring agent; or pH-controlling agent such as an acid, base or buffer, such as benzoic acid. Biomolecules such as enzymes, bacteriocins, anti-bodies etc. may also be included, as well as bleaching and whitening agents such as peroxy compounds.
The compositions of the present invention may also contain additional anti-caries agents, such as sodium fluoride, sodium monofluorophosphate, stannous fluoride, calcium glycerophophate, sodium trimetaphosphate, casein and casein derivatives etc..
For a fuller discussion of the formulation of oral compositions, reference is made to Harry's Cosmeticology, Seventh Edition, 1982, Edited by J.B. Wilkinson and £.J. Moore, pages 609 to 617.
The following Examples illustrate the invention. Percentages and parts are by weight.

The combination of the anti-caries agents of the invention may also be included in foodstuffs -for-caries-reduction/prevention.

Example 1
Salivary sediment experiments were carried out similar to those reported by Weinberg in Arch. Oral Biol., Vol. 28, 11, (1983), page 1007.
Two panellists fasted and refrained from oral hygiene for 12 hours before the experiment. Fifteen miUilitres of stimulated saliva were then collected and placed in weighed centrifuge tubes. The sediment was centrifuged and washed twice with KCl solution. It was diluted with the same weight of KCl solution and incubated at 37°C for three hours.
Amounts of solutions added :
All the solutions were taken to pH 7 and mixed together. The sediment was then also set to pH 7 and this was then added to. the mixture of solutions. The pH of the solutions were then measured at 0, 15, 30,'!45, 60 90, 120, 150, 180 and 210 minutes. The data was then plotted on a pH v time graph. Final concentrations of solutions:
KCl 135mM
Glucose 2.8mM
Pyruvate 33mM
Arginine 33mM
Urea 1.5mM
Glucose 20M1
Test 100M!
Sediment 500al
KCl 2.48ml, 2.38ml or 2.28ml
(Dependant on the amount of test solution
added)

For the solutions containing pyruvate and another agent 100/xl of each solution were added so the final concentrations were the same.
a
If required to ensure a large pH drop extra glucose was added after 30 minutes. The following results were obtained:

Time
(mins) Water Pyruvate Arginine Urea Pyr + Arg Pyr + Urea
0 7.32 7.32 7.40 7.33 7.44 7.36
15 6.75 6.67 6.88 7.12 6.77 6.99
30 6.6! 6.67 6.79 6.95 6.72 6.99
45 6.42 6.58 6.71 6.91 6.68 6.97
60 6.40 6.67 6.65 6.88 6.73 6.91
90 5.72 6.39 6.39 6.56 6.59 6.78
120 5.36 6.30 6.28 6.40 6.63 6.70
150 5.25 6.23 6.30 6.50 6.57 6.72
180 5J3 6.22 6.59 6.58 6.62 6.68
210 5.35 6.14 6.83 6.71 6.73 6.71
Fig. 1 and 2 these data.

We claim:
1. A synergistic oral preparation having an anti-caries activity comprising a selective combination of pyruvic acid or an orally-acceptable salt thereof and urea or a derivative thereof and/or arginine or a derivative thereof.
2. A synergistic oral preparation as claimed in claim 1, comprising 1-50% by weight of pyruvic acid or an orally acceptable salt thereof, and 1-20% by weight of urea or a derivative thereof and/or 1-50% by weight of arginine or a derivative thereof.
3. A synergistic oral preparation as claimed in claim 2, wherein the weight percentages are 5-10%, 5-10% and 1-10% respectively.
Dated this 13th day of November, 2000 Anjan Sen
Of Anjan Sen & Associates (Applicants Agent)

Documents:

1020-mum-2000-cancelled pages(15-11-2000).pdf

1020-mum-2000-claims(granted)-(15-11-2000).doc

1020-mum-2000-claims(granted)-(15-11-2000).pdf

1020-mum-2000-correspondence(1)-(19-09-2001).pdf

1020-mum-2000-correspondence(2)-(13-09-2007).pdf

1020-mum-2000-correspondence(ipo)-(29-10-2007).pdf

1020-mum-2000-drawing(15-11-2000).pdf

1020-mum-2000-form 1(02-04-2007).pdf

1020-mum-2000-form 1(05-02-2001).pdf

1020-mum-2000-form 1(15-11-2000).pdf

1020-mum-2000-form 13(02-04-2007).pdf

1020-mum-2000-form 13(24-08-2007).pdf

1020-mum-2000-form 19(23-06-2003).pdf

1020-mum-2000-form 2(granted)-(15-11-2000).doc

1020-mum-2000-form 2(granted)-(15-11-2000).pdf

1020-mum-2000-form 3(13-09-2007).pdf

1020-mum-2000-form 3(15-11-2000).pdf

1020-mum-2000-form 3(24-07-2007).pdf

1020-mum-2000-form 5(15-11-2000).pdf

1020-mum-2000-pettition undre rule 137(13-09-2007).pdf

1020-mum-2000-pettition undre rule 138(13-09-2007).pdf

1020-mum-2000-power of auttorney(02-04-2007).pdf

1020-mum-2000-power of auttorney(15-11-2000).pdf

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Patent Number

211634

Indian Patent Application Number

1020/MUM/2000

PG Journal Number

43/2008

Publication Date

24-Oct-2008

Grant Date

05-Nov-2007

Date of Filing

15-Nov-2000

Name of Patentee

HINDUSTAN UNILEVER LIMITED

Applicant Address

HINDUSTAN LEVER HOUSE, 165/166, BACKBAY RECLAMATION, BOMBAY,

Inventors:

#	Inventor's Name	Inventor's Address
1	See attached documents	See attached documents

PCT International Classification Number

A61K 7/16

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA