TREATING INFLAMMATORY CONDITIONS AND IMPROVING ORAL
HYGIENE USING METAL MODULATORS WITH
METHYLSULFONYLMETHANE AS TRANSPORT ENHANCER
INVENTORS:
Rajiv BHUSHAN, Jerry GIN and Amit GOSWAMY
CROSS-RELATION TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. provisional patent application Serial No.
61/642,441 filed May 3, 2012 the entirety of which is incorporated herein by reference.
TECHNICAL FIELD OF THE INVENTION
[0002] This disclosure relates generally to the field of pharmacotherapy related to the
treatment of disorders related to the oral cavity, dental and gingival diseases, and other
adverse oral conditions. More particularly, the invention pertains to a formulation for the
prevention and treatment of various adverse oral conditions, including those associated with
dental disease. The invention pertains to the use of the formulation in improving oral health
and the cosmetic appearance of tissues in the oral cavity applicable in a variety of fields,
including dentistry, geriatrics, immune disorders, oncology and cosmeceuticals.
BACKGROUND OF THE INVENTION
[0003] Biofilm, calculus and plaque are commonly known as the primary cause of dental
caries gingivitis, periodontitis, mucositis and other oral conditions. Dental plaque, which
exists not only on the tooth surface but also under the gums, can be defined as a diverse
community of microorganisms in the form of a biofilm. The microorganisms bind tightly to
one another, in addition to the solid tooth surface, by means of an extracellular matrix
consisting of polymers of both host and microbial origin.
[0004] As a biofilm, dental plaque exhibits an open architecture much like that of other
biofilms. The open architecture, which consists of channels and voids, helps to achieve the
flow of nutrients, waste products, metabolites, enzymes, and oxygen through the biofilm.
Because of this structure, a variety of microbial organisms can make up biofilms, including
both aerobic and anaerobic bacteria.
[0005] Experts agree that most forms of periodontal disease are caused by specific
pathogens, particularly gram-negative bacteria. The microbial composition of dental biofilms
includes over 700 species of bacteria and archaea, which all exist in a relatively stable
environment called microbial homeostasis. (Kroes I, Lepp PW, Reiman DA Bacterial
diversity within the human subgingival crevice. Proc Natl Acad Sci USA 1999;
96(25): 14547-14552.)
[0006] The recognition that dental plaque is a biofilm helps to explain why periodontal
diseases have been so difficult to prevent and to treat. Periodontal pathogens within a biofilm
environment behave very differently from free-floating bacteria. The protective extracellular
slime matrix makes bacteria extremely resistant to antibiotics, antimicrobial agents, and host
defense mechanisms.
[0007] Antibiotic doses that kill free-floating bacteria, for example, need to be increased as
much as 1,500 times to kill biofilm bacteria. At these high doses, the antibiotic is more likely
to kill the patient before the biofilm bacteria. (Elder MJ, at al. Biofilm-related infections in
ophthalmology. Eye 1995; vol. 9 (Pt. 1): 102-109.) It is likely that several mechanisms are
responsible for biofilm resistance to antibiotics and antimicrobial agents. The slime layer may
prevent the drugs from penetrating fully into the depth of the biofilm. Bacteria can develop
resistance to antimicrobial drugs by producing a thicker protective slime layer. The slime
layer may protect the bacteria against leukocytes (defensive cells of the body's immune
system). Antibiotic or antimicrobial therapy usually will not kill the biofilm. Mechanical
removal is the most effective treatment currently available for the control of dental plaque
biofilms.
[0008] Dental plaque biofilms are 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). However, biofilms are present on healthy
teeth as well. A significant problem in the art is the cross-reactions that occur between
different formulation types and/or active agents when multiple formulations with each having
a different function, have to be used to treat patients with multiple oral disorders.
[0009] Therefore, there is a need for effective prophylaxis and treatment of oral conditions
and disorders using formulations that eliminate cross-reactivity between different functional
ingredients.
SUMMARY OF THE INVENTION
[0010] The present invention provides multifunctional formulations suitable for oral and
dental therapy where at least one component of the formulation, and preferably two or more
formulation components, are "multifunctional" in that they are useful in preventing or treating
multiple conditions and disorders, or have more than one mechanism of action, or both.
[0011] In some embodiments, the present invention relates to methods for use of the
multifunctional formulations for prophylaxis and treatment of adverse oral conditions and
disorders.
[0012] The present invention further relates to localized uses of an oral formulation for
prevention and treatment of adverse oral conditions such as gingivitis, periodontal disease,
removal of calculus to improve dental hygiene, and control of dental plaque and biofilm.
[0013] In one aspect of the invention, methods are provided for use of the formulations for
prevention and treatment of other adverse oral conditions including inflammation and
oxidative and/or free radical damage within the oral cavity are provided. Treatable conditions
may relate to other conditions or diseases, including diabetes, AIDS and cancer.
[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)
[0015] wherein R1 and R2 are independently selected from C2 -C6 alkyl, Ci-C 6 heteroalkyl,
C6-Ci4 aralkyl, and C2-Ci 2 heteroaralkyl, any of which may be substituted, and Q is S or P,
wherein the transport enhancer is present in an amount effective to facilitate transport of the
chelating agent such that the chelating agent is delivered in an amount effective to treat an
adverse oral condition.
[0016] The transport enhancing agent can be, for example, methylsulfonylmethane (also
referred to as methylsulfone, dimethylsulfone, and DMS0 2), and the chelating agent can be
ethylene diamine tetra-acetic acid (EDTA) and the like.
[0017] The oral formulation may be administered in any form suitable for oral
administration, e.g., as a solution, suspension, paste, ointment, gel, liposomal dispersion,
colloidal micro-particle suspension, or the like, or in an oral insert, e.g., in an optionally
biodegradable controlled release polymeric matrix. Significantly, at least one component of
the formulation, and preferably two or more formulation components, is "multifunctional" in
that it is useful in preventing or treating multiple conditions and disorders, or have more than
one mechanism of action, or both. Accordingly, the present formulations eliminate a
significant problem in the art, namely, cross-reaction between different formulation types
and/or active agents when multiple formulations are used to treat a patient with multiple oral
disorders. Additionally, in a preferred embodiment, the formulation is entirely composed of
components that are naturally occurring and/or as GRAS ("Generally Regarded as Safe") by
the U.S. Food and Drug Administration.
[0018] 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.
[0019] The invention further provides formulations for use in the aforementioned methods.
[0020] 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.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] The following drawings form part of the present specification and are included to
further demonstrate certain aspects of the present disclosure, the inventions of which can be
better understood by reference to one or more of these drawings in combination with the
detailed description of specific embodiments presented herein.
[0022] Figure 1A shows attraction of bacterial species to the tooth under physiologic ionic
strength. Figure IB shows increased attraction of bacterial species to the tooth under
increased ionic strength.
DETAILED DESCRIPTION OF THE INVENTION
[0023] 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.
[0024] 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.
[0025] 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.
[0026] 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:
[0027] 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.
[0028] 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."
[0029] "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.
[0030] 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.
[0031] 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.
[0032] 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 "nonimmediate 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.
[0033] 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.
[0034] 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.
[0035] 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.
[0036] 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
[0037] 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 NH3 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.
[0038] 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.
[0039] 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.
[0040] 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), dimercaptosuccinic 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., diimines, 2,2'-bipyridines, etc.); and polyamines such as cyclam (1,4,7,1 1-
tetraazacyclotetradecane), N—(C1-C30 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 desferoxamine B and DFO).
[0041] 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), 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.
[0042] EDTA and ophthalmologically acceptable EDTA salts are particularly preferred,
wherein representative ophthalmologically acceptable EDTA salts are typically selected from
diammonium EDTA, disodium EDTA, dipotassium EDTA, triammonium EDTA, trisodium
EDTA, tripotassium EDTA, and calcium disodium EDTA.
[0043] 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.
[0044] 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.
[0045] 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.
[0046] 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 through one or more of the sites of oral cavity or teeth in a
subject than would otherwise be the case without the inclusion of the transport enhancer
within the formulation.
[0047] 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 1 wt.% to about 11 wt.%, and most typically in the range of about 2 wt.% to about 8
wt .%, for instance, 5 wt.%>.
[0048] The transport enhancer is generally of the formula (I)
(I)
o
Q
i
o
[0049] wherein R1 and R2 are independently selected from C2-C6 alkyl, Ci-C6 heteroalkyl,
C6-Ci4 aralkyl, and C2-Ci2 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.
[0050] 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.
Treating Dental Plaque Biofilms
[0051] The formation of dental plaque biofilms includes a series of steps that begins with the
initial colonization of the pellicle and ends with the complex formation of a mature biofilm.
Dental plaque biofilms exist on a variety of tooth surfaces including fissures, smooth surfaces
and gingival crevices, however they are most likely to be seen in their mature state in the
more stagnant sites, like fissures and crevices, as these places provide protection from the
forces of removal, like a toothbrush. Additionally, through the growth process of the plaque
biofilm, the microbial composition changes from one that is primarily gram-positive and
streptococcus-rich to a structure filled with gram-negative anaerobes in its more mature state.
[0052] The first step in plaque biofilm development is the adsorption of host and bacterial
molecules to the tooth surface. Within minutes of tooth eruption or a cleaning, pellicle
formation begins, which can be defined as a thin coat of salivary proteins. The pellicle acts
like an adhesive by sticking to the tooth surface and encouraging a conditioning film of
bacteria to attach to the pellicle. This conditioning film directly influences the initial
microbial colonization, and continues to adsorb bacteria to the tooth surface.
[0053] Healthy tooth surfaces and gingivae tend to only be associated with this first phase of
biofilm development. It consists of an initial few layers (1-20) of mostly gram-positive cocci
bacteria, followed by some gram-positive rods and fillaments and a very small amount of
gram-negative cocci.
[0054] The mouth comprises a number of quite distinct habitats most of which are bathed in
saliva. In order to survive in the mouth bacteria must attach to one of its surfaces or risk
being swallowed. Bacteria attaching to exposed smooth surfaces in the mouth must be quite
firmly attached to resist the flow of saliva. Any build-up of cells due to multiplication is more
easily dislodged because the mass of bacteria experiences a greater shear force. This does not
mean that the exposed, smooth, surfaces of teeth are devoid of attached bacteria because
some species have evolved efficient adhesion mechanisms. It does mean, however, that any
significant build-up is inhibited and that plaque accumulation is limited to sheltered sites such
as interproximal areas, the gingival margin and fissures. Bacteria will also accumulate in
defects.
[0055] Before plaque can accumulate, the tooth has to be colonized by bacteria which then
multiply and attract further colonizers. These "first colonizers" are known as pioneer species
and, in the mouth comprise: (a) Streptococcus oralis; (b) Streptococcus mitis; and (c)
Streptococcus sanguis.
[0056] The surfaces of these cells and, in fact the surfaces of nearly all cells, are negatively
charged because of the presence of proteins and other wall and cell membrane components
which contain phosphate, carboxyl and other acidic groups. Furthermore, nearly all nonbiological
surfaces are also negatively charged. Sometimes this is due to the accumulation of
organic material which adsorbs to the surface from the environment and sometimes because
the surface is inherently negatively charged because of its chemistry. However, the presence
of high amounts of positively charged ionic calcium in both the saliva, and in the plaque
fluid, causes the bacteria to be attracted to the negatively charged surface.
[0057] In accordance with the Derjaguin and Landau, Verwey and Overbeek (DLVO) theory
on the causes of precipitation of colloidal particles (Derjaguin, B.; Landau, L. (1941) Acta
Physico Chemica URSS 14: 633; Verwey, E. J . W.; Overbeek, J . Th. G. (1948), Theory of the stability
oflyophobic colloids, Amsterdam: Elsevier), both electrostatic forces of attraction and repulsion,
as well as the attractive van der Waal's forces play a key role in causing the migration of
bacteria to the surface of the teeth. Increasing the concentration of ionic calcium in the plaque
fluid causes the electric double layer surrounding the microbes to shrink. This reduces the
electrostatic repulsive forces, and enables the bacteria to come into the domain of the much
stronger van der Waal forces. This can be seen in Figures 1A and IB.
[0058] As the concentration of calcium continues to build in the plaque, it reaches levels,
where small changes in pH can cause the precipitation of the calcium phosphate onto the
surface in the form of brushite, the major component of dental calculus. These precipitates
build up over time both sub and supra gingivally. This deposit will then injure and damage
the gingivae, leading to inflammation and subsequently gingivitis.
[0059] Since calcium is involved in plaque production, calculus production, and in the
causation of inflammation, a reduction in calcium levels will play a key role in treating the
adverse conditions in the oral cavity. Current treatment modalities do not take this approach,
but rather depend upon mechanical removal of plaque and calculus, and there is an attempt to
control the inflammation by means of steroids or NSAIDs.
[0060] Removal of calcium could be accomplished by means of calcium chelators. However
chelators are also negatively charged molecules, and are therefore repelled from the plaque
surface. Therefore to accomplish the task of getting these chelators into the plaque and close
to the calcium, a charge masking, permeation enhancing carrier would allow the chelators to
get to the target metal ion, e.g. calcium. The sequestration inactivating moiety may also
facilitate transport of the metal ion sequestering agent through biological membranes.
[0061] Without wishing to be bound by theory, it appears that a significant role played by the
biocompatible chelating agent in the present formulations is in the removal of the calcium
from the dental plaque and will allow for easier mechanical removal, and slow down the
rebuilding of the unhealthy plaque. In addition, by chelating metal ions such as copper, iron,
and calcium, which are critical to the formation and proliferation of free radicals in the oral
tissue, the chelating agent forms complexes that are flushed into the bloodstream and
excreted renally. In this way, the production of oxygen free radicals and reactive molecular
fragments is reduced, in turn reducing pathological lipid peroxidation of cell membranes,
DNA, enzymes, and lipoproteins, allowing the body's natural healing mechanisms to halt and
reverse disease processes in progress.
[0062] Accordingly, the chelating agent is multifunctional in the context of the present
invention, insofar as the agent serves to decrease unwanted proteinase (e.g., collagenase)
activity, prevent formation of mineral deposits, and/or reduce mineral deposits that have
already formed, and reduce calcification, in addition to acting as a preservative and
stabilizing agent. The formulation also includes an effective amount of a permeation
enhancer that facilitates penetration of the formulation components through cell membranes,
tissues, and extracellular matrices, including the gums and other oral tissue. The "effective
amount" of the permeation enhancer represents a concentration that is sufficient to provide a
measurable increase in penetration of one or more of the formulation components through
membranes, tissues, and extracellular matrices as just described. 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.
[0063] 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. Furthermore, MSM per se
provides medicative effects, and can serve as an anti-inflammatory agent as well as an
analgesic. MSM also acts to improve oxidative metabolism in biological tissues, and is a
source of organic sulfur, which assists in the reduction of scarring. 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 1 wt.% to about 4, 5, 6, 7, 8, 10, 15 wt.%, and
preferably between about 1.5 wt. % to 8.0 wt. %.
[0064] 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. DMSO also
serves as a free radical scavenger, thereby reducing the potential for oxidative damage. 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.
[0065] The formulations of the invention are useful in treating a wide variety of adverse oral
conditions, including gingivitis, periodontal disease, dental caries and cavities, mouth sores,
and all kinds of oral inflammation. It is also useful for treating oral plaque and dental
calculus.
Formulations
[0066] 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, 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.
[0067] 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.
[0068] 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.
[0069] 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, cited previously
herein.
[0070] The formulations of the invention may also be prepared as a hydrogel, dispersion, or
colloidal suspension. Hydrogels are formed by incorporation of a swellable, gel-forming
polymer such as those set forth above as suitable thickening agents (i.e., MC, HEC, HPC,
HPMC, NaCMC, PVA, or hyaluronic acid or a salt thereof, e.g., sodium hyaluronate), except
that a formulation referred to in the art as a "hydrogel" typically has a higher viscosity than a
formulation referred to as a "thickened" solution or suspension. In contrast to such preformed
hydrogels, a formulation may also be prepared so as to form a hydrogel in situ following
application into the oral cavity. Such gels are liquid at room temperature but gel at higher
temperatures (and thus termed "thermoreversible" hydrogels), such as when placed in contact
with body fluids. Biocompatible polymers that impart this property include acrylic acid
polymers and copolymers, N-isopropylacrylamide derivatives, and ABA block copolymers of
ethylene oxide and propylene oxide (conventionally referred to as "poloxamers" and available
under the Pluronic® trade name from BASF-Wyandotte). The formulations can also be
prepared in the form of a dispersion or colloidal suspension. Preferred dispersions are
liposomal, in which case the formulation is enclosed within "liposomes," microscopic
vesicles composed of alternating aqueous compartments and lipid bilayers. Colloidal
suspensions are generally formed from microparticles, i.e., from microspheres, nanospheres,
microcapsules, or nanocapsules, wherein microspheres and nanospheres are generally
monolithic particles of a polymer matrix in which the formulation is trapped, adsorbed, or
otherwise contained, while with microcapsules and nanocapsules, the formulation is actually
encapsulated. The upper limit for the size for these microparticles is about 5m to about 10m.
[0071] The formulations may also be incorporated into a sterile oral insert that provides for
controlled release of the formulation over an extended time period, generally in the range of
about 1 hours to 60 days, and possibly up to 1 months or more, following implantation of
the insert into any tissue of the of the oral cavity. One type of oral insert is an implant in the
form of a monolithic polymer matrix that gradually releases the formulation to the oral tissues
through diffusion and/or matrix degradation. With such an insert, it is preferred that the
polymer be completely soluble and or biodegradable (i.e., physically or enzymatically eroded
in the tissues) so that removal of the insert is unnecessary. These types of inserts are well
known in the art, and are typically composed of a water-swellable, gel-forming polymer such
as collagen, polyvinyl alcohol, or a cellulosic polymer. Another type of insert that can be
used to deliver the present formulation is a diffusional implant in which the formulation is
contained in a central reservoir enclosed within a permeable polymer membrane that allows
for gradual diffusion of the formulation out of the implant. Osmotic inserts may also be used,
i.e., implants in which the formulation is released as a result of an increase in osmotic
pressure within the implant following application to the oral tissue and subsequent
absorption.
[0072] 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).
[0073] The amount of chelating agent administered will depend on a number of factors and
will vary from subject to subject and depend on the particular chelating agent, the particular
disorder or condition being treated, the severity of the symptoms, the subject's age, weight
and general condition, and the judgment of the prescribing physician. The term "dosage
form" denotes any form of a pharmaceutical composition that contains an amount of
chelating agent and transport enhancer sufficient to achieve a therapeutic effect with a single
administration or multiple administrations. The frequency of administration that will provide
the most effective results in an efficient manner without overdosing will vary with the
characteristics of the particular active agent, including both its pharmacological
characteristics and its physical characteristics, such as hydrophilicity.
[0074] 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.
[0075] The dosage 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 doses per day, with a course of treatment lasting
from a single dose to multiple doses over a day or several days to several months, or until a
cure is effected or a diminution of disease state or other adverse condition is achieved.
EXAMPLES
[0076] 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: Preparation of Oral Formulation A
[0077] Lotions comprising the formulations were prepared using EDTA (tetrasodium salt)
and MSM, which were purchased from Sigma. All examples used Oral Formulation A, which
contained 2.6% EDTA and 5.4% MSM.
[0078] Effectiveness of Lotion A is tested on subjects suffering from adverse oral conditions,
including gingivitis, periodontal disease, dental caries and cavities, mouth sores, and all kinds
of oral inflammation.
[0079] 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.
[0080] 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.

WE CLAIM:-

1. An oral formulation, comprising:
a biocompatible chelating agent at a concentration of at least 0.1% by weight; and an
effective concentration of a permeation enhancer.
2. The formulation of claim 1, wherein the carrier is at least partially aqueous.
3. The formulation of claim 2, comprising a solution.
4. The formulation of claim 2, comprising a suspension.
5. The formulation of claim 2, wherein the carrier further includes a water-swellable polymer
and the formulation comprises a hydrogel.
6. The formulation of claim 2, wherein the carrier comprises a thermo-reversible hydrogelforming
polymer such that the formulation forms a hydrogel in situ following administration.
7. The formulation of claim 1, wherein the carrier is an ointment base, and the formulation
comprises an ointment.
8. The formulation of claim 1, wherein the carrier is a lotion base, and the formulation
comprises a lotion.
9. An oral delivery system comprising a liposomal dispersion of the formulation of claim 1.
10. The delivery system of claim 9, comprising a colloidal suspension of microspheres,
nanospheres, microcapsules, or nanocapsules containing the formulation of claim 1.
11. The formulation of claim 1, wherein the biocompatible chelating agent is selected from
ethylenediamine tetraacetic acid (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, curcumin, and acceptable salts thereof,
and combinations of any of the foregoing.
12. The formulation of claim 10, wherein the biocompatible chelating agent is selected from
EDTA and acceptable salts thereof.
13. The formulation of claim 11, wherein the biocompatible chelating agent is EDTA or
acceptable salts thereof.
14. The formulation of claim 11, wherein the biocompatible chelating agent is an acceptable
EDTA salt.
15. The formulation of claim 14, wherein the acceptable EDTA salt is selected from
diammonium EDTA, disodium EDTA, dipotassium EDTA, triammonium EDTA, trisodium
EDTA, tetrasodium EDTA, tripotassium EDTA, calcium disodium EDTA, and combinations
thereof.
16. The formulation of claim 1, wherein the chelating agent is selected from chelating
antibiotics, chelating agents containing two or more chelating nitrogen atoms, phosphates, and
deferoxamine.
17. The formulation of claim 15, wherein the chelating agent is a chelating antibiotic selected
from chloroquine and tetracycline.
18. The formulation of claim 15, wherein the chelating agent is selected from pyrophosphates,
tripolyphosphates, hexametaphosphates, and combinations thereof.
19. The formulation of claim 1, wherein the permeation enhancer is selected from
methylsulfonylmethane, dimethyl sulfoxide, and combinations thereof.
20. The formulation of claim 1, wherein the permeation enhancer is methylsulfonylmethane.
21. The formulation of claim 18, comprising: methylsulfonylmethane and dimethyl sulfoxide at
a weight ratio of approximately 1:50 to about 50: 1.
22. The formulation of claim 1, further including at least one additive selected from thickeners,
isotonic agents, and buffering agents.
23. The formulation of claim 1, having a pH in the range of about 4.5 to about 9.0.
24. The formulation of claim 31, having a pH in the range of about 6.8 to about 7.8.
25. An oral formulation, comprising:
a biocompatible chelating agent at a concentration of at least 0.1% by weight;
an effective permeation-enhancing amount of methylsulfonylmethane; and
a pharmaceutically acceptable carrier.
26. The formulation of claim 25, wherein the carrier is distilled or deionized water.
27. The formulation of claim 26, wherein the biocompatible chelating agent is selected from
EDTA and acceptable salts thereof.
28. The formulation of claim 27, wherein the biocompatible chelating agent represents up to 15
wt. % of the formulation.
29. The formulation of claim 25, wherein the methylsulfonylmethane represents approximately
0.1 wt. %to 40 wt. % of the formulation.
30. The formulation of claim 29, further comprising approximately 1.0 wt. % to 2.0 wt. %
dimethyl sulfoxide.
3 1. The formulation of claim 25, further including at least one additive selected from thickeners,
isotonic agents, and buffering agents.
32. A sterile insert for delivery of a formulation to the oral cavity, comprising:
a controlled release implant housing the formulation of any one of claims 1, 25, and 29
and suitable for implantation into any part of the oral cavity.
33. The insert of claim 32, wherein the implant is comprised of a polymeric matrix that
gradually releases the formulation to the oral tissues through diffusion and/or matrix degradation.
34. The insert of claim 33, wherein the polymeric matrix is completely biodegradable.
35. The insert of claim 32, wherein the implant is comprised of a laminated structure in which
an inner core housing the formulation is contained between outer layers of a permeable polymer
through which the formulation gradually diffuses.
36. A sterile insert for delivery of a formulation to the oral tissues, comprising a controlled
release implant housing the formulation of any one of claims 1, 25, and 29 and suitable for
implantation into any part of the oral cavity.
37. The insert of claim 36, wherein the implant is comprised of a polymeric matrix that
gradually releases the formulation to the oral tissues through dissolution of the matrix and/or
diffusion.
38. The insert of claim 37, wherein the polymeric matrix is completely soluble and/or
biodegradable in the oral tissues.
39. The insert of claim 38, wherein the implant comprises a reservoir housing the formulation
and enclosed in a polymeric membrane through which the formulation gradually diffuses.
40. The insert of claim 36, wherein the implant comprises an osmotic system from which the
formulation is gradually released as a result of increased osmotic pressure within the system
following implantation in the oral tissues.
4 1.A method for preventing or treating a mammalian individual susceptible to or afflicted with
an adverse oral conditions, comprising:
topically administering the formulation of any one of claims 1, 25, and 29 to any part of
the oral cavity of the individual.
42. The method of claim 41, wherein the adverse oral condition is associated with oxidative
and/or free radical damage to the oral tissues.
43. The method of claim 41, wherein the adverse oral condition is a condition, disease, or
disorder of the oral cavity.
44. The method of claim 41, wherein the adverse oral condition is associated with aging.
45. The method of claim 41, wherein the adverse oral condition is gingivitis.
46. The method of claim 41, wherein the adverse oral condition is periodontal disease.
47. The method of claim 41, wherein the adverse oral condition relates to the formation of
mineral deposits, dirty teeth, calculus, or tartar.
48. The method of claim 41, wherein the adverse oral condition relates to the formation of
bacterial biofilms, or plaque.
49. The method of claim 41, wherein the adverse oral condition is dental cavities.
50. The method of claim 41, wherein the adverse oral condition is dental caries.
5 1. The method of claim 41, wherein the adverse oral condition relates to sores.
52. The method of claim 41, wherein the adverse oral condition relates to inflammation.
53. The method of claim 41, wherein the adverse oral condition relates to AIDS.
54. The method of claim 41, wherein the adverse oral condition relates to cancer.
55. The method of claim 41, wherein the adverse oral condition relates to diabetes.
56. A method for improving the oral health of a mammalian individual, comprising:
administering the formulation of any one of claims 1, 25, and 29 to a part of the oral
cavity of an individual.
57. A sterile insert for administration of a biocompatible chelating agent to the oral tissues,
comprising:
a controlled release implant housing a formulation consisting essentially of the
biocompatible chelating agent and a pharmaceutically acceptable carrier.
58. The insert of claim 57, wherein the biocompatible chelating agent is selected from EDTA
and acceptable salts thereof.
59. The insert of any one of claims 57, or 58, wherein the implant is comprised of a polymeric
matrix that gradually releases the formulation to the oral tissues through dissolution of the matrix
and/or diffusion.
60. The insert of claim 59, wherein the polymeric matrix is completely soluble and/or
biodegradable in the oral tissues.
6 1. The insert of any one of claims 57 and 58, wherein the implant is comprised of a reservoir
housing the formulation and wherein the implant is enclosed in a polymeric membrane through
which the formulation is released gradually.
62. The insert of claim 6 1, wherein the implant is comprised of an osmotic system from which
the formulation is released gradually as a result of increased osmotic pressure within the system
following implantation in the oral tissues.