CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This international application filed under the Paris Convention Treaty (PCT) claims
priority to U.S. Provisional Patent Application Serial No. 61/740,391 filed December 20,
201 and titled ANTIPLAQUE ORAL COMPOSITIONS, the contents of which are
incorporated herein in their entirety.
TECHNICAL FIELD OF THE INVENTION
[0002] This disclosure relates generally to the field of pharmacotherapy related to the
treatment of disorders related to dental plaque. In particular, the invention relates to
antiplaque oral compositions containing a transport enhancer and a chelating agent. More
particularly, it relates to such compositions which contain MSM and EDTA.
BACKGROUND OF THE INVENTION
[0003] Dental plaque is responsible for many of the diseases common to the oral cavity
including dental caries, periodontitis, gingivitis, and the less common peri-implantitis (similar
to periodontitis, but with dental implants).
[0004] Dental calculus is an ash gray, yellowish or dark brown calcified substance depositing
on dental crowns, exposed dental root surfaces, or surfaces of restorative dental materials.
Plaque (dental plaque) adheres to surfaces of human teeth. In the plaque, a reaction occurs by
which inorganic salts become more adhesive, and calcification starts from a layer which
touches a tooth surface. The calcification advances as the plaque becomes older and thicker,
and new plaques adhere to the surface of the calcified plaques and causes calcification.
Dental calculus is formed by repetition of this process.
[0005] Seventy to eighty percents of components of supragingival dental calculus consist of
inorganic salts, and most of them consist of hydroxyapatite (Caio(P04)6(OFf)2). Calcium
phosphate, calcium carbonate, magnesium phosphate and the like may sometimes be also
contained. Further, dibasic calcium phosphate and tribasic calcium phosphate may sometimes
be contained. Organic components contained in dental calculus are bacterial cells, and they
include cell walls of gram positive bacteria and endotoxins as outer membrane components of
gram negative bacteria. Dental plaque formation more easily progresses on dental calculus
surfaces than on smooth tooth surfaces, and dental plaque adhering to dental calculus
stimulates periodontal soft tissues to become etiologic substance. Accordingly, scaling of
teeth is important as one of the fundamental treatments in prophylaxis and therapy of
periodontal diseases.
[0006] For removal of dental calculus, methods involving mechanical removal of calculus by
using a scaler or the like have been conventionally applied. However, the methods have
problems in that the treatment takes a long period of time due to hardness of dental calculus,
and thus patients, dentists, or dental hygienists bear burdens. As a means for chemically
dissolving and removing dental calculus agents for dissolving dental calculus are known.
However, the dissolution action of the agent is inefficient from a practical point of view. Due
to irritation caused by the chemicals on periodontal soft tissues, such agents are not been used
in the field of clinical dentistry.
[0007] Various oral compositions, such as toothpastes and mouthrinses, that have been
manufactured and sold, have primarily based their cleaning abilities on surfactants, soaps,
and or detergents along with mild abrasives. Some formulations have added antimicrobial
agents, for example TRICLOSAN® or stannous fluoride to enhance antiplaque action.
[0008] Therefore it is desired to develop an agent for dissolving dental plaque that can
dissolve dental plaque or calculus in a short period of time and does not irritate or damage
tissues in oral cavity such as periodontal soft tissues or dental tissues.
SUMMARY OF THE INVENTION
[0009] MSM and EDTA (chelators in general) were not known to have an anti-plaque effect.
Calcium chelators (like EDTA) are expected to have a negative impact on dental enamel and
teeth in general. MSM also does not have any anti-plaque properties. However, treatment
with a combination of MSM/EDTA surprisingly and unexpectedly showed dramatic
reductions in plaque formation.
[0010] In some embodiments, the present invention relates to methods for use of the
formulations comprising a transport enhancer (such as MSM) and a chelating agent (such as
EDTA) for prophylaxis and treatment of adverse oral conditions and disorders.
[0011] In particular embodiments, the chelating agents are selected from the tetrasodium salt
of iminodisuccinic acid (Baypure® CXI 00; LANXESS GMBH (previously Bayer
Chemicals) Leverkusen, DE) or salts of poly-asparatic acid (Baypure® DS100; LANXESS
GMBH, Leverkusen, DE).
[0012] In some embodiments, the chelating agents are tetra sodium salts of L-glutamic acid
N,N-diacetic acid (GLDA - Dissolvine®, AkzoNobel, Netherlands).
[0013] In one aspect of the invention, methods are provided for prevention or treatment of
dental plaque or calculus in a subject.
[0014] The method involves administering to the subject an effective amount of a
formulation composed of a therapeutically effective amount of a chelating agent and an
effective transport-enhancing amount of a transport enhancer having the formula (I)
(I)
o
I I
o
wherein R and R2 are independently selected from C2-C alkyl, Ci-C heteroalkyl, C -Ci4
aralkyl, and C2-C12 heteroaralkyl, any of which may be substituted, and Q is S or P.
[0015] The transport enhancing agent can be, for example, methylsulfonylmethane (MSM;
also referred to as methylsulfone, dimethylsulfone, and DMSO2), and the chelating agent can
be ethylene diamine tetra-acetic acid (EDTA) and the like.
[0016] The formulation may be administered in any form suitable including paste, gel, solid
and particulate solid state compositions, such as toothpastes, gel dentifrices, tooth powders,
chewing gums, tablets and lozenges. Additionally, in a particular embodiment, the
formulation is entirely composed of components that are naturally occurring and/or classified
as GRAS ("Generally Regarded as Safe") by the U.S. Food and Drug Administration.
However, the invention also contemplates non-GRAS components in the formulations.
[0017] The invention also pertains to methods of using the inventive formulation in the
prevention and treatment of adverse oral conditions, generally although not necessarily
involving oxidative and/or free radical damage in the oral cavity, and including, by way of
example, conditions, diseases, or disorders of the oral cavity.
[0018] The invention further provides methods for use of the aforementioned formulations
and treatment regimens that result in significant reduction of dental plaque.
[0019] These and other aspects will become apparent from the following description of the
preferred embodiment taken in conjunction with the following drawings, although variations
and modifications therein may be affected without departing from the spirit and scope of the
novel concepts of the disclosure.
DETAILED DESCRIPTION OF THE INVENTION
[0020] The terms used in this specification generally have their ordinary meanings in the art,
within the context of the invention, and in the specific context where each term is used.
Certain terms that are used to describe the invention are discussed below, or elsewhere in the
specification, to provide additional guidance to the practitioner regarding the description of
the invention. For convenience, certain terms may be highlighted, for example using italics
and/or quotation marks. The use of highlighting has no influence on the scope and meaning
of a term; the scope and meaning of a term is the same, in the same context, whether or not it
is highlighted. It will be appreciated that same thing can be said in more than one way.
Consequently, alternative language and synonyms may be used for any one or more of the
terms discussed herein, nor is any special significance to be placed upon whether or not a
term is elaborated or discussed herein. Synonyms for certain terms are provided. A recital of
one or more synonyms does not exclude the use of other synonyms. The use of examples
anywhere in this specification including examples of any terms discussed herein is illustrative
only, and in no way limits the scope and meaning of the invention or of any exemplified
term. Likewise, the invention is not limited to various embodiments given in this
specification.
[0021] Where a range of values is provided, it is understood that each intervening value, to
the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between
the upper and lower limit of that range and any other stated or intervening value in that stated
range, is encompassed within the invention. The upper and lower limits of these smaller
ranges may independently be included in the smaller ranges, and are also encompassed within
the invention, subject to any specifically excluded limit in the stated range. Where the stated
range includes one or both of the limits, ranges excluding either or both of those included
limits are also included in the invention.
[0022] Throughout this application, various publications, patents and published patent
applications are cited. The inventions of these publications, patents and published patent
applications referenced in this application are hereby incorporated by reference in their
entireties into the present invention. Citation herein of a publication, patent, or published
patent application is not an admission the publication, patent, or published patent application
is prior art.
[0023] As used herein and in the appended claims, the singular forms "a," "and," and "the"
include plural referents unless the context clearly dictates otherwise. Thus, for example, "a
transport enhancer" encompasses a plurality of transport enhancers as well as a single
transport enhancer. Reference to "a chelating agent" includes reference to two or more
chelating agents as well as a single chelating agent, and so forth. In this specification and in
the claims that follow, reference will be made to a number of terms, which shall be defined to
have the following meanings:
[0024] When referring to a formulation component, it is intended that the term used, e.g.,
"agent," encompass not only the specified molecular entity but also its pharmaceutically
acceptable analogs, including, but not limited to, salts, esters, amides, prodrugs, conjugates,
active metabolites, and other such derivatives, analogs, and related compounds.
[0025] The terms "treating" and "treatment" as used herein refer to the administration of an
agent or formulation to a clinically symptomatic individual afflicted with an adverse
condition, disorder, or disease, so as to effect a reduction in severity and/or frequency of
symptoms, eliminate the symptoms and/or their underlying cause, and/or facilitate
improvement or remediation of damage. The terms "preventing" and "prevention" refer to the
administration of an agent or composition to a clinically asymptomatic individual who is
susceptible to a particular adverse condition, disorder, or disease, and thus relates to the
prevention of the occurrence of symptoms and/or their underlying cause. Unless otherwise
indicated herein, either explicitly or by implication, if the term "treatment" (or "treating") is
used without reference to possible prevention, it is intended that prevention be encompassed
as well, such that "a method for the treatment of gingivitis" would be interpreted as
encompassing "a method for the prevention of gingivitis."
[0026] "Optional" or "optionally present" - as in an "optional substituent" or an "optionally
present additive" means that the subsequently described component (e.g., substituent or
additive) may or may not be present, so that the description includes instances where the
component is present and instances where it is not.
[0027] By "pharmaceutically acceptable" is meant a material that is not biologically or
otherwise undesirable, e.g., the material may be incorporated into a formulation of the
invention without causing any undesirable biological effects or interacting in a deleterious
manner with any of the other components of the dosage form formulation. However, when
the term "pharmaceutically acceptable" is used to refer to a pharmaceutical excipient, it is
implied that the excipient has met the required standards of toxicological and manufacturing
testing and/or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food
and Drug Administration. As explained in further detail infra, "pharmacologically active" (or
simply "active") as in a "pharmacologically active" derivative or analog refers to derivative or
analog having the same type of pharmacological activity as the parent agent. The terms
"treating" and "treatment" as used herein refer to reduction in severity and/or frequency of
symptoms, elimination of symptoms and/or underlying cause, prevention of the occurrence of
symptoms and/or their underlying cause, and improvement or remediation of an undesirable
condition or damage. Thus, for example, "treating" a subject involves prevention of an
adverse condition in a susceptible individual as well as treatment of a clinically symptomatic
individual by inhibiting or causing regression of the condition. The term "chelating agent" (or
"active agent") refers to any chemical compound, complex or composition that exhibits a
desirable effect in the biological context, i.e., when administered to a subject or introduced
into cells or tissues in vitro. The term includes pharmaceutically acceptable derivatives of
those active agents specifically mentioned herein, including, but not limited to, salts, esters,
amides, prodrugs, active metabolites, isomers, analogs, crystalline forms, hydrates, and the
like. When the term "chelating agent" is used, or when a particular chelating agent is
specifically identified, it is to be understood that pharmaceutically acceptable salts, esters,
amides, prodrugs, active metabolites, isomers, analogs, etc. of the agent are intended as well
as the agent per se.
[0028] By an "effective" amount or a "therapeutically effective" amount of an active agent is
meant a nontoxic but sufficient amount of the agent to provide a beneficial effect. The
amount of active agent that is "effective" will vary from subject to subject, depending on the
age and general condition of the individual, the particular active agent or agents, and the like.
Unless otherwise indicated, the term "therapeutically effective" amount as used herein is
intended to encompass an amount effective for the prevention of an adverse condition and/or
the amelioration of an adverse condition, i.e., in addition to an amount effective for the
treatment of an adverse condition.
[0029] The term "controlled release" refers to an agent-containing formulation or fraction
thereof in which release of the agent is not immediate, i.e., with a "controlled release"
formulation, administration does not result in immediate release of the agent into an
absorption pool. The term is used interchangeably with "non-immediate release" as defined in
Remington: The Science and Practice of pharmacy, Nineteenth Ed. (Easton, Pa.: Mack
Publishing Company, 1995). In general, the term "controlled release" as used herein refers to
"sustained release" rather than to "delayed release" formulations. The term "sustained
release" (synonymous with "extended release") is used in its conventional sense to refer to a
formulation that provides for gradual release of an agent over an extended period of time.
[0030] An adverse oral condition as that term is used herein may be a "normal" condition that
is frequently seen in individuals (e.g., increased dental calculus) or a pathologic condition
that may or may not be associated with a named disease. The latter adverse oral conditions
include a wide variety of dental disorders and diseases, associated with deposition of mineral
deposits, biofilm build-up, infections and inflammation. It should also be emphasized that the
present formulation can be advantageously employed to improve oral health, in general, in
any mammalian individual.
[0031] As will be apparent to those of skill in the art upon reading this invention, each of the
individual embodiments described and illustrated herein has discrete components and features
which may be readily separated from or combined with the features of any of the other
several embodiments without departing from the scope or spirit of the present invention. Any
recited method can be carried out in the order of events recited or in any other order that is
logically possible.
[0032] Unless otherwise indicated, the invention is not limited to specific formulation
components, modes of administration, chelating agents, manufacturing processes, or the like,
as such may vary.
[0033] Unless otherwise defined, all technical and scientific terms used herein have the same
meaning as commonly understood by one of ordinary skill in the art to which this invention
pertains. In the case of conflict, the present document, including definitions will control.
Definitions
[0034] Chelating agent: Chelation is a chemical combination with a metal in complexes in
which the metal is part of a ring. An organic ligand is called a chelator or chelating agent, the
chelate is a metal complex. The larger number of ring closures to a metal atom the more
stable is the compound. The stability of a chelate is also related to the number of atoms in the
chelate ring. Monodentate ligands which have one coordinating atom like H20 or N¾ are
easily broken apart by other chemical processes, whereas polydentate chelators, donating
multiple binds to metal ion, provide more stable complexes. Chlorophyll, a green plant
pigment, is a chelate that consists of a central magnesium atom joined with four complex
chelating agent (pyrrole ring). Heme is an iron chelate which contains iron (II) ion in the
center of the porphyrin. Chelating agents offers a wide range of sequestrants to control metal
ions in aqueous systems. By forming stable water soluble complexes with multivalent metal
ions, chelating agents prevent undesired interaction by blocking normal reactivity of metal
ions. EDTA (ethylenediamine tetraacetate) is a good example of common chelating agents
which have nitrogen atoms and short chain carboxylic groups.
[0035] Examples of chelators of iron and calcium include, but are not limited to, Diethylene
triamine pentaacetic acid (DTPA), ethylene diamine tetraacetic acid (EDTA), nitrilotriacetic
acid (NTA), 1,3-propylene diamine tetraacetic acid (PDTA), Ethylene diamine disuccinic
acid (EDDS), and ethylene glycol tetraacetic acid (EGTA). Any suitable chelating agent
known in the art, which is biologically safe and able to chelate iron, calcium or other metals,
is suitable for the invention.
[0036] Compounds useful as chelating agents herein include any compounds that coordinate
to or form complexes with a divalent or polyvalent metal cation, thus serving as a sequestrant
of such cations. Accordingly, the term "chelating agent" herein includes not only divalent and
polyvalent ligands (which are typically referred to as "chelators") but also monovalent
ligands capable of coordinating to or forming complexes with the metal cation.
[0037] Suitable biocompatible chelating agents useful in conjunction with the present
invention include, without limitation, monomelic polyacids such as EDTA,
cyclohexanediamine tetraacetic acid (CDTA), hydroxyethylethylenediamine triacetic acid
(HEDTA), diethylenetriamine pentaacetic acid (DTPA), dimercaptopropane sulfonic acid
(DMPS), dimercaptosuccinic acid (DMSA), aminotrimethylene phosphonic acid (ATPA),
citric acid, pharmaceutically acceptable salts thereof, and combinations of any of the
foregoing. Other exemplary chelating agents include: phosphates, e.g., pyrophosphates,
tripolyphosphates, and hexametaphosphates.
[0038] EDTA and acceptable EDTA salts are particularly preferred, wherein representative
acceptable EDTA salts are typically selected from diammonium EDTA, disodium EDTA,
dipotassium EDTA, triammonium EDTA, trisodium EDTA, tripotassium EDTA, and calcium
disodium EDTA.
[0039] EDTA has been widely used as an agent for chelating metals in biological tissue and
blood, and has been suggested for inclusion in various formulations. For example, U.S. Pat.
No. 6,348,508 to Denick Jr. et al. describes EDTA as a sequestering agent to bind metal ions.
In addition to its use as a chelating agent, EDTA has also been widely used as a preservative
in place of benzalkonium chloride, as described, for example, in U.S. Pat. No. 6,21 1,238 to
Castillo et al. U.S. Pat. No. 6,265,444 to Bowman et al. discloses use of EDTA as a
preservative and stabilizer. However, EDTA has generally not been applied topically in any
significant concentration formulations because of its poor penetration across biological
membranes and biofilms including skin, cell membranes and even biofilms like dental
plaque.
[0040] Among the chelating/sequetering materials which may be included in the
compositions there may be mentioned biocompatible chelating agents include, without
limitation, monomeric polyacids such as EDTA, cyclohexanediamine tetraacetic acid
(CDTA), hydroxyethylethylenediamine triacetic acid (HEDTA), diethylenetriamine
pentaacetic acid (DTPA), dimercaptopropane sulfonic acid (DMPS), dimercaptosuccimc acid
(DMSA), aminotrimethylene phosphonic acid (ATPA), citric acid, pharmaceutically
acceptable salts thereof, and combinations of any of the foregoing.
[0041] Other exemplary chelating agents include: phosphates, e.g., pyrophosphates,
tripolyphosphates, and hexametaphosphates. Other exemplary chelating agents include:
phosphates, e.g., pyrophosphates, tripolyphosphates, and hexametaphosphates; chelating
antibiotics such as chloroquine and tetracycline; nitrogen-containing chelating agents
containing two or more chelating nitrogen atoms within an amino group or in an aromatic
ring (e.g., di-amines, 2,2'-bipyridines, etc.); and polyamines such as cyclam (1,4,7,1 1-
tetraazacyclotetradecane), N-(Ci-C 3o alkyl)-substituted cyclams (e.g., hexadecyclam,
tetramethylhexadecylcyclam), diethylenetriamine (DETA), spermine, diethylnorspermine
(DENSPM), diethylhomo-spermine (DEHOP), deferoxamine (N'-{5-
[Acetyl(hydroxy)amino]pentyl} -N-[5-( {4- [(5-aminopentyl)(hydroxy)amino]-4-
oxobutanoyl} amino)pentyl]-N-hydroxysuccinamide, or N'-[5-(Acetyl-hydroxyamino)
pentyl]-N- [5-[3-(5-aminopentyl-hydroxy-carbamoyl) propanoylaminojpentyl] -Nhydroxy-
butane diamide); also known as desferoxamine B, desferoxamine B, DFO-B,
DFOA, DFB or desferal), deferiprone, pyridoxal isonicotinoyl hydrazone (PIH),
salicylaldehyde isonicotinoyl hydrazone (SIH), ethane- 1,2-bis(N-l -amino-3-ethylbutyl-3-
thiol).
[0042] Additional, suitable biocompatible chelating agents which may be useful for the
practice of the current disclosure include EDTA-4-aminoquinoline conjugates such as ([2-
(Bis-ethoxycarbonylmethyl-amino)-ethyl]-{[2-(7-chloro-quinolin-4-ylamino)-
ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester, ([2-(Bis-ethoxycarbonylmethylamino)-
propyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic
acid ethyl ester, ([3-(Bis-ethoxycarbonylmethyl-amino)-propyl]-{[2-(7-chloro-quinolin-4-
ylamino)-ethylcarbamoyl] -methyl} -amino)-acetic acid ethyl ester, ([4-(Bisethoxycarbonylmethyl-
amino)-butyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-
methyl}-amino)-acetic acid ethyl ester, ([2-(Bis-ethoxymethyl-amino)-ethyl]-{[2-(7-chloroquinolin-
4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester, ([2-(Bisethoxymethyl-
amino)-propyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-
amino)-acetic acid ethyl ester, ([3-(Bis-ethoxymethyl-amino)-propyl]-{[2-(7-chloro-quinolin-
4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester, ([4-(Bis-ethoxymethylamino)-
butyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic
acid ethyl ester as described in Solomon et al., Med. Chem. 2 : 133-138, 2006.
[0043] Additionally, natural chelators including, but not limited to citric acid, phytic acid,
lactic acid, acetic acid and their salts. Other natural chelators and weak chelators include but
are not limited to curcumin (turmeric), ascorbic acid, succinic acid, and the like.
[0044] In some embodiments, the chelating agents are selected from the tetrasodium salt of
iminodisuccinic acid (Baypure® CX100; LANXESS GMBH (previously Bayer Chemicals)
Leverkusen, DE) or salts of poly-asparatic acid (Baypure® DS100; LANXESS GMBH,
Leverkusen, DE). In some embodiments, the chelating agents are tetra sodium salts of Lglutamic
acid N ,N-diacetic acid (GLDA - Dissolvine®, AkzoNobel, Netherlands).
[0045] In some embodiments, the chelating agent incorporated in the formulation is a
prochelator. A prochelator is any molecule that is converted to a chelator when exposed to the
appropriate chemical or physical conditions. For example, BSIH (isonicotinic acid [2-
(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzylidene]-hydrazide) prochelators are
converted by hydrogen peroxide into SIH (salicylaldehyde isonicotinoyl hydrazone) ironchelating
agents that inhibit iron-catalyzed hydroxyl radical generation.
[0046] The inactivated metal ion sequestering agent is sometimes referred to herein as a
"prochelator," although sequestration of metal ions can involve sequestration and
complexation processes beyond the scope of chelation per se. The term "prochelator" is
analogous to the term "prodrug" insofar as a prodrug is a therapeutically inactive agent until
activated in vivo, and the prochelator, as well, is incapable of sequestering metal ions until
activated in vivo.
[0047] Transport Enhancer: The transport enhancer is selected to facilitate the transport of a
chelating agent through the tissues, extra-cellular matrices, and/or cell membranes of a body.
An "effective amount" of the transport enhancer represents an amount and concentration
within a formulation of the invention that is sufficient to provide a measurable increase in the
penetration of a chelating agent into one or more of the sites of oral cavity and/or biofilms on
oral surfaces in a subject than would otherwise be the case without the inclusion of the
transport enhancer within the formulation.
[0048] In certain instances, the transport enhancer may be present in a formulation of the
invention in an amount that ranges from about 0.01 wt.% or less to about 30 wt.% or more,
typically in the range of about 0.1 wt.% to about 20 wt.%, more typically in the range of
about 0.5 wt.% to about 11 wt.%, and most typically in the range of about 1.0 wt.% to about
8 wt.%, for instance, 5 wt.%.
[0049] The transport enhancer is generally of the formula (I)
(I)
o
R —Q— 2
O
[0050] wherein R1 and R2 are independently selected from C2-C alkyl, Ci-C heteroalkyl,
C -C14 aralkyl, and C2-C12 heteroaralkyl, any of which may be substituted, and Q is S or P.
Compounds wherein Q is S and R1 and R2 are C1-C3 alkyl are preferred, with
methylsulfonylmethane (MSM) being the optimal transport enhancer.
[0051] The phrase "having the formula" or "having the structure" is not intended to be
limiting and is used in the same way that the term "comprising" is commonly used. With
respect to the above structure, the term "alkyl" refers to a linear, branched, or cyclic saturated
hydrocarbon group containing 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, t-butyl, cyclopentyl, cyclohexyl and the like. If not otherwise
indicated, the term "alkyl" includes unsubstituted and substituted alkyl, wherein the
substituents may be, for example, halo, hydroxyl, sulfhydryl, alkoxy, acyl, etc. The term
"alkoxy" intends an alkyl group bound through a single, terminal ether linkage; that is, an
"alkoxy" group may be represented as -O-alkyl where alkyl is as defined above. The term
"aryl" refers to an aromatic substituent containing a single aromatic ring or multiple aromatic
rings that are fused together, directly linked, or indirectly linked (such that the different
aromatic rings are bound to a common group such as a methylene or ethylene moiety).
Preferred aryl groups contain 5 to 14 carbon atoms. Exemplary aryl groups are contain one
aromatic ring or two fused or linked aromatic rings, e.g., phenyl, naphthyl, biphenyl,
diphenylether, diphenylamine, benzophenone, and the like. "Aryl" includes unsubstituted and
substituted aryl, wherein the substituents may be as set forth above with respect to optionally
substituted "alkyl" groups. The term "aralkyl" refers to an alkyl group with an aryl
substituent, wherein "aryl" and "alkyl" are as defined above. Preferred aralkyl groups contain
6 to 14 carbon atoms, and particularly preferred aralkyl groups contain 6 to 8 carbon atoms.
Examples of aralkyl groups include, without limitation, benzyl, 2-phenyl-ethyl, 3 -phenylpropyl,
4-phenyl-butyl, 5 -phenyl -pentyl, 4-phenylcyclohexyl, 4-benzylcyclohexyl, 4-
phenylcyclohexylmethyl, 4-benzylcyclohexylmethyl, and the like. The term "acyl" refers to
substituents having the formula -(CO)-alkyl, -(CO)-aryl, or -(CO)-aralkyl, wherein "alkyl,"
"aryl, and "aralkyl" are as defined above. The terms "heteroalkyl" and "heteroaralkyl" are
used to refer to heteroatom-containing alkyl and aralkyl groups, respectively, i.e., alkyl and
aralkyl groups in which one or more carbon atoms is replaced with an atom other than
carbon, e.g., nitrogen, oxygen, sulfur, phosphorus or silicon, typically nitrogen, oxygen or
sulfur.
Treatment of Dental Plaque
[0052] While studying the impact of chelating agents combined with MSM, we looked at the
Loe Sillness dental plaque index on subjects that brushed their teeth with such formulations.
A plaque reducing effect superior to TRICLOSAN® containing toothpastes was observed.
Further, it was also observed that continued use of the formulation prevented the reformation
of the dental plaque to a very large extent compared to a leading "anti-plaque" toothpaste.
[0053] Following a single brushing, the MSM/EDTA toothpaste showed 106% greater
reduction in plaque compared to a TRICLOSAN® containing toothpaste. This showed a high
degree of statistical significance. (See Example 1)
[0054] Following two weeks of twice daily brushings, the MSM + chelator results compared
to control showed extremely high statistical significance. (See Example 2)
Formulations
[0055] In accordance with the present invention an antiplaque oral composition comprises an
orally acceptable vehicle or base for such composition, an effective antiplaque proportion of a
chelator or metal sequestrant and methylsulfonylmethane (MSM) for the oral composition in
a proportion which produces an unexpected antiplaque action on the teeth of a user of the oral
composition.
[0056] Neither chelators nor MSM have previously been known as an effective antiplaque
compound. Unexpectedly, the two compounds used together reduce plaque formation when
the combination is effectively applied to the teeth. EDTA is the highly preferred
chelator/sequesterant of this invention. However, other chelators/sequesterents may be
employed in replacement of it, such as sodium lactate or sodium citrate or
hexametaphosphates, or any other agent known for chelating and/or metal sequestering
action. Such agents are preferred in oral compositions because multivalent metals are known
to increase plaque adhesion to the teeth.
[0057] A variety of means can be used to formulate the compositions of the invention.
Techniques for formulation and administration may be found in "Remington: The Science
and Practice of Pharmacy," Twentieth Edition, Lippincott Williams & Wilkins, Philadelphia,
PA (1995). For human or animal administration, preparations should meet sterility,
pyrogenicity, and general safety and purity standards comparable to those required by the
FDA. Administration of the pharmaceutical formulation can be performed in a variety of
ways, as described herein.
[0058] The formulation includes an effective amount of a permeation enhancer. Suitable
permeation enhancers include, by way of example, methylsulfonylmethane (MSM; also
referred to as methyl sulfone), combinations of MSM with dimethylsulfoxide (DMSO), or a
combination of MSM and, in a less preferred embodiment, DMSO, with MSM particularly
preferred.
[0059] MSM is an odorless, highly water-soluble (34% w/v @ 79° F.) white crystalline
compound with a melting point of 108-1 10° C. and a molecular weight of 94.1 g/mol. MSM
serves as a multifunctional agent herein, insofar as the agent not only increases cell
membrane permeability, but also acts as a "transport facilitating agent" (TFA) that aids in the
transport of one or more formulation components to oral tissues. MSM additionally possesses
unique and beneficial solubilization properties, in that it is soluble in water, as noted above,
but exhibits both hydrophilic and hydrophobic properties because of the presence of polar
S=0 groups and nonpolar methyl groups. The molecular structure of MSM also allows for
hydrogen bonding with other molecules, i.e., between the oxygen atom of each S=0 group
and hydrogen atoms of other molecules, and for formation of van der Waal associations, i.e.,
between the methyl groups and nonpolar (e.g., hydrocarbyl) segments of other molecules.
Ideally, the concentration of MSM in the present formulations is in the range of about 0 .1 wt.
% to 40 wt. %, or from about 0.5 wt.% to about 4, 5, 6, 7, 8, 10, 15, 25 wt.%, and preferably
between about 1.5 wt. % to 8.0 wt. %.
[0060] Other optional additives in the present formulations include secondary enhancers, i.e.,
one or more additional permeation enhancers. For example, formulation of the invention can
contain added DMSO. Since MSM is a metabolite of DMSO (i.e., DMSO is enzymatically
converted to MSM), incorporating DMSO into an MSM-containing formulation of the
invention will tend to gradually increase the fraction of MSM in the formulation. If DMSO is
added as a secondary enhancer, the amount is preferably in the range of about 1.0 wt. % to
2.0 wt. % of the formulation, and the weight ratio of MSM to DMSO is typically in the range
of about 1:50 to about 50:1.
[0061] The biocompatible chelating agent is a sequestrant of divalent or polyvalent metal
cations, and generally represents about 0.1 wt. % to 15 wt. %, about 0.6 wt. % to 10 wt. %, or
preferably about 1.0 wt. % to 5.0 wt. %, of the formulation. The invention is not limited with
regard to specific biocompatible chelating agents, and any biocompatible chelating agent can
be used providing that it is capable of being buffered to a pH in the range of about 4.5 to
about 9.0 and does not interact with any other component of the formulation. Suitable
biocompatible chelating agents useful in conjunction with the present invention include,
without limitation, monomeric polyacids such as EDTA, cyclohexanediamine tetraacetic acid
(CDTA), hydroxyethylethylenediamine triacetic acid (HEDTA), diethylenetriamine
pentaacetic acid (DTPA), dimercaptopropane sulfonic acid (DMPS), dimercaptosuccimc acid
(DMSA), aminotrimethylene phosphonic acid (ATPA), citric acid, acceptable salts thereof,
and combinations of any of the foregoing. Other exemplary chelating agents include:
phosphates, e.g., pyrophosphates, tripolyphosphates, and, hexametaphosphates; chelating
antibiotics such as chloroquine and tetracycline; nitrogen-containing chelating agents
containing two or more chelating nitrogen atoms within an imino group or in an aromatic ring
(e.g., diamines, 2,2'-bipyridines, etc.); polyamines such as cyclam (1,4,7,11-
tetraazacyclotetradecane), ~ (Ci-C o alkyl)-substituted cyclams (e.g., hexadecyclam,
tetramethylhexadecylcycla- m), diethylenetriamine (DETA), spermine, diethylnorspermine
(DENSPM), diethylhomo-spermine (DEHOP), and deferoxamine (N'-[5-[[4-[[5-(acetylhydroxyamino)
pentyl]amino]-l,4-dioxobutyl]hydroxyamino]pentyl]-N'-(5-aminopent- yl)-Nhydroxybutanediamide;
also known as desferrioxamine B and DFO); tetrasodium salt of
iminodisuccinic acid; salts of poly-asparatic acid; and tetra sodium salts of L-glutamic acid
N ,N-diacetic acid (GLDA).
[0062] The various oral compositions of the invention may contain adjuvants and additional
active components to make them more acceptable to the consumer and to make them more
effective in use.
[0063] Among the active materials which may be included in the compositions are
azacycloalkane diphosphonic compounds, such as azacycloheptane diphosphonic acid and
salts thereof, which have an anticalculus effect. (U.S. Pat. No. 5.096,699). Synthetic anionic
polymeric polycarboxylates, such as copolymers of maleic acid or maleic anhydride with
vinyl methyl ether, and their salts, e.g., sodium salts, which are sold under the trademark
Gantrez®, improve the anticalculus action of the mentioned diphosphonic compounds and
also have stabilizing and other desirable effects on other active materials, such as
polyphosphates, e.g., sodium pyrophosphate, which are employed as antitartar agents.
Fluorides and other sources of fluoride ions, such as sodium fluoride and sodium
monofluorophosphate, are also active components which may be utilized, for their tooth
hardening effects.
[0064] A source of fluoride ions may be water soluble or relatively water insoluble, so long
as it releases a sufficient quantity of such ions during use. Among the useful sources of
fluoride ions are: soluble alkali metal fluorides, such as sodium and potassium fluorides;
copper fluorides, such as cuprous fluoride; tin fluorides, such as stannous fluoride;
ammonium fluorosilicate; sodium fluorozirconate; ammonium fluorozirconate; sodium
monofluorophosphate; aluminum fluorophosphates (mono-, di- and tri-); and fluorinated
sodium calcium pyrophosphate. Of these, alkali metal and tin fluorides, such as sodium and
stannous fluorides, sodium monofluorophosphate (MFP®) and mixtures thereof, are
preferred.
[0065] Polyphosphate anti-tartar agents may include any of various suitable polyphosphates,
such as alkali metal tripolyphosphates and pyrophosphates, but sodium pyrophosphate is
preferred.
[0066] Synthetic anionic polymeric polycarboxylates (SAPP's), which stabilize the
polyphosphates and improve the present antiplaque oral compositions too, may be of
molecular weights in the range of about 5,000-2,000,000, preferably about 50,000-1,500,000
and more preferably 500,000-1,000,000, e.g., about 1,000,000, and are available from GAF
Corporation under the designations Gantrezes® AN-169, AN- 139, AN-1 19 and S-97,
pharmaceutical grade. Such SAPP's are all linear copolymers but cross-linked polymers, such
as those sold under the trade mark Carbopol®, of B. F. Goodrich, e.g., Carbopols 934, 940
and 941, may be substituted, preferably only in part. Corresponding analogues of the SAPP's
may also be substituted, in whole or in part, including known polysulfonates, polysulfates and
polyphosphonates. Other olefmic monomers that are copolymerizable with the described
acids or anhydrides include vinyl acetates, vinyl chloride, dimethyl maleate and similar
unsaturated monomers, and the copolymers made will contain a sufficient proportion of
acidic groups or neutralized or neutralizable acidic groups to make them water soluble or
swellable. Some such polycarboxylate copolymers are those disclosed in U.S. Pat. Nos.
4,138,477 and 4,183,914, and include copolymers of maleic anhydride with styrene,
isobutylene or vinyl ethyl ether, polyacrylic, polyitaconic and polymaleic acids, and
sulfoacrylic oligomers of comparatively low molecular weights, such as Uniroyal® ND-2.
[0067] Because the compositions are intended for oral uses they can be sweetened with
saccharin or aspartame or sucralose or natural sweeteners like STEVIA®. Coloring agents
may be employed, as may be speckles or other visual attractants, and in cases where
undesirable reactions could occur between components during storage before use, some of
such reactants may be separated from others by being incorporated in such speckles or by
being packed in dispensing containers having separate sections to prevent such reactions.
[0068] Other possible additives for incorporation into the formulations that are at least
partially aqueous include, without limitation, thickeners, isotonic agents, buffering agents,
and preservatives, providing that any such excipients do not interact in an adverse manner
with any of the formulation's other components. It should also be noted that preservatives are
not generally necessarily in light of the fact that the selected chelating agent itself serves as a
preservative. Suitable thickeners will be known to those of ordinary skill in the art of
formulation, and include, by way of example, cellulosic polymers such as methylcellulose
(MC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose
(HPMC), and sodium carboxymethylcellulose (NaCMC), and other swellable
hydrophilic polymers such as polyvinyl alcohol (PVA), hyaluronic acid or a salt thereof (e.g.,
sodium hyaluronate), and crosslinked acrylic acid polymers commonly referred to as
"carbomers" (and available from B.F. Goodrich as Carbopol® polymers). Various organic
gums such as but not limited to Xanthan gum and Konjac gum. The preferred amount of any
thickener is such that a viscosity above 10,000 cps is provided, as a gel having a viscosity
above this figure generally considered optimal for both comfort and retention of the
formulation on the oral tissues. Any suitable isotonic agents and buffering agents commonly
used in oral formulations may be used, providing the pH of the formulation is maintained in
the range of about 4.5 to about 9.0, preferably in the range of about 6.8 to about 7.8, and
optimally at a pH of about 7.4.
[0069] The formulations of the invention also include a pharmaceutically acceptable carrier,
which will depend on the particular type of formulation. For example, the formulations of the
invention can be provided as an oral solution, suspension, paste or gel, in which case the
carrier is at least partially aqueous. The formulations may also be ointments, in which case
the pharmaceutically acceptable carrier is composed of an ointment base. Preferred ointment
bases herein have a melting or softening point close to body temperature, and any ointment
bases commonly used in oral preparations may be advantageously employed. Common
ointment bases include petrolatum and mixtures of petrolatum and mineral oil.
[0070] The pharmaceutical formulation may be a solid, semi-solid or liquid, such as, for
example, a liquid, a cream, a suspension, an emulsion, beads, a powder, or the like,
preferably in unit dosage form suitable for single administration of a precise dosage. Suitable
pharmaceutical formulations and dosage forms may be prepared using conventional methods
known to those in the field of pharmaceutical formulation and described in the pertinent texts
and literature, e.g., in Remington: The Science and Practice of Pharmacy, 2 1st edition,
Lippincott Williams & Wilkins, 2005.
[0071] The chelating agent may be administered, if desired, in the form of a salt, ester,
crystalline form, hydrate, or the like, provided it is pharmaceutically acceptable. Salts, esters,
etc. may be prepared using standard procedures known to those skilled in the art of synthetic
organic chemistry and described, for example, by J . March, Advanced Organic Chemistry:
Reactions, Mechanisms and Structure, 4th Ed. (New York: Wiley- Interscience, 1992).
[0072] The oral formulations may also include conventional additives such as opacifiers,
flavoring agents, antioxidants, fragrance, colorant, gelling agents, thickening agents,
stabilizers, surfactants, and the like. Other agents may also be added, such as antimicrobial
agents, to prevent spoilage upon storage, i.e., to inhibit growth of microbes such as yeasts and
molds. Suitable antimicrobial agents are typically selected from the methyl and propyl esters
of p-hydroxybenzoic acid (i.e., methyl and propyl paraben), sodium benzoate, sorbic acid,
imidurea, and combinations thereof.
[0073] The antiplaque oral compositions of this invention are preferably mouthwashes or
mouthrinses, or dentifrices, such as toothpastes and gels, but various other such compositions
may also be given the described improved antiplaque properties by including in them a
chelating/sequestrating agent and MSM. Such compositions include tooth powders, tooth
hardeners, anti-tartar compositions, anti-calculus compositions, gums, tablets and lozenges.
For liquid state compositions of the invention, such as mouth-rinses, mouthwashes, tooth
hardeners and antiplaque and anti-tartar compositions the liquid medium in which the active
components are present will normally be aqueous and may be aqueous alcoholic, with ethanol
being the preferred alcohol. Such compositions often also contain a humectant, such as a
polyol, e.g., glycerol, sorbitol, mannitol, polyethylene glycol, propylene glycol, or a mixture
of two or more thereof, and a surfactant, such as a dental detergent or a mixture of such
detergents. Other adjuvants and active components may also be present and such will be
described later.
[0074] For the paste, gel, solid and particulate solid state compositions of the invention, such
as toothpastes, gel dentifrices, tooth powders, chewing gums, tablets and lozenges, the base
or the medium for the active components will usually be any which is employed in such
compositions that do not contain the combination of a chelating/sequestrating agent and
MSM. For the toothpaste and gel dentifrices such bases will usually comprise: water;
humectant; polishing agent, such as finely divided silica, calcium carbonate, tricalcium
phosphate, dicalcium phosphate and/or insoluble sodium metaphosphate (of which the finely
divided silica polishing agent is preferred); and a surfactant, such as sodium lauryl sulfate,
sodium N-coco, N-methyl taurate, sodium N-lauroyl sarcosine, or other compatible dental
detergent. A thickener, which will preferably be a natural or synthetic gum, such as
carrageenan or hydroxymethyl cellulose, or a siliceous thickener such as fumed silica, or a
mixture of such thickeners will also often be employed to help to increase paste or gel
viscosity or body and it can function as a gelating agent. Other known thickeners and gelating
agents may be employed in place of those specifically mentioned above and other known
polishing agents, humectants and surfactants may also be used. Bases for tooth powders will
normally be almost entirely of polishing agent, with some surfactant desirably being present.
The base for the gum can be an elastomer of a type normally employed in chewing gums,
e.g., chicle, gum or rubber, and the tablets and lozenges may have a hard sugar or candy base
but preferably will be of sorbitol or a gummy material, such as gelatin.
[0075] A chewing gum of the above formula is made by blending together MSM/EDTA with
an elastomer (chicle), a humectant (sorbitol/mannitol), a sweetener, a filler (talc), and
optionally an anionic polymeric polycarboxylate (gantrez®) in a suitable mixer, such as a
Banbury mixer. Such a chewing gum is effective in inhibiting the development of plaque on
the teeth when chewed daily, preferably several times daily, for at least seven to ten days. It is
also effective when the proportion of the active components, MSM and EDTA are altered
while still remaining within the ranges previously given in this specification. For best
antiplaque effects the gum should be chewed several times daily for one or more minutes at a
time for at least a week.
[0076] The treatment regimen will depend on a number of factors that may readily be
determined, such as severity of the condition and responsiveness of the condition to be
treated, but will normally be one or more treatments per day, with a course of treatment
lasting from a day or several days to several months, or until a significant diminution of
dental plaque is achieved. Noticeable reduction in dental plaque is observed after about 14
days of twice daily usage.
[0077] Typically a significant reduction in dental plaque is at least about 10% reduction as
measured by Loe-Sillness dental plaque index following about 4-6 weeks of twice daily
brushings. Alternately, significant plaque reduction can be measured as a reduction by about
1.5-fold over control toothpaste as measured by Loe-Sillness dental plaque index following
about 4-6 weeks of twice daily brushings. Typical control toothpaste is a standard over-thecounter
fluoride containing toothpaste.
[0078] When the formulation is provided as a mouth-rinse or mouthwash, exemplary
treatment regimens employ rinsings of a duration of at least 30 seconds, at least twice a day,
for example in the morning and in late afternoon, for at least 4, or 5, or 7, or 15 days, or a
month.
[0079] When the formulation is provided as a toothpaste or tooth powder, exemplary
treatment regimens employ brushings at least once, at least twice or at least three times a day,
for at least 1 day, at least 3 days, at least a week, at least 2 weeks or at least a month.
[0080] When the formulation is provided as a lozenge or tablet, exemplary treatment
regimens comprise use at least once or twice a day, for at least a week, or 2 weeks or a
month, or 2 months.
[0081] When the formulation is provided as a chewing gum, exemplary treatment regimens
comprise use at least once or twice or several times a day, for at least a week.
EXAMPLES
[0082] The following examples are put forth so as to provide those skilled in the art with a
complete invention and description of how to make and use embodiments in accordance with
the invention, and are not intended to limit the scope of what the inventors regard as their
discovery. Efforts have been made to ensure accuracy with respect to numbers used (e.g.
amounts, temperature, etc.) but some experimental errors and deviations should be accounted
for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average
molecular weight, temperature is in degrees Centigrade, and pressure is at or near
atmospheric.
Example 1: Reduction of Plaque development after single brushing
[0083] Toothpaste was prepared comprising EDTA (tetrasodium salt) and MSM, which were
purchased from Sigma. Control was a leading "anti-plaque" toothpaste available in the
market.
[0084] The MSM/EDTA toothpaste showed 106% greater reduction in plaque. This showed a
high degree of statistical significance.
Example 2: Reduction of Plaque development after repeated brushings
[0085] Toothpaste was prepared comprising EDTA (tetrasodium salt) and MSM, which were
purchased from Sigma. Control was a leading "anti-plaque" toothpaste available in the
market. Loe Sillness dental plaque index was measured on subjects after 2 weeks of twice
daily brushing, after an initial prophylaxis.
[0086] The MSM+chelator results compared to control showed extremely high statistical
significance.
[0087] All publications and patent applications cited in this specification are herein
incorporated by reference as if each individual publication or patent application were
specifically and individually indicated to be incorporated by reference.
[0088] Although the foregoing invention has been described in some detail by way of
illustration and example for purposes of clarity of understanding, it will be readily apparent to
those of ordinary skill in the art in light of the teachings of this invention that certain changes
and modifications may be made thereto without departing from the spirit or scope of the
appended claim.

CLAIMS
What is claimed is:
1. An antiplaque oral formulation, comprising:
a chelating agent or salts thereof;
a transport enhancer;
an orally acceptable vehicle or base for such composition; and
one or more additives,
wherein the chelating agent and the transport enhancer are present in a proportion
effective to bring about a significant antiplaque action on the teeth of a user of the oral
composition, and
wherein the percentage of chelator is about 0.1% to 40% and the percentage of transport
in the composition is about 0.1% to 80% by weight, respectively..
2. The formulation of claim 1, wherein the transport enhancer is MSM.
3. The formulation of claim 1, wherein the transport enhancer is DMSO.
4. The formulation of claim 2, wherein the proportion of the chelator to MSM is in the range of
about 1:100-100:1.
5. The formulation of claim 1, wherein the composition is selected from a toothpaste, a gel
dentifrice, a tooth powder, a mouth-rinse, a mouthwash, a tooth hardener, an anti-calculus
composition, a gum, a lozenge or a format suitable applying the composition to an oral surface,
teeth, or gums.
6. The formulation of claim 1, wherein the chelating agent is selected from ethylenediamine t et
raacetic acid (EDTA), ethylene glycol tetraacetic acid (EGTA), cyclohexanediamine tetraacetic
acid (CDTA), hydroxyethylethylenediamine triacetic acid (HEDTA), diethylenetriamine
pentaacetic acid (DTPA), dimercaptopropane sulfonic acid (DMPS), dimercaptosuccinic acid
(DMSA), aminotrimethylene phosphonic acid (ArPA), citric acid, acetic acid and acceptable
salts thereof, and any combinations thereof.
7. The formulation of claim 7, wherein the EDTA salt is selected from diammonium EDTA,
disodium EDTA, dipotassium EDTA, triammonium EDTA, trisodium EDTA, tripotassium
EDTA, tetrasodium EDTA, tetrapotassium EDTA, calcium disodium EDTA, and combinations
thereof.
8. The formulation of claim 1, wherein the chelating agent is selected from phosphates,
pyrophosphates, tripolyphosphates, and hexametaphosphates.
9. The formulation of claim 1, wherein the chelating agent is a chelating antibiotic, chloroquine
or tetracycline.
10. The formulation of claim 1, wherein the chelating agent is a nitrogen-containing chelating
agents containing two or more chelating nitrogen atoms within an amino group or in an aromatic
ring, diamines, or 2,2'-bipyridines.
11. The formulation of claim 1, wherein the chelating agent is a polyamine selected from cyclam
(1,4,7,1 1-tetraazacyclotetradecane), N-(Ci-C 3o alkyl)-substituted cyclams (e.g., hexadecyclam,
tetramethylhexadecylcyclam), diethylenetriamine (DETA), spermine, diethylnorspermine
(DENSPM), diethylhomo-spermine (DEHOP), deferoxamine (N'-{5-
[Acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-
oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide, or N'-[5-(Acetyl-hydroxy-amino)pentyl]-N-
[5-[3-(5-aminopentyl-hydroxy-carbamoyl) propanoylamino]pentyl]-N-hydroxy-butane diamide),
desferrioxamine B, desferoxamine B, DFO-B, DFOA, DFB, desferal, deferiprone, pyridoxal
isonicotinoyl hydrazone (PIH), salicylaldehyde isonicotinoyl hydrazone (SIH), ethane- l,2-bis(N-
1-amino-3-ethylbutyl-3-thiol).
12. The formulation of claim 1, wherein the chelating agent is a EDTA-4-aminoquinoline
conjugate selected from ([2-(Bis-ethoxycarbonylmethyl-amino)-ethyl]-{[2-(7-chloro-quinolin-4-
ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester, ([2-(Bisethoxycarbonylmethyl-
amino)-propyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-
methyl}-amino)-acetic acid ethyl ester, ([3-(Bis-ethoxycarbonylmethyl-amino)-propyl]-{[2-(7-
chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester, ([4-(Bisethoxycarbonylmethyl-
amino)-butyl] -{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-
methyl} -amino)-acetic acid ethyl ester, ([2-(Bis-ethoxymethyl-amino)-ethyl]-{[2-(7-chloroquinolin-
4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester, ([2-(Bisethoxymethyl-
amino)-propyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-
amino)-acetic acid ethyl ester, ([3-(Bis-ethoxymethyl-amino)-propyl]-{[2-(7-chloro-quinolin-4-
ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester, ([4-(Bis-ethoxymethylamino)-
butyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid
ethyl ester.
13. The formulation of claim 1, wherein the chelating agent is a tetrasodium salt of
iminodisuccinic acid.
14. The formulation of claim 1, wherein the chelating agent is a salt of poly-asparatic acid.
15. The formulation of claim 1, wherein the chelating agent is a tetra sodium salt of L-glutamic
acidN,N-diacetic acid.
16. The formulation of claim 1, wherein the chelating agent is a natural chelator selected from
citric acid, phytic acid, lactic acid, acetic acid and their salts and curcumin.
17. The formulation of claim 1, wherein the additives comprise one or more of polishing agents,
thickening agents, surfactants, humectants, solvents, sweeteners, tooth hardeners, anti-tartar
agents, anti-calculus agents, flavoring agents and antibacterial agents.
18. The formulation of claim 17, wherein the polishing agent is selected from one or more of
finely divided silica, calcium carbonate, tricalcium phosphate, dicalcium phosphate and insoluble
sodium metaphosphate.
1 . The formulation of claim 17, wherein the surfactant is selected from one or more of sodium
lauryl sulfate, sodium N-coco, N-methyl taurate, sodium N-lauroyl sarcosine, or a compatible
dental detergent.
20. The formulation of claim 17, wherein the thickener is selected from one or more of a natural
or synthetic gum, carrageenan, hydroxymethyl cellulose, a siliceous thickener or fumed silica.
2 1. The formulation of claim 17, wherein the sweetener is selected from one or more of
saccharin, aspartame, cyclamate, sucralose, Stevia, mannitol, sorbitol, xylitol and similar glycols.
22. The formulation of claim 17, wherein the anticalculus agent is selected from one or more of
an azacycloalkane diphosphonic compound, azacycloheptane diphosphonic acid and salts
thereof, synthetic anionic polymeric polycarboxylates, and copolymers of maleic acid or maleic
anhydride with vinyl methyl ether, and their salts.
23. The formulation of claim 17, wherein the tooth hardening agent is selected from soluble
alkali metal fluorides, sodium fluoride, potassium fluoride; copper fluoride, tin fluorides,
ammonium fluorosilicate, sodium fluorozirconate, ammonium fluorozirconate, sodium
monofluorophosphate, aluminum fluorophosphates (mono-, di- and tri-), fluorinated sodium
calcium pyrophosphate, sodium monofluorophosphate and mixtures thereof,
24. The formulation of claim 17, wherein the anti-tartar agent is selected from polyphosphates,
alkali metal tripolyphosphates, alkali metal pyrophosphates and sodium pyrophosphate.
25. The formulation of claim 17, wherein the anti-bacterial agent is selected from 2', 4, 4'-
trichloro-2-hydroxy-diphenyl ether (Triclosan®), chlorine dioxide, chlorhexadine, noncationic
diphenyl ethers, 2,2'-dihydroxy5,5'-dibromo-diphenyl ether and halogenated andhydroxysubstituted
diphenyl ethers.
26. The formulation of claim 17, wherein the flavoring agent is a phenolic flavoring agent
selected from eucalyptol, thymol, methyl salicylate, menthol, chlorothymol, phenol, wintergreen
oil, spearmint oil, peppermint oil and similar essential pils, and halogenated and other derivatives
thereof.
27. A process for treating teeth to inhibit plaque development on them, the process comprising:
applying to the teeth a plaque inhibiting amount of a formulation of claim 1,
wherein a significant decline in dental plaque is measured..
28. The process of claim 27, wherein the formulation is a tooth paste or tooth powder and the
application requires brushing with the formulation at least once a day for at least 3 days.
29. The process of claim 27, wherein the formulation is a mouth-rinse or mouthwash and the
application requires rinsing with the formulation at least twice a day for 4 or more days.
30. The process of claim 27, wherein the formulation is a lozenge or tablet and the application
requires use of the formulation at least twice a day for one week or more.
3 1. The process of claim 27, wherein the formulation is a chewing gum and the application
requires use of the formulation at least twice a day for one week or more.