Dear Dentist at Large.

Fluoride poisoning (excess in your body) Via being in Water, toothpaste, food, mouthwash, tablets, vitamins, fruits, vegetables, etc.,
Causes FLUOROSIS- a Damaging of the Bone-aka Teeth,
structurally and visually damaged for life.
Fluoride in Tooth Paste  Can Cause LOOSE- TEETH, Gingivitis,
and Periodontal Disease which you go to the DENTIST

and  WE PAY HUGE DOLLARS TO CURE the Disease that ( ADA  Dentist Recommended)
to use Fluoride Toothpaste.
And PAY HUGE  DOLLARS TO BUY DENTURES -CAPS Etc., To REPAIR
The DAMAGE by Fluoride Fluorosis.
(ADA Dentist Promote)  
(Private trade organization NOT a Professional Organization ADA, American dental  dollar? association) 

That is what I read between the lines, below. In the Patent Disclosure.

Now, You Try! Read below as stated by the inventors
( They are just trying to help prevent the damage from fluoride I presume.) I would just stop using the Fluoride ToothPaste!
Go back to Baking Soda and or Peroxide 3% food grade. I use. My Grand-Mother used Baking Soda Daily.
At 65 years Beautiful, she had zero cavities.

Baking Soda neutralizes Acids... Like from Sugar 20 minutes after eating-chewing-sucking-drinking it.

Okay your turn, Go read it for yourself!

"It is also known that under certain circumstances sodium fluoride and
fluoroaluminates can activate G proteins and thereby induce prostaglandin
production in endothelial cells and leukotriene production in platelets,
granulocytes and monocytes. The metabolites of arachidonic acid have been
implicated as important biochemical mediators of tissue destruction in various
inflammatory diseases."

The term periodontal diseases relates to conditions in which the gingiva and
underlying alveolar bone are attacked. The condition exists in a number of
species of warm blooded animals including humans and canines, and appears at
least initially to involve an inflammatory and immunological response to the
stimulus of bacterial plaque. Clinically, the advance of the disease involves
conversion of chronic gingivitis, involving primarily inflammation of the
gingiva, to chronic destructive periodontitis, in which resorption of the
alveolar bone, increased mobility of the teeth, and in advanced stages, loss of
teeth are observed.

SUMMARY OF THE INVENTION

We have found that fluoride, in the concentration range in which it is employed
for the prevention of dental caries, stimulates the production of prostaglandins
and thereby exacerbates the inflammatory response in gingivitis and
periodontitis.

      United States Patent: 5,807,541 

United States Patent 5,807,541 
      Aberg ,   et al. September 15, 1998 


NSAID/fluoride periodontal compositions and methods 


Abstract
A method for preventing dental caries by administering fluoride and, at the same 

time controlling periodontal bone loss precipitated by the fluoride, by
 
providing a combination of fluoride and NSAID is disclosed. Topical medicament 
compositions including NSAIDS and fluoride are also disclosed. 


      Inventors: Aberg; Gunnar (Westborough, MA); Jerussi; Thomas Patrick 
      (Framingham, MA); McCullough; John R. (Worcester, MA) 
      Assignee: Sepracor, Inc. (Marlborough, MA) 
      Appl. No.: 636150
      Filed: April 22, 1996

      Current U.S. Class:424/52; 424/673; 424/676 
      Intern'l Class: A61K 007/16; A61K 007/18; A61K 033/16
      Field of Search: 424/49-58 




References Cited [Referenced By]



U.S. Patent Documents
      4933172Jun., 1990Clark, Jr. et al.424/49. 
      5190981Mar., 1993Wechter514/900. 
      5240696Aug., 1993Van Der Ouderaa et al.424/49. 
      5294433Mar., 1994Singer et al.424/52. 
      5364616Nov., 1994Singer et al.424/52. 
      5464609Nov., 1995Kelm et al.424/54. 
      5500206Mar., 1996Charbonneau424/50. 
      5500448Mar., 1996Cummins et al.514/717. 
      Foreign Patent Documents
      6-305946., 1994JP. 



  Other References
      Offenbacher et al. "Effects of NSAIDs on beagle crevicular cyclooxygenase 
      metabolites . . . " J. Periodontal Res.27, 207-213 (1992). 
      Jeremy et al. "Differential inhibitory potencies of non-steroidal 
      antiinflammatory . . . "E. J. Pharm. 182, 83-89 (1990). 
      Dodam et al. "Effect of fluoride on cardiopulmonary function and release 
      of . . . " J. Appl. Physiol., 569-577 (1995). 
      Kawase et al. "Aluminofluoride--and Epidermal Growth Factor-Stimulated DNA 
      Synthesis" Pharmacol. Toxicol. 69 330-337 (1991). 
      Kopczyk et al. "Clinical and Microbiological Effects of a 
      Sanguinaria-Containing Mouthrinse . . . " J. Periodontol. 62, 617-622 
      (1991). 
      Honda et al. "Introduction of Cyclo-oxygenase Synthesis in Human . . . " 
      Biochem. J.272, 259-262 (1990). 
      Parker et al. "Prevalence and severity of periodontitis in a high fluoride 
      area" Comm. Dental Oral Epido 13 108-112 (1985). 

Primary Examiner: Rose; Shep K. 
Attorney, Agent or Firm: Heslin & Rothenberg, P.C. 



Claims

We claim: 

1. A method for preventing dental caries and at the same time controlling 
periodontal bone loss which comprises administering, together with an amount of 
a fluoride salt sufficient to provide a 0.01% to 0.1% solution of fluoride at an 
alveolar surface, an amount of S-ketoprofen sufficient to provide a 10.sup.-7 to 
10.sup.-9 M solution of S-ketoprofen at said alveolar surface. 

2. A method according to claim 1 wherein said fluoride salt and said 
S-ketoprofen are administered as a toothpaste or mouthwash. 


Description


FIELD OF THE INVENTION 

The invention relates to dental compositions. In another aspect this invention 
relates to methods and compositions for controlling periodontal bone loss. 

BACKGROUND OF THE INVENTION 

The role of topical and systemic fluoride in the inhibition of dental caries is 
well established. There is good evidence that professionally applied topical 
fluoride and the use of dentifrices and mouthwashes containing fluoride are 
effective in preventing dental caries among high risk patients. The amount of 
fluoride ion employed in most dentifrices and mouthwashes ranges from 0.05 to 
0.15% weight-to-volume. Most commonly sodium fluoride, and sodium 
monofluorophosphate, less commonly, stannous fluoride and amine fluoride, are 
employed as sources of fluoride ion. 

It is also known that under certain circumstances sodium fluoride and 
fluoroaluminates can activate G proteins and thereby induce prostaglandin 
production in endothelial cells and leukotriene production in platelets, 
granulocytes and monocytes. The metabolites of arachidonic acid have been 
implicated as important biochemical mediators of tissue destruction in various 
inflammatory diseases. 

The term periodontal diseases relates to conditions in which the gingiva and 
underlying alveolar bone are attacked. The condition exists in a number of 
species of warm blooded animals including humans and canines, and appears at 
least initially to involve an inflammatory and immunological response to the 
stimulus of bacterial plaque. Clinically, the advance of the disease involves 
conversion of chronic gingivitis, involving primarily inflammation of the 
gingiva, to chronic destructive periodontitis, in which resorption of the 
alveolar bone, increased mobility of the teeth, and in advanced stages, loss of 
teeth are observed. 

SUMMARY OF THE INVENTION 

We have found that fluoride, in the concentration range in which it is employed 
for the prevention of dental caries, stimulates the production of prostaglandins 
and thereby exacerbates the inflammatory response in gingivitis and 
periodontitis. 

The present invention is a method for preventing dental caries by administering 
a fluoride salt into the oral cavity while at the same time controlling 
periodontal bone loss by administering, in addition to the fluoride salt, an 
amount of an NSAID sufficient to inhibit the production of prostaglandins 
induced by the fluoride. 

In one aspect the invention relates to a method for preventing dental caries and 
at the same time controlling periodontal bone loss which comprises administering 
into the oral cavity a fluoride salt together with a therapeutically effective 
amount of an NSAID, particularly a propionic acid or acetic acid NSAID. More 
particularly, the method comprises administering (a) an amount of a fluoride 
salt sufficient to stimulate eicosanoid anabolism and (b) an amount of an NSAID 
sufficient to counteract the stimulation of eicosanoid anabolism that arises 
from the administration of the fluoride ion. Preferred NSAIDS include racemic 
ketoprofen and its enantiomers, racemic ketorolac and its enantiomers and 
racemic flurbiprofen and its enantiomers. S-ketoprofen, S-flurbiprofen and 
R-ketorolac are particularly preferred. In the method of the invention, the 
fluoride salt and NSAID may be administered as a toothpaste or a mouth wash. 

In another aspect the invention relates to a composition comprising (a) a 
fluoride salt; (b) a therapeutically effective amount of a propionic or acetic 
acid NSAID; and (c) a pharmaceutically acceptable carrier for topical 
application in an oral cavity. Preferred compositions are dentifrices and mouth 
washes containing an amount of fluoride salt sufficient to stimulate eicosanoid 
anabolism; an amount of NSAID sufficient to counteract the stimulation of 
eicosanoid anabolism; and a pharmaceutically acceptable carrier. Preferred 
sources of fluoride ion are sodium fluoride, sodium monofluorophosphate and 
stannous fluoride, providing fluoride at from 0.01 to 0.2%, preferably 0.01 to 
0.1%, weight-to-volume at the alveolar surface. The appropriate NSAID may be 
present at from 2.5.times.10.sup.-3 to 5% by weight. 

BRIEF DESCRIPTION OF THE DRAWING 

FIG. 1 is a graph of percent increase in prostaglandin E.sub.2 output as a 
function of fluoride ion concentration in human promyelocytic leukemia cells. 

DETAILED DESCRIPTION 

The present invention is based on the discovery that fluoride ion at 
concentrations between about 5 and about 50 mM stimulates the production of 
prostaglandin E.sub.2, (PGE.sub.2) reaching a peak of 200% of control at about 
10 mM. Increased synthesis of cyclooxgenase products, especially PGE.sub.2 and 
thromboxane A.sub.2 have been associated with an increased severity and 
progression of periodontal lesions in humans. Offenbacher et al. ›J. Periodontal 
Research 27, 207-213 (1992)! have presented data that support the concept that 
the increase in PGE.sub.2 and thromboxane which occurs during disease 
progression is not a result of an epiphenomenal association with tissue 
destruction, but rather represents a cell mediated process which directly 
elicits tissue damage. Thus, the inclusion of fluoride in toothpastes and 
mouthwashes for the purpose of inhibiting the development of caries may, at the 
same time, accelerate the process of chronic, destructive periodontitis. 
According to the present invention, an NSAID, which inhibits products of the 
cyclooxygenase pathway, is combined with fluoride to provide a medicament that 
inhibits the development of both dental caries and periodontal bone loss. The 
fluoride ion is present at a concentration which is effective to prevent caries 
but, which in the absence of a cyclooxygenase inhibitor, would promote 
periodontal bone loss. The NSAID is present at a concentration that effectively 
inhibits the fluoride-stimulated production of prostaglandins. 

We have found that the dose response curve for fluoride ion-induced stimulation 
of prostaglandins is biphasic. At concentrations below about 5 mM (i.e., below 
about 0.01% w/v), fluoride has no significant effect on stimulated PGE.sub.2 
secretion; above about 50 mM (i.e., above about 0.1% W/v), fluoride ion becomes 
inhibitory to PGE.sub.2 secretion. The concentration of sodium fluoride found in 
currently marketed dentifrices (0.15%), when it is diluted with saliva, gives 
rise to solutions that are presumably below about 50 mM at the alveolar surface, 
and therefore stimulate prostaglandin production. It may be contemplated that a 
dentifrice or mouthwash that provided concentrations of fluoride greater than 
about 50 mM at the alveolar surface would inhibit both caries formation and 
periodontal bone loss. Unfortunately, fluoride ion is extremely toxic and the 
therapeutic ratio is quite small. As a result, if the dose of fluoride in the 
composition is increased to provide an oral concentration of fluoride ion that 
would fall in the inhibitory range of the PGE.sub.2 secretion curve, safety 
becomes an issue. We have found that the addition of an NSAID to the 
fluoride-containing composition reduces the stimulatory effect of fluoride on 
prostaglandin levels, and enables one to take advantage of the caries-preventing 
activity of non-toxic doses of fluoride while not exacerbating periodontitis. 

NSAIDS can be characterized into five groups: 

(1) the propionic acids; 

(2) the acetic acids; 

(3) the fenamic acids; 

(4) the biphenylcarboxylic acids; and 

(5) the oxicams. 

"Propionic acid NSAIDS" as defined herein are non-narcotic 
analgesics/nonsteroidal antiinflammatory drugs having a free --CH(CH.sub.3)COOH 
group, which optionally can be in the form of a pharmaceutically acceptable salt 
group, e.g., --CH(CH.sub.3)COO.sup.- Na.sup.+. The propionic acid side chain is 
typically attached directly or via a carbonyl function to a ring system, 
preferably to an aromatic ring system. Exemplary propionic acid NSAIDS include: 
ibuprofen, indoprofen, ketoprofen, naproxen, benoxaprofen, flurbiprofen, 
fenoprofen, fenbufen, pirprofen, carpofen, oxaprozin, pranoprofen, miroprofen, 
tioxaprofen, suprofen, alminoprofen, tiaprofen, fluprofen, and bucloxic acid. 
Structurally related propionic acid derivatives having similar analgesic and 
antiinflammatory properties are also intended to be included in this group. 

As is evident from the structural formula above, profens exist in enantiomeric 
forms. NSAIDs from other classes may also exhibit optical isomerism. The 
invention contemplates the use of pure enantiomers and mixtures of enantiomers, 
including racemic mixtures, although the use of the substantially optically pure 
eutomer will generally be preferred. "Acetic acid NSAIDS" as defined herein are 
non-narcotic analgesics/nonsteroidal antiinflammatory drugs having a free 
--CH.sub.2 COOH group (which optionally can be in the form of a pharmaceutically 
acceptable salt group, e.g. --CH.sub.2 COO.sup.- Na.sup.+, typically attached 
directly to a ring system, preferably to an aromatic or heteroaromatic ring 
system. Exemplary acetic acid NSAIDS include: ketorolac, indomethacin, sulindac, 
tolmetin, zomepirac, diclofenac, fenclofenac, alclofenac, ibufenac, isoxepac, 
furofenac, tiopinac, zidometacin, acematacin, fentiazac, clidanac, oxpinac, and 
fenclozic acid. Structurally related acetic acid derivatives having similar 
analgesic and antiinflammatory properties are also intended to be encompassed by 
this group. 

"Fenamic acid NSAIDs" are non-narcotic analgesics/nonsteroidal antiinflammatory 
drugs having a substituted N-phenylanthranilic acid structure. Exemplary fenamic 
acid derivatives include mefenamic acid, meclofenamic acid, flufenamic acid, 
niflumic acid, and tolfenamic acid. 

"Biphenylcarboxylic acid NSAIDS" are non-narcotic analgesics/nonsteroidal 
antiinflammatory drugs incorporating the basic structure of a biphenylcarboxylic 
acid. Exemplary biphenylcarboxylic acid NSAIDs include diflunisal and 
flufenisal. 

"Oxicam NSAIDs" are N-aryl derivatives of 4-hydroxyl-1,2-benzothiazine 
1,1-dioxide-3-carboxamide. Exemplary oxicam NSAIDs are piroxicam, sudoxicam and 
isoxicam. 

The effects of fluoride ion, as sodium fluoride, were studied on PGE.sub.2 
secretion in human promyelocytic leukemia cells at 10 concentrations in 
duplicate (from 52 .mu.m to 0.26M) to evaluate its inhibitory and stimulatory 
effects on a wide range of concentrations. The method is described in an article 
by Honda et al. ›Biochem. J. 272, 259-262 (1990)!, the entire disclosure of 
which is incorporated herein by reference. Results are expressed as a percentage 
of control after subtraction of background. The IC.sub.50 value and Hill 
coefficient (n.sub.H) were determined by non linear regression analysis of the 
competition curve. These parameters were obtained by Hill equation curve fitting 
using the Sigmaplot.TM. software (Jandel). The effects of fluoride tested at the 
ten concentrations are illustrated in FIG. 1, for which the numerical values are 
reported in Table I: 


                  TABLE 1
    ______________________________________
              % Control
    F % (molarity)
                1st Value    2nd value
                                      mean
    ______________________________________
    0.0001 (52 .mu.M)
                80.1         87.4     83.7
    0.001 (520 .mu.M)
                94.1         74.9     84.5
    0.01 (5.2 mM)
                117.7        99.8     108.7
    0.02 (10.4 mM)
                188.7        208.8    198.8
    0.05 (26 mM)
                157.9        177.3    167.6
    0.07 (36 mM)
                142.1        142.1    142.1
    0.1 (52 mM) 115.1        112.6    113.9
    0.2 (104 mM)
                5.2          8.9      7.0
    0.3 (156 mM)
                4.9          3.1      4.0
    0.5 (260 mM)
                0.5          1.7      1.1
    ______________________________________



Racemic ketoprofen and its enantiomers were tested alone and in combination with 
fluoride for inhibition of prostaglandin production in HL-60 cells. Compounds 
were screened in duplicate at the following concentrations: 10.sup.-10, 
10.sup.-9, 10.sup.-8 and 10.sup.-7 M for ketoprofen, and 0.05, 0.1, and 0.5% for 
fluoride as NaF. The data are tabulated below. Numbers in Table II represent % 
inhibition of PGE.sub.2 ; those in parentheses () indicate % stimulation. 


                  TABLE II
    ______________________________________
    Fluoride     Ketoprofen Concentration
    Concentration
                 10.sup.-10 M
                         10.sup.-9 M
                                   10.sup.-8 M
                                         10.sup.-7 M
    ______________________________________
    none         --       40       63    82
    26 mM        (125)   (125)     --    66
    52 mM        --       11       46    85
    260 mM       102     101       97    98
    ______________________________________



Fluoride alone at the 26 mM concentration (0.05%) caused a 108% stimulation of 
PGE.sub.2 production, whereas inhibition of 12 and 92% were respectively 
observed at 52 mM and 260 mM (data not in Table II). In combination with low 
concentrations of ketoprofen, a stimulation (125%) was also observed. However at 
the highest concentration of ketoprofen (10.sup.-7), the stimulation induced by 
F.sup.- was overcome. In fact, at 260 mM fluoride, PGE.sub.2 production was 
totally inhibited by 10.sup.-10 M ketoprofen, whereas inhibition by 10.sup.-10 M 
of ketoprofen alone was undetected, and in another study, the same concentration 
of ketoprofen inhibited PGE.sub.2 levels only 26%. The data from racemic 
ketoprofen alone (no F) and racemic ketoprofen plus 52 mM fluoride were then 
plotted, fit with regression lines, and IC.sub.50 s calculated: RS-ketoprofen 
IC.sub.50 =2.8 nM; RS-ketoprofen+52 mM F IC.sub.50 =11.8 nM. Fluoride at 0.1 % 
(52 mM) increased the IC.sub.50 for ketoprofen alone by approximately 4-fold. 
However, the ketoprofen curve was not merely shifted to the right (indicative of 
competitive antagonism), but rather, as the concentration of ketoprofen was 
increased, the antagonistic effect of F.sup.- was diminished. Therefore it 
appeared that ketoprofen and F.sup.- were not competing at the same site. 

The effects of (R)- and (S) ketoprofen associated with sodium fluoride on 
A23187-induced PGE.sub.2 secretion are indicated in Tables III and IV. The 
results are expressed as % of control; they are the mean of two determinations. 
The IC.sub.50 value determined for indomethacin under the same conditions (in 
the absence of fluoride) was 9.2.times.10.sup.-10 M. 


                  TABLE III
    ______________________________________
    Effects of (R)-Ketoprofen and Fluoride on
    A23187-Induced PGE.sub.2 Secretion
                                  % stimulation
    (R)-Ketoprofen
               F         %        (stimulation
    (M)        (%)       Inhibition
                                  factor)
    ______________________________________
    0          0.05               16 (.times.1.16)
    0          0.1       26
    0          0.5       96
    .sup. 10.sup.-10
               0         14
    10.sup.-9  0         6
    10.sup.-8  0         39
    10.sup.-7  0         81
    .sup. 10.sup.-10
               0.05               27 (.times.1.27)
    10.sup.-9  0.05               14 (.times.1.14)
    10.sup.-8  0.05      5
    10.sup.-7  0.05      47
    .sup. 10.sup.-10
               0.1       23
    10.sup.-9  0.1       2
    10.sup.-8  0.1       32
    10.sup.-7  0.1       75
    .sup. 10.sup.-10
               0.5       98
    10.sup.-9  0.5       99
    10.sup.-8  0.5       99
    10.sup.-7  0.5       100
    ______________________________________
              TABLE IV
    ______________________________________
    Effects of (S)-Ketoprofen and Fluoride on
    A23187-Induced PGE.sub.2 Secretion
                                  % stimulation
    (S)-Ketoprofen
               F         %        (stimulation
    (M)        (%)       Inhibition
                                  factor)
    ______________________________________
    0          0.05               16 (.times.1.16)
    0          0.1       26
    0          0.5       96
    .sup. 10.sup.-10
               0         10
    10.sup.-9  0         70
    10.sup.-8  0         89
    10.sup.-7  0         96
    .sup. 10.sup.-10
               0.05               27 (.times.1.22)
    10.sup.-9  0.05      35
    10.sup.-8  0.05      82
    10.sup.-7  0.05      95
    .sup. 10.sup.-10
               0.1       18
    10.sup.-9  0.1       54
    10.sup.-8  0.1       89
    10.sup.-7  0.1       98
    .sup. 10.sup.-10
               0.5       100
    10.sup.-9  0.5       100
    10.sup.-8  0.5       98
    10.sup.-7  0.5       99
    ______________________________________



To summarize, fluoride has no effect on PGE.sub.2 secretion from 0.0001 to 
0.01%. It induces stimulation from 0.02 to 0.07% (maximum at 0.02% with a 99% 
stimulation) and then it completely inhibits PGE.sub.2 secretion above 0.2%. 
S-Ketoprofen is more potent than R-ketoprofen; they respectively inhibit 
PGE.sub.2 secretion with IC.sub.50 values of around 4.times.10.sup.-10 and 
1.times.10.sup.-7 M. 

In the presence of fluoride, the effects of R- and S-ketoprofen are modified. At 
26 mM, fluoride induces a decrease of the inhibitory effects of R- and 
S-ketoprofen; in contrast at 260 mM, fluoride amplifies its inhibitory effects. 
These results are in accordance with the stimulatory and inhibitory effects 
observed with fluoride alone. 

The preferred NSAIDs for use in mouthwashes and dentifrices are propionic and 
acetic acids and their pharmaceutically acceptable salts. Typical formulations 
are shown below: 


    ______________________________________
    Ingredient          Parts
    ______________________________________
    Toothpaste Composition
    Example 1A
    S(+) Flurbiprofen   1.0
    Magnesium aluminum silicate
                        1.0
    Dicalcium phosphate 47.0
    Sodium carboxymethylcellulose
                        0.5
    Mint flavor         4.0
    Sodium lauryl sulfate
                        2.0
    Benzoic acid        0.1
    Sodium monofluorophosphate
                        0.73
    Water               44.4
    Example 1B
    Deionized Water     28.0
    Glycerine           25.0
    Silica              40.0
    Sodium Lauryl Sulfate
                        1.2
    Mint Flavor         1.0
    Xanthan Gum         1.0
    Sodium Benzoate     0.5
    Sodium Saccharin    0.3
    Sodium Fluoride     0.24
    Titanium Dioxide    0.5
    Ketoprofen          2.5
    Mouthwash Composition
    Example 2
    Alcohol U.S.P.      15.0
    Sorbitol            20.0
    Pluronic F-127      1.0
    Flavor              0.4
    Sodium Saccharin    0.03
    Sodium Fluoride     0.05
    Ketorolac           1.0
    Deionized Water q.s.
                        100.00
    ______________________________________

* * * * *