CA1127970A - Oral composition for improving oral health - Google Patents
Oral composition for improving oral healthInfo
- Publication number
- CA1127970A CA1127970A CA334,067A CA334067A CA1127970A CA 1127970 A CA1127970 A CA 1127970A CA 334067 A CA334067 A CA 334067A CA 1127970 A CA1127970 A CA 1127970A
- Authority
- CA
- Canada
- Prior art keywords
- oral
- ascorbic acid
- mouthwash
- zinc
- composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/67—Vitamins
- A61K8/676—Ascorbic acid, i.e. vitamin C
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
- A61K8/27—Zinc; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
Abstract
AN ORAL COMPOSITION FOR IMPROVING ORAL HEALTH
Abstract of the Disclosure A therapeutic composition is disclosed for use in improving the physiological tone of the oral tissues, which among other beneficial effects nourishes said tissues and causes them to approach normal condition. The thera-peutic composition also has an antimicrobial effect on the oral microflora including those difficult to eliminate pathogenic genera known to be implicated in dental caries and periodontal disease. The therapeutic composition com-prises a pharmaceutically acceptable, water soluble zinc salt and ascorbic acid or an active analog thereof. The zinc salt and the ascorbic acid are present in an amount sufficient to provide a synergistic combination which has a greater than additive antimicrobial effect on such oral genera as Actinomyces, Streptococcus, Staphylococcus, Can-dida, Pseudomonas and Escherichia.
Abstract of the Disclosure A therapeutic composition is disclosed for use in improving the physiological tone of the oral tissues, which among other beneficial effects nourishes said tissues and causes them to approach normal condition. The thera-peutic composition also has an antimicrobial effect on the oral microflora including those difficult to eliminate pathogenic genera known to be implicated in dental caries and periodontal disease. The therapeutic composition com-prises a pharmaceutically acceptable, water soluble zinc salt and ascorbic acid or an active analog thereof. The zinc salt and the ascorbic acid are present in an amount sufficient to provide a synergistic combination which has a greater than additive antimicrobial effect on such oral genera as Actinomyces, Streptococcus, Staphylococcus, Can-dida, Pseudomonas and Escherichia.
Description
?J~J 9111 11Z~7970 This invention relates to a composition for oral administration which improves the physiological tone of t~e oral tissues and which has an antimicrobial effect on the oral microflora.
All of the causative factors in the etiology of a healthy oral condition are not known. It i8 known, however, that a reduction in the amount of zinc ions or in the amount of ascorbic acid available to nourish the ~ral tissues ad-versely affect~ their physiolo~ica~ tone. How much of thi~
is the result of enzymatic, microbial and other factors has not been determlned. What has been clinically observed, however, is that sometimes the oral tissues b~come edematous, inflammed and ~usceptib~e to microbial attack.
It ha~ been known for centuries that vltamin C de-ficiency causes scurvy. More recently, it ha~ become known that the formation of normal collagen depends on ascorbic acid. Since ascorbic acid is involved in some hydroxylation reactions, the ~lowness with which scorbutics commonly heal may be caused by in~ufficient cro~s-linking in collagen due to decreased hydroxylation of proline.
It is known that a diet deficient in ascorbic acid or zinc renders the gingiva more susceptible to bacterial attack. Exces~ amounts of dietary ascorbic acid or zinc, however, do not increase the amount of these materials in the saliva and have no corresponding beneficial effect on the oral tissues.
All of the causative factors in the etiology of a healthy oral condition are not known. It i8 known, however, that a reduction in the amount of zinc ions or in the amount of ascorbic acid available to nourish the ~ral tissues ad-versely affect~ their physiolo~ica~ tone. How much of thi~
is the result of enzymatic, microbial and other factors has not been determlned. What has been clinically observed, however, is that sometimes the oral tissues b~come edematous, inflammed and ~usceptib~e to microbial attack.
It ha~ been known for centuries that vltamin C de-ficiency causes scurvy. More recently, it ha~ become known that the formation of normal collagen depends on ascorbic acid. Since ascorbic acid is involved in some hydroxylation reactions, the ~lowness with which scorbutics commonly heal may be caused by in~ufficient cro~s-linking in collagen due to decreased hydroxylation of proline.
It is known that a diet deficient in ascorbic acid or zinc renders the gingiva more susceptible to bacterial attack. Exces~ amounts of dietary ascorbic acid or zinc, however, do not increase the amount of these materials in the saliva and have no corresponding beneficial effect on the oral tissues.
- 2 ~7g7~0 There have been studies which have shown that the amount of zinc and vitamin C is depleted in the blood and in the cells by stress. It is also known that the plasma concentration of zinc decreases during pregnancy, and among some patients on oral contraceptives. Other studies have shown that ~inc plays a role in the taste ~ud ~upport sys-tem and in the mechanism of tastant-receptor binding. Zinc depletion is known to occur in patients ta~ing drugs like Dilantin or in subjects on diets heavy in fiber or phytate.
Still other factors are known to interfere with the intes-tinal absorpt$on or with the utilization of zinc $on~ as well as of ascorbic acid.
The physiological tone of the oral muco~a, how-ever, i~ not the only factor in maintaining a healthy oral condition. Epidemiological ~tudies have suggested that microblal plaque i8 a ma~or factor contributing to dental caries and periodontal disease. Numerous mechanisms by which dental caries may occur have been suggested. Accord-ing to the most widely accepted concept, speciflc microbes present in bacterial plaque colonize the surface of the teeth, ferment dietary carbohydrates and produce organic acids. These acids demineralize the teeth, cau~ing the enamel to decay.
Plaque is also implicated in periodontal disease.
Although the precise cause of periodontal disease remains unclear, it is widely accepted that the primary cause is ~acterial plaque located in the gingival crevice bet~een the surface of the teeth and the gingiva.
2J~1 9111 ' ~1~7~
~echanical debridement of plaque by brushing and use of floss is still the primary recommended and ac-cepted method for the prevention of dental caries and periodontal disease. This approach is successful when rigorously practiced but is ~o highly labor-intensive that most people are not sufficiently motivated to prac-tice it consistently. Since plaque i8 quic~ly reformed, continual brushing and flossing axe essential to this method of therapy. Moreover, in the pre~ence of ging$val inflammation, mechanical methods of plaque removal fre-quently cau~e gingival hemorrhage. Thls often causes the patient to divert from his brushing and flo~ing regimen.
The focu~ in oral hygiene has been on a chemical method for dealing with oral plaque. While this clearly would have an obvious clinical advantage for u~e alone or more effectively in combination with mechanical methods, a more perfect therapeutic compo~ition wou~d also have a beneflcial effect on the oral mucosa beyond that of a mere antimicrobial agent.
The problem~ in ~ust dealing with plaque, how-ever, should not be underestimated. In search of an effec-tive chemical, it i~ lmportant to keep in mind that the periodontal ti~sue~ may be colonized by a~ many as 150 dif-ferent species of microorgani~m~. The particular microbial flora in any given area of the mouth at any given time i5 the result of the microbial succession that ha~ ta~en place up to that tirle. Not all of the oral mi~xoflora are implicated 2JW ~ 9111 llZ7970 in dental caries or in periodontal disease but those pathogenic genera which are responsible are, in general, among those most difficult to kill. Moreover, the net de~elopment of dental caries and periodontal disease is the result of the interplay of numerous organisms. From this, it is clear that an effective chemical method of ~ust treating plaque must have a broad antimicrobial ~pectrum and be effective against those specific organisms that cause the problem.
In search of an effective chemical method for dealing with oral plaque, many chemicals have been tried.
Several forms of antibiotics such as penicillin inhibit plaque ~ormation, but the developm~nt of re~istant organ-i8m8 and patient sensitiv$ty along with other ~ide effects ~15 have seriously re~tricted their application.
To avoid the problem~ associated with ~ystemic antibiotics,dental reaeaxch has focu~ed on antiseptic~
and on drugs uniquely involvea in the biology of the mouth.
Among the many material~ tested for thi~ purpose have been zinc salts and ascorbic acid. For example, zinc salts have been used a# a~tringents in mouthwa~he~ for the purpose of flocculating and precipltatlng proteinaceous material ~o that it can be removed by flushing. ~scorbic acid ha~ been tried in the prevention of dental plaque.
U. S. patent No. 2,470,906 to R. Taylor.
Combinations of ~inc ~alt~ with certain other an-tibacterial agents have been tried. U. S. patent No.
~JW ~ ~ ~ O 9111 4,022,880 to L. Vin~on et al. Still others have tried zinc salts with enzymes. U. S. patent No. 4,082,841 to M. Pader. Oxidizing preparations containing ascorbic acid, a peroxide and a metal ion catalyst have also been tried. U. S. patent No. 3,065,139 to S. Ericsson et al.
It has now been found that a combination of zinc ions and ascorbic acid provides a therapeutic com-position which improves the physiolog~cal tone of the oral tissues as well as providing a therapeutic composi-tion which is ~urprisingly effective against the oral microflora re~ponsible for plaque. More particularly, it has been found that when these agents are combined a greater tban additi~e antimicrobial effect can be ob-tained.
In view of the above, among the seYeral objects of the present invention may b~ noted th~ proviQion of a therapeutic compoQition for us~ in ~mproving the physio-logical tone of the oral tissues and for use in reducing oral plaque. Other object~ and features will be in part 2Q apparent and in part pointed out hereinafter.
In general, the new compo~itions embodying the present invention contain a pharmaceutically acceptable, water soluble zinc salt and ascorbic acid or an active analog thereof. To be use~ul herein for the purpose of both improving physiological tone and reducing plaque, the zinc salt and the ascorhic acid must be present in an amount sufficient to provide a synergistic combination which has a 2JW ~ 9111 1~27970 grea~er than additive antimicrobial effect on the micro-flora found in the oral cavity. At the heart of the inven-tion is the discovery of such synergistic combinations.
The provision of such a therapeutic composition is a major accomplishment. For example, to be effective for the present purpose, the composition must provide an antiseptic with a broad antimicrobial spectrum. On the other hand, to avoid harming the mucosa, it cannot be too concentrated. Since, as such, it cannot be formulated strong enough to kill all of the organisms right away, it is important that it not be immediately cleared from the oral cavity but continues to be effective for some time thereafter. There is also the diluting effect of the saliva and the reinoculation of th~ oral cavity to contend lg with. Sinc~ the composition may act by chemical combina-tion with the mucosal and microbial protoplasm, it i8 lm-portant that the therapeutic composition not be inactivated by combination with the constituents of the saliva or exudates of the infections. Finally, it is important that the present combinations be shelf stable and compatible with pharmaceutical carriers and other ingredients normally found in oral preparations. It is a further definite ad-vantage that the combination is relatively inexpensive to formulate.
Insofar as known prior to the present discovery, it was not known that a combination of zinc ions and ascor-bic acid could give rise to a synergistic combination if 2J~ 9111 present at effective levels. Nor was it known that such a combination would provide a therapeutic effect after the combination is emptied from the mouth. While some of the benefits observe for higher levels of zinc and as-corbic acid may have been expected, there was no teaching in the prior art as to how those levels could be effec-tively raised in the oral cavity.
The therapeuti compositions of the present in-vention comprise a mixture of a pharmaceutically acceptable water soluble zinc salt and ascorbic acid or an active analog thereof. They are non-toxic and innocuous tasting and they produce no normal irritation or allergic reactions.
In the context of the present invention, ascorbic acid includes l-ascorbic acid, dehydroascorbic acid and ~odium ascorbate. Its active analogs include l-glucoascorb~c acid, d-araboa~corbic acid, l-rhamnoascorbic acid, 6-desoxy-1-ascorbic acid and the like.
Suitable zinc salts include those zinc compounds which are soluble in water at body temperature. Suitable ~ sa~ts must be pharmaceutically acceptable. As such, they must be safe and organoleptically tolerable in the oral cavity and have no significant side effects either orally or systemically. Among the useful zinc salts are those formed from the following organic and inorganic anions:
acetate, benzoate, borate, bromide, carbonate, citrate, chloride, glycerophosphate, hexafluorosilicate, phenolsulfonate, silicate, alkanoates having 6 to 18 carbon atoms, such as 2~ 9111 1~27970 zinc stearate, sulfate, tannate, titanate, tetrafluoro-borate or the like. If the combînation is to be stored, to prevent the oxidation of ascorbic acid, it is pre-ferred that oxidizing zinc salts such as zinc peroxide be avoided. It is also preferred that an antioxidant such as vitamin E be added. The zinc salts may be used singly or in combination but zinc sulfate used alone is pre-ferred.
In accordance with the present invention, the zinc salt and the ascorbic acid is present in that amount sufficient to provide a synergistic combination effective as an antimicrobial agent again~t such difficult to ~ill oral microflora as Actinomyces viscosus, alpha Streptococcus, Candida albicans, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus epidermldis and Streptococcus mutans. Ex-cessive amounts of zinc salt~ beyond that necessary to pro-vide an effective combination should be avoided s$nce such compositions are unpleasantly astringent. Similarly, exces-~ive amounts of ascorbic acid should be avoided since such compositions are unpleasantly acidic. The pH of the mixture is preferably between about 4 and 5, most prefer-ably about 4.5. This can be easily achieved by providing the ascorbic acid partly in the form of sodium ascorbate.
Normally, the xinc salt and ascorbic acid is in a pharmaceutical carrier which may be either a liquid or solid. For example, where the oral composition i8 a mouth-wash, the balance of the preparation may consist of water, 2JW ~Z7970 9111 ethyl alcohol and a polyhydric alcohol such as glycerol or sorbitol. Flavoring agents and sweeteners may also be added along with stabilizers such as TWEEN 80.*
The composition of the present invention can also be formulated as a paste, powder or liquid dentrifrice, chewing gum, tablet, lozenge or the like. When the compo-sition is a toothpa~te, there may be present polishing agents, foaming agents and 80 forth which are compatible with the zinc salt and with the ascorbic acid.
When the zinc salt is ZnS04 7H20, an effective mouthwash i8 prepared wherein the concentration of said salt is at least 0.5 percent by weight/volume and wherein the ascorbic acid is present in a similar amaunt. Pre~er-ably, the amount of ~nS047H20 and the amount of ascorbic acid should not be more than about 2.0 percent by weight/
volume to avoid excessive astringency and acidity, respec-tively. Depending on the solubility of the zinc salt, the amounts thereof mu~t be ad~usted to provide an effective synergistic combination.
In use, the therapeutic composition i8 contacted with the oral ti~sues for several minute~ and then empt~ed.
It ha~ an immediate antimicrobial effect and continues t~
exert an antimicrobial and therapeutic effect for some time thereafter.
The following examples illustrate the invention.
*Trade Mark for poloxyethylene sorbitan monooleate l~Z7970 Example 1 A mouthwash was prepared from the follo~ing com-ponents:
95% Ethyl Alcohol200 ml ZnSO 7~ o 20 g Ascorbic Acid 20 g Glycerin 100 ml Water q. s. 1000 ml Example 2 Twenty guinea pigs weighing ~50 + 12 grams were treated wi~h 4 ml of the mouthwash described in Example 1 twice daily for ninety days. The mouthwash was applied with a ~terile cotton ~wab into the oral cavity of each -- animal.
The animals were sacrificed after ninety days.
Tissues from the glngiva, saliYary gland~ and mucosa of the oral cavity were obtained and fixed for histological examination. The results showed no pathological changes in the tissues and no irritation or edema a~ compared to ten control animals that received no treatment.
xamp le 3 To evaluate the mouthwash described in Example 1 for its effect in reducing oral plaque and in improving the physiological tone of the oral tissues, sixty patients were clinicall~ observed. The symptoms and conditions presented 2JW - ~ 9111 7~
by the patients were diverse but could be ~enerally divided into five categories: gingivitis periodontitis, perio-dontal abscess, acute necrotizing ulcerative gingivitisf ju~enile periodontitis and desquamative gingivitis.
S The patients were asked not to change any of their daily habits or to alter the intake of any medication that they were presently taking. Approximately half of the patients were given the mouthwash described in ~xample 1.
These patients were instructed to use it twice daily, diluting it 1:1 with water, taking a mouthful, holding it in the mouth with agitation for two minutes and then empty-ing.
The other half of the patients were given a mouth-wash like that described in Example 1 but without any as--- --lS -corbic acid. These patients were also given l$quid ascorbic acid and the instruction to put 4 or 5 drops of it in the mouth, hold it for two minutes and then ~wallow.
Most of the patlents were obserYed at one-week ~ntervals. Before treatment, typical ~ymptoms of unhealthy gingiva were swelling, mild to gros~ edema and mild to ~rank hemorrha~e. A majority had an obvious disagreea~le mouth odor and all had a desire to improve. Consequently, it can be a~sumed that they were reasonably consi~tent in the use of the mouthwash and the ascorbic acid as directed.
2~ Those patients with extreme patholo~ical conditions showed marked improvement in 1 to 3 days. In all cases, there wa~ a marked clinical improvement at the end of one ~`
2~ 9111 l~Z7970 wee~. In most instances, the frank hemorrhage had stopped, edema lessened, appearance of stippling increased and color begun to change from bright red to a lighter pink.
At the end of the second and third weeks, the improvement was even more evident.
Without exception, each of the patientq said that his mouth and teeth felt cleaner, fresher and more comfort-able even after the first day but markedly so after several days' use. All wanted to continue to use the mouthwash.
10 The gingival and periodontal index was determined by the technique described by J. Silliness et al, Acta. Odont.
Scand. 22, 121 and by photography before each patient uqed the mouthwash and ~ weeks, 1 month and ~ months ~ft¢r using the mouthwash. With disclosing wafers, there was obviou~
15 clinical evidence of less bacteriological plaque accumulation after using the mouthwash. Plaque accumulation decrea~ed con~istently as the patient continued ~o use the mouthwash.
Example 4 To evaluate the mouthwash described in Example 1 20 for it~ effect in killing oral bacteria, twenty-thre~ patients ran~ln~ in age from 19 to 52 years were tested. The patients were di~ided into two groups. The patients in Group I were given a placebo mouthwash like that in Example 1 but with no zinc sul~ate or ascorbic acid. Those in Group II were given 25 the mouthwash described in Example 1.
Each patient was asked to rinse his mouth with the mouthwash for 2 minutes and then to empty. A swab culture was 112~70 taken before and at 5, 10 and 30 minute intervals after using the mouthwash. The results are reported in Table I
below and show that the mouthwash described in Example 1 significantly decreased the bacteria in the oral cavity even after the mouthwash had been discharged.
Table I
Number of Bacterial cells/ml Group I Group II
Before using mouthwash 4.8x107+0.98 4.9x107+0.78 5 minutes after mouthwash 4.7x107+0.65 3.1x106+0.45 10 minutes after mouthwash 4.9xlQ7+0.74 1.3x106+0.61 30 minutes after mouthwash 4.8x107+0.34 0.5x106+0.04 Example 5 Seventeen pregnant women, ranging in age from 20 to 32 years, in the third trimester, suffering from pregnancy ginglvitis were examined and cla~sified into one of two categories. Those with gingivitis without any hyperplastic signs and those with gingivitis gravidarum.
Seven o the patients were classifiea as havin~ gingivitis without any hyperplastic signs and ten patients were classi-fied as having gingivitis gravidarum with hyperplastic signs.
Patients were divided into two groups for treat-ment. Three patients from the first category and five patients from the second category were given daily amounts ~ '' ` 9111 ~7970 of 50 mg of ZnSO4 71~2O and 100 mg of vitamin C orally for one month.
` The remaining nine patients were given the mouth-wash described in Example 1 and instructed to use i~ twice S daily.
The treatment with orally administered zinc 6ul-fate and ascorbic acid was not effective. There was no in-crease in the zinc or ascorbic acid levels in the saliva but there was an increase in the blood level due to the treat-ment.
With the other patients, bleeding stopped after ~ne week and the gingiva returned to its normal pink color after one month. A~corbic acid in the ~aliva increased !: ` from 15.6~g/gram to 31.2 ~g/gram and the zinc level in the saliva increased from 10 ~g/gram to 18.6~g/gram. Hence, ~ t i8 seen that treatment with the mouthwash of ~xample 1 during pregnancy has a greater effect than treatment with zinc salt and vitamin C orally.
Example 6 Eleven patient~ suffexing with canker sores, not of herpes simplex origin, were ins~xucted to r~nse thrPe times a day with the mouthwash descri~ed in Example 1.
After one day, the patients were relieved and could drink acidic liquids such as orange juice which had been painful before. After four days, the can~er sore3 were completely healed and the treatment was stopped.
7~0 In the first year, the patients had recurrent canker sores six times. Each time, the sores were treated for four days. In the second year, they experienced re-currence two timeq, in the third year there was no recur-rence. The patients have been followed four y~ars. To date there has been no recurrence.
Eight other patients with canker sores, nct of herpes simplex origin, were instructed to use the mouth-wash described in Example 1 twice a day, once in the morn-ing and once before bedtime. In the first year, the patients experienced recurrent sores three to four times a year.
In the second year, there ha~ been no recurrence.
Example 7 Sixteen men suffering with throat infection were , .
given the mouthwash described in Example 1 and advised to use it twice a day for a week. Before treatment, swab cultures revealed heavy growth of alpha Streptococcus, Staphylococcu~ epidermidis, Escherichia coli and Candida albicans.
2~ At the beginning of the treatment, some of the patients could not swallow food due to the infection.
Twenty-four hours after using the mouthwash, the situation had eased. All patients could eat normally after two days.
After six days, swab cultures revealed no growth of the above-mentioned organisms. No adverse side effects or dis-comfort because of the treatment was noted.
2J~ 9111 ~127~7U
Example 8 A mouthwash was prepared from the following components:
95~ Ethyl alcohol 200 ml 4 2 20 g Ascorbic acid 20 g TWEEN 80* 100 ml Vitamin E 1,000 I. U.
Water, q.s. 1,000 ml *polyoxyethylene sorbitan monooleate Example 9 .
Sixty-three patients ranging in a~e from 40 to 68 years were tested for taste acuity determined by measure-ment of the detection and xecognition thresholds for four taste qualities: NaCl for salt, sucrose for sweet, ~ICl for sour and urea for bitter. Twenty-two of the patient~ had normal taste and 41 had idiopathic hypog~u~ia.
Each of the hypogeusia patients was instructed to rinse his mouth twice a day with the mouthwash provided 2~ therefor. To note the placebo effect, nine of ~he idiopathic hypogeusia patients were given a placebo like the mouthwash described in Example 8 but without zinc sulfate or ascorblc acid. All of.the other patients used the mouthwash described 2JW 9lll ~279'~0 in Example ~. Parotid saliva was collected before treat-ment and one and three months after treatment. The re-sults are reported in Table II below. The hypogeusia patients receiving the placebo did not improve during the
Still other factors are known to interfere with the intes-tinal absorpt$on or with the utilization of zinc $on~ as well as of ascorbic acid.
The physiological tone of the oral muco~a, how-ever, i~ not the only factor in maintaining a healthy oral condition. Epidemiological ~tudies have suggested that microblal plaque i8 a ma~or factor contributing to dental caries and periodontal disease. Numerous mechanisms by which dental caries may occur have been suggested. Accord-ing to the most widely accepted concept, speciflc microbes present in bacterial plaque colonize the surface of the teeth, ferment dietary carbohydrates and produce organic acids. These acids demineralize the teeth, cau~ing the enamel to decay.
Plaque is also implicated in periodontal disease.
Although the precise cause of periodontal disease remains unclear, it is widely accepted that the primary cause is ~acterial plaque located in the gingival crevice bet~een the surface of the teeth and the gingiva.
2J~1 9111 ' ~1~7~
~echanical debridement of plaque by brushing and use of floss is still the primary recommended and ac-cepted method for the prevention of dental caries and periodontal disease. This approach is successful when rigorously practiced but is ~o highly labor-intensive that most people are not sufficiently motivated to prac-tice it consistently. Since plaque i8 quic~ly reformed, continual brushing and flossing axe essential to this method of therapy. Moreover, in the pre~ence of ging$val inflammation, mechanical methods of plaque removal fre-quently cau~e gingival hemorrhage. Thls often causes the patient to divert from his brushing and flo~ing regimen.
The focu~ in oral hygiene has been on a chemical method for dealing with oral plaque. While this clearly would have an obvious clinical advantage for u~e alone or more effectively in combination with mechanical methods, a more perfect therapeutic compo~ition wou~d also have a beneflcial effect on the oral mucosa beyond that of a mere antimicrobial agent.
The problem~ in ~ust dealing with plaque, how-ever, should not be underestimated. In search of an effec-tive chemical, it i~ lmportant to keep in mind that the periodontal ti~sue~ may be colonized by a~ many as 150 dif-ferent species of microorgani~m~. The particular microbial flora in any given area of the mouth at any given time i5 the result of the microbial succession that ha~ ta~en place up to that tirle. Not all of the oral mi~xoflora are implicated 2JW ~ 9111 llZ7970 in dental caries or in periodontal disease but those pathogenic genera which are responsible are, in general, among those most difficult to kill. Moreover, the net de~elopment of dental caries and periodontal disease is the result of the interplay of numerous organisms. From this, it is clear that an effective chemical method of ~ust treating plaque must have a broad antimicrobial ~pectrum and be effective against those specific organisms that cause the problem.
In search of an effective chemical method for dealing with oral plaque, many chemicals have been tried.
Several forms of antibiotics such as penicillin inhibit plaque ~ormation, but the developm~nt of re~istant organ-i8m8 and patient sensitiv$ty along with other ~ide effects ~15 have seriously re~tricted their application.
To avoid the problem~ associated with ~ystemic antibiotics,dental reaeaxch has focu~ed on antiseptic~
and on drugs uniquely involvea in the biology of the mouth.
Among the many material~ tested for thi~ purpose have been zinc salts and ascorbic acid. For example, zinc salts have been used a# a~tringents in mouthwa~he~ for the purpose of flocculating and precipltatlng proteinaceous material ~o that it can be removed by flushing. ~scorbic acid ha~ been tried in the prevention of dental plaque.
U. S. patent No. 2,470,906 to R. Taylor.
Combinations of ~inc ~alt~ with certain other an-tibacterial agents have been tried. U. S. patent No.
~JW ~ ~ ~ O 9111 4,022,880 to L. Vin~on et al. Still others have tried zinc salts with enzymes. U. S. patent No. 4,082,841 to M. Pader. Oxidizing preparations containing ascorbic acid, a peroxide and a metal ion catalyst have also been tried. U. S. patent No. 3,065,139 to S. Ericsson et al.
It has now been found that a combination of zinc ions and ascorbic acid provides a therapeutic com-position which improves the physiolog~cal tone of the oral tissues as well as providing a therapeutic composi-tion which is ~urprisingly effective against the oral microflora re~ponsible for plaque. More particularly, it has been found that when these agents are combined a greater tban additi~e antimicrobial effect can be ob-tained.
In view of the above, among the seYeral objects of the present invention may b~ noted th~ proviQion of a therapeutic compoQition for us~ in ~mproving the physio-logical tone of the oral tissues and for use in reducing oral plaque. Other object~ and features will be in part 2Q apparent and in part pointed out hereinafter.
In general, the new compo~itions embodying the present invention contain a pharmaceutically acceptable, water soluble zinc salt and ascorbic acid or an active analog thereof. To be use~ul herein for the purpose of both improving physiological tone and reducing plaque, the zinc salt and the ascorhic acid must be present in an amount sufficient to provide a synergistic combination which has a 2JW ~ 9111 1~27970 grea~er than additive antimicrobial effect on the micro-flora found in the oral cavity. At the heart of the inven-tion is the discovery of such synergistic combinations.
The provision of such a therapeutic composition is a major accomplishment. For example, to be effective for the present purpose, the composition must provide an antiseptic with a broad antimicrobial spectrum. On the other hand, to avoid harming the mucosa, it cannot be too concentrated. Since, as such, it cannot be formulated strong enough to kill all of the organisms right away, it is important that it not be immediately cleared from the oral cavity but continues to be effective for some time thereafter. There is also the diluting effect of the saliva and the reinoculation of th~ oral cavity to contend lg with. Sinc~ the composition may act by chemical combina-tion with the mucosal and microbial protoplasm, it i8 lm-portant that the therapeutic composition not be inactivated by combination with the constituents of the saliva or exudates of the infections. Finally, it is important that the present combinations be shelf stable and compatible with pharmaceutical carriers and other ingredients normally found in oral preparations. It is a further definite ad-vantage that the combination is relatively inexpensive to formulate.
Insofar as known prior to the present discovery, it was not known that a combination of zinc ions and ascor-bic acid could give rise to a synergistic combination if 2J~ 9111 present at effective levels. Nor was it known that such a combination would provide a therapeutic effect after the combination is emptied from the mouth. While some of the benefits observe for higher levels of zinc and as-corbic acid may have been expected, there was no teaching in the prior art as to how those levels could be effec-tively raised in the oral cavity.
The therapeuti compositions of the present in-vention comprise a mixture of a pharmaceutically acceptable water soluble zinc salt and ascorbic acid or an active analog thereof. They are non-toxic and innocuous tasting and they produce no normal irritation or allergic reactions.
In the context of the present invention, ascorbic acid includes l-ascorbic acid, dehydroascorbic acid and ~odium ascorbate. Its active analogs include l-glucoascorb~c acid, d-araboa~corbic acid, l-rhamnoascorbic acid, 6-desoxy-1-ascorbic acid and the like.
Suitable zinc salts include those zinc compounds which are soluble in water at body temperature. Suitable ~ sa~ts must be pharmaceutically acceptable. As such, they must be safe and organoleptically tolerable in the oral cavity and have no significant side effects either orally or systemically. Among the useful zinc salts are those formed from the following organic and inorganic anions:
acetate, benzoate, borate, bromide, carbonate, citrate, chloride, glycerophosphate, hexafluorosilicate, phenolsulfonate, silicate, alkanoates having 6 to 18 carbon atoms, such as 2~ 9111 1~27970 zinc stearate, sulfate, tannate, titanate, tetrafluoro-borate or the like. If the combînation is to be stored, to prevent the oxidation of ascorbic acid, it is pre-ferred that oxidizing zinc salts such as zinc peroxide be avoided. It is also preferred that an antioxidant such as vitamin E be added. The zinc salts may be used singly or in combination but zinc sulfate used alone is pre-ferred.
In accordance with the present invention, the zinc salt and the ascorbic acid is present in that amount sufficient to provide a synergistic combination effective as an antimicrobial agent again~t such difficult to ~ill oral microflora as Actinomyces viscosus, alpha Streptococcus, Candida albicans, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus epidermldis and Streptococcus mutans. Ex-cessive amounts of zinc salt~ beyond that necessary to pro-vide an effective combination should be avoided s$nce such compositions are unpleasantly astringent. Similarly, exces-~ive amounts of ascorbic acid should be avoided since such compositions are unpleasantly acidic. The pH of the mixture is preferably between about 4 and 5, most prefer-ably about 4.5. This can be easily achieved by providing the ascorbic acid partly in the form of sodium ascorbate.
Normally, the xinc salt and ascorbic acid is in a pharmaceutical carrier which may be either a liquid or solid. For example, where the oral composition i8 a mouth-wash, the balance of the preparation may consist of water, 2JW ~Z7970 9111 ethyl alcohol and a polyhydric alcohol such as glycerol or sorbitol. Flavoring agents and sweeteners may also be added along with stabilizers such as TWEEN 80.*
The composition of the present invention can also be formulated as a paste, powder or liquid dentrifrice, chewing gum, tablet, lozenge or the like. When the compo-sition is a toothpa~te, there may be present polishing agents, foaming agents and 80 forth which are compatible with the zinc salt and with the ascorbic acid.
When the zinc salt is ZnS04 7H20, an effective mouthwash i8 prepared wherein the concentration of said salt is at least 0.5 percent by weight/volume and wherein the ascorbic acid is present in a similar amaunt. Pre~er-ably, the amount of ~nS047H20 and the amount of ascorbic acid should not be more than about 2.0 percent by weight/
volume to avoid excessive astringency and acidity, respec-tively. Depending on the solubility of the zinc salt, the amounts thereof mu~t be ad~usted to provide an effective synergistic combination.
In use, the therapeutic composition i8 contacted with the oral ti~sues for several minute~ and then empt~ed.
It ha~ an immediate antimicrobial effect and continues t~
exert an antimicrobial and therapeutic effect for some time thereafter.
The following examples illustrate the invention.
*Trade Mark for poloxyethylene sorbitan monooleate l~Z7970 Example 1 A mouthwash was prepared from the follo~ing com-ponents:
95% Ethyl Alcohol200 ml ZnSO 7~ o 20 g Ascorbic Acid 20 g Glycerin 100 ml Water q. s. 1000 ml Example 2 Twenty guinea pigs weighing ~50 + 12 grams were treated wi~h 4 ml of the mouthwash described in Example 1 twice daily for ninety days. The mouthwash was applied with a ~terile cotton ~wab into the oral cavity of each -- animal.
The animals were sacrificed after ninety days.
Tissues from the glngiva, saliYary gland~ and mucosa of the oral cavity were obtained and fixed for histological examination. The results showed no pathological changes in the tissues and no irritation or edema a~ compared to ten control animals that received no treatment.
xamp le 3 To evaluate the mouthwash described in Example 1 for its effect in reducing oral plaque and in improving the physiological tone of the oral tissues, sixty patients were clinicall~ observed. The symptoms and conditions presented 2JW - ~ 9111 7~
by the patients were diverse but could be ~enerally divided into five categories: gingivitis periodontitis, perio-dontal abscess, acute necrotizing ulcerative gingivitisf ju~enile periodontitis and desquamative gingivitis.
S The patients were asked not to change any of their daily habits or to alter the intake of any medication that they were presently taking. Approximately half of the patients were given the mouthwash described in ~xample 1.
These patients were instructed to use it twice daily, diluting it 1:1 with water, taking a mouthful, holding it in the mouth with agitation for two minutes and then empty-ing.
The other half of the patients were given a mouth-wash like that described in Example 1 but without any as--- --lS -corbic acid. These patients were also given l$quid ascorbic acid and the instruction to put 4 or 5 drops of it in the mouth, hold it for two minutes and then ~wallow.
Most of the patlents were obserYed at one-week ~ntervals. Before treatment, typical ~ymptoms of unhealthy gingiva were swelling, mild to gros~ edema and mild to ~rank hemorrha~e. A majority had an obvious disagreea~le mouth odor and all had a desire to improve. Consequently, it can be a~sumed that they were reasonably consi~tent in the use of the mouthwash and the ascorbic acid as directed.
2~ Those patients with extreme patholo~ical conditions showed marked improvement in 1 to 3 days. In all cases, there wa~ a marked clinical improvement at the end of one ~`
2~ 9111 l~Z7970 wee~. In most instances, the frank hemorrhage had stopped, edema lessened, appearance of stippling increased and color begun to change from bright red to a lighter pink.
At the end of the second and third weeks, the improvement was even more evident.
Without exception, each of the patientq said that his mouth and teeth felt cleaner, fresher and more comfort-able even after the first day but markedly so after several days' use. All wanted to continue to use the mouthwash.
10 The gingival and periodontal index was determined by the technique described by J. Silliness et al, Acta. Odont.
Scand. 22, 121 and by photography before each patient uqed the mouthwash and ~ weeks, 1 month and ~ months ~ft¢r using the mouthwash. With disclosing wafers, there was obviou~
15 clinical evidence of less bacteriological plaque accumulation after using the mouthwash. Plaque accumulation decrea~ed con~istently as the patient continued ~o use the mouthwash.
Example 4 To evaluate the mouthwash described in Example 1 20 for it~ effect in killing oral bacteria, twenty-thre~ patients ran~ln~ in age from 19 to 52 years were tested. The patients were di~ided into two groups. The patients in Group I were given a placebo mouthwash like that in Example 1 but with no zinc sul~ate or ascorbic acid. Those in Group II were given 25 the mouthwash described in Example 1.
Each patient was asked to rinse his mouth with the mouthwash for 2 minutes and then to empty. A swab culture was 112~70 taken before and at 5, 10 and 30 minute intervals after using the mouthwash. The results are reported in Table I
below and show that the mouthwash described in Example 1 significantly decreased the bacteria in the oral cavity even after the mouthwash had been discharged.
Table I
Number of Bacterial cells/ml Group I Group II
Before using mouthwash 4.8x107+0.98 4.9x107+0.78 5 minutes after mouthwash 4.7x107+0.65 3.1x106+0.45 10 minutes after mouthwash 4.9xlQ7+0.74 1.3x106+0.61 30 minutes after mouthwash 4.8x107+0.34 0.5x106+0.04 Example 5 Seventeen pregnant women, ranging in age from 20 to 32 years, in the third trimester, suffering from pregnancy ginglvitis were examined and cla~sified into one of two categories. Those with gingivitis without any hyperplastic signs and those with gingivitis gravidarum.
Seven o the patients were classifiea as havin~ gingivitis without any hyperplastic signs and ten patients were classi-fied as having gingivitis gravidarum with hyperplastic signs.
Patients were divided into two groups for treat-ment. Three patients from the first category and five patients from the second category were given daily amounts ~ '' ` 9111 ~7970 of 50 mg of ZnSO4 71~2O and 100 mg of vitamin C orally for one month.
` The remaining nine patients were given the mouth-wash described in Example 1 and instructed to use i~ twice S daily.
The treatment with orally administered zinc 6ul-fate and ascorbic acid was not effective. There was no in-crease in the zinc or ascorbic acid levels in the saliva but there was an increase in the blood level due to the treat-ment.
With the other patients, bleeding stopped after ~ne week and the gingiva returned to its normal pink color after one month. A~corbic acid in the ~aliva increased !: ` from 15.6~g/gram to 31.2 ~g/gram and the zinc level in the saliva increased from 10 ~g/gram to 18.6~g/gram. Hence, ~ t i8 seen that treatment with the mouthwash of ~xample 1 during pregnancy has a greater effect than treatment with zinc salt and vitamin C orally.
Example 6 Eleven patient~ suffexing with canker sores, not of herpes simplex origin, were ins~xucted to r~nse thrPe times a day with the mouthwash descri~ed in Example 1.
After one day, the patients were relieved and could drink acidic liquids such as orange juice which had been painful before. After four days, the can~er sore3 were completely healed and the treatment was stopped.
7~0 In the first year, the patients had recurrent canker sores six times. Each time, the sores were treated for four days. In the second year, they experienced re-currence two timeq, in the third year there was no recur-rence. The patients have been followed four y~ars. To date there has been no recurrence.
Eight other patients with canker sores, nct of herpes simplex origin, were instructed to use the mouth-wash described in Example 1 twice a day, once in the morn-ing and once before bedtime. In the first year, the patients experienced recurrent sores three to four times a year.
In the second year, there ha~ been no recurrence.
Example 7 Sixteen men suffering with throat infection were , .
given the mouthwash described in Example 1 and advised to use it twice a day for a week. Before treatment, swab cultures revealed heavy growth of alpha Streptococcus, Staphylococcu~ epidermidis, Escherichia coli and Candida albicans.
2~ At the beginning of the treatment, some of the patients could not swallow food due to the infection.
Twenty-four hours after using the mouthwash, the situation had eased. All patients could eat normally after two days.
After six days, swab cultures revealed no growth of the above-mentioned organisms. No adverse side effects or dis-comfort because of the treatment was noted.
2J~ 9111 ~127~7U
Example 8 A mouthwash was prepared from the following components:
95~ Ethyl alcohol 200 ml 4 2 20 g Ascorbic acid 20 g TWEEN 80* 100 ml Vitamin E 1,000 I. U.
Water, q.s. 1,000 ml *polyoxyethylene sorbitan monooleate Example 9 .
Sixty-three patients ranging in a~e from 40 to 68 years were tested for taste acuity determined by measure-ment of the detection and xecognition thresholds for four taste qualities: NaCl for salt, sucrose for sweet, ~ICl for sour and urea for bitter. Twenty-two of the patient~ had normal taste and 41 had idiopathic hypog~u~ia.
Each of the hypogeusia patients was instructed to rinse his mouth twice a day with the mouthwash provided 2~ therefor. To note the placebo effect, nine of ~he idiopathic hypogeusia patients were given a placebo like the mouthwash described in Example 8 but without zinc sulfate or ascorblc acid. All of.the other patients used the mouthwash described 2JW 9lll ~279'~0 in Example ~. Parotid saliva was collected before treat-ment and one and three months after treatment. The re-sults are reported in Table II below. The hypogeusia patients receiving the placebo did not improve during the
3 month trial period but the taste of the patients using the mouthwash described in Example 8 improved after one month and became normal after three months.
Table II
Zinc Concentration ppb in Saliva Mouthwash Before One Month Three Months Normal Placebo 49+16 53+12 50+18 Hypogeusia Example 18 13+2 38+10 47+13 Example 10 In this example, zinc sulfate and ascorbic acid was checked for its effectiveness on two of the bacterial species known to be implicated in dental plaque. These results were then compared with the effect of a synergistic combination of zinc sulfate and ascorbic acid.
Culture media were prepared with ZnSO4 7~12O or ascorbic acid or a combination thereof in Tryplic Soy Broth and in a concentration of 0.5, 1, 2, 4, 8 or 10 percent by weightfvo~ume. These broths were then placed in 1 ml tubes and 0.001 ml of an inoculum containing 1 x 10 alpha Streptococci cells/ml or the same concentration of Staphylo-coccus epidermidis was added to the tubes. The tubes were :J lll ~lZ7970 then incubated over night and the bacterial growth was determined the next day.
All of the tubes showed no growth in the streptococci-inoculated media in the presence of all S levels of zinc sulfate or ascorbic acid. In the case of the staphylococci-inoculated media, 80 percent of the cultured bacteria were killed in the presence of 0.5 percent by weight/volume of ZnSO4~7H2O or a~corbic acid.
~hen the concentration of the ZnSO4 7~2O or ascorbic acid was increased to S percent by weight/volume, all of the 6taphylococci were also killed. The same re-sult, however, was obtained with a combination of 0.5 per-cent ZnSO4 7~2O with 0.5 percent ascorbic acid. This in-dicates a synergistic effect between zinc ions and ascorbic acid in their antimicrobial activity again~t the organisms tested.
Exam~le 11 In this example the effect of the mouthwash pre-pared in Example 1 was tested against the same bacteria as in Example 10. An 0.001 ml aliquant of a staphylococcus inoculum containing 6 x 1011 cells~ml or a similar ali~uant of a streptococcus inoculum containing 4.2 x 101 cells/ml was added to a test tube.
A volume of the mouthwash described in Example 1 was added to each tube such that the concentration of ~ 19 -llZ7970 ZnSO4 7H2O and ascorbic acid were both 0.5 percent by weight/volume. In another set of experiments, the mouth-wash of Example 1 was diluted with water 1:1 such that the concentration of the zinc sulfate and acid wa~ half of that described above.
The concentration of the bacteria was then de-termined after 30 sec and after 1, 2, 5 and 30 minutes.
The results are reported in Table III below.
Table III
30 sec 1 min 2 min 5 min 30 min Mouthwash from Example 1 Concentrated Staphylococcus NG* NG NG ~G NG
Streptococcus 3X106 NG NG NG NG
Diluted 1:1 Staphylococcus 3x105 4xlO5 9x104 6x104 lx103 Streptococcus 1.5x106 2.9x105 2.3x105 NG NG
*No Growth Example 12 Culture media were prepared with ZnSO4 7H2O or ascorbic acid or a combination thereof in Tryplic Soy Broth as described in Example 10. These broths were then inocu-lated with 0.1 ml of an inoculum containing 8 x 108 cells/ml of Escherichia coli ~TCC-25922 or 5 x 1o8 cells/ml of Pseudomonas aeruginosa. The results are reported in Table IV
- 2~ -~ 9111 below wherein and throughout the following examples the symbol H~ indicates that there was heavy growth, M+
moderate growth, S~ scant growth and NG that there was no growth.
Table IV
Concentration percent by weight/volume 0.25 0.5 1.0 2.0 4.0 8.0 Control ZnSO 7~1 O
E. coli - H+ NG NG NG NG H+
P. aeruginosa - H+ S+ S+ S+ S+ H+
Ascorbic a_id E. coli - S+ H+ NG NG NG H+
P. aeruginosa - H+ M+ S+ NG NG R~
-Combination ænso 7H2O and asco~bic acid E. coli H+ M+ S~ NG N~, - H+
P. aeruginosa S+ S+ NG NG NG - H+
~ .
The effectiveness of the-mout.hwash described in Example l was tested for its antimicrobial effect on Strep~ococcus mutans, ATCC No. 25175, Actinomyce~ viscosus, ATCC No. 19246 and Candida albicans, ATCC No. 18804. It was found effective in inhibiting the growth of all of the test organisms.
~127~70 _xample 14 The effectiveness of zinc salts, ascorbic acid and a combination thereof ~ras tried in an amount below that necessary for a syner~istic combination. ~lore par-ticularly, ZnS04~7~120, ascor~ic acid and combinations thereof were tested at the o.t, 0.2, 0.3 and 0.4 percent by weight/volume level for its antimicrobial effect against alpha Streptococcus, Streptococcus mutans, Staphylococcus aureus, Staphylococcus epidermidis, ~ctinomyces israeli and Actinomyces viscosus. All samples showed heavy growth with zinc alone, ascorbic acid alone or their 1:1 combina-tion at the 0.1, 0.2, 0.3 and 0.4 concentrations.
Example 15 The effectiveness of the mouthwash described in - 15 Example 1 in the presence of biological fluids such as sterile animal serum was tested for its antimicrobial ef-fect on alpha Streptococci and Staphylococcus epidermidis.
It was found that the mouthwash was effective against these organisms in the presence of the serum.
Exam~le 16 Ascor~ic acid when dissolved in water tends to oxidize and is not stable for a long period of time. ~ow-ever, when ZnS04 7~l20 is added to an ascorbic acid solu-tion, it become~ more stable. Stability can be extended to one year by adding 1000 I~ U. Vitamin E per liter of 2.~W 9111 ~lZ7970 solution containing 0.5 percent by weight/volume of ZnSO4-7~l2O and of ascorbic acid. The results of these tests are reported in Table V below.
Table V
-Active Ascorbic Acid 0 1 month 3 months 6 months1 year 2% Ascorbic acid 20 16.6 15.4 12.2 10.1 2% Ascorbic acid and ZnS4-7H2 20 20 19.8 18.7 17.6 Mouthwash Example 1 20 20 20 19.6 18~4 Mouthwash Example 18 20 20 20 20 19.5 From the above, it is seen that TWEEN*also in-crease~ the stability of the vitamin C.
In view of the above, lt will be seen that the several objects of the invention are achieved and other advantageous results attained. As various changes could be made in the above compoait$ons and methods without de-parting from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense.
The invention accordingly comprises the composition~ and methods hereinbefore described, the scope of the invention being indicated by the subjoined claims.
*Trade Mark for polyoxyethylene sorbitan monooleate
Table II
Zinc Concentration ppb in Saliva Mouthwash Before One Month Three Months Normal Placebo 49+16 53+12 50+18 Hypogeusia Example 18 13+2 38+10 47+13 Example 10 In this example, zinc sulfate and ascorbic acid was checked for its effectiveness on two of the bacterial species known to be implicated in dental plaque. These results were then compared with the effect of a synergistic combination of zinc sulfate and ascorbic acid.
Culture media were prepared with ZnSO4 7~12O or ascorbic acid or a combination thereof in Tryplic Soy Broth and in a concentration of 0.5, 1, 2, 4, 8 or 10 percent by weightfvo~ume. These broths were then placed in 1 ml tubes and 0.001 ml of an inoculum containing 1 x 10 alpha Streptococci cells/ml or the same concentration of Staphylo-coccus epidermidis was added to the tubes. The tubes were :J lll ~lZ7970 then incubated over night and the bacterial growth was determined the next day.
All of the tubes showed no growth in the streptococci-inoculated media in the presence of all S levels of zinc sulfate or ascorbic acid. In the case of the staphylococci-inoculated media, 80 percent of the cultured bacteria were killed in the presence of 0.5 percent by weight/volume of ZnSO4~7H2O or a~corbic acid.
~hen the concentration of the ZnSO4 7~2O or ascorbic acid was increased to S percent by weight/volume, all of the 6taphylococci were also killed. The same re-sult, however, was obtained with a combination of 0.5 per-cent ZnSO4 7~2O with 0.5 percent ascorbic acid. This in-dicates a synergistic effect between zinc ions and ascorbic acid in their antimicrobial activity again~t the organisms tested.
Exam~le 11 In this example the effect of the mouthwash pre-pared in Example 1 was tested against the same bacteria as in Example 10. An 0.001 ml aliquant of a staphylococcus inoculum containing 6 x 1011 cells~ml or a similar ali~uant of a streptococcus inoculum containing 4.2 x 101 cells/ml was added to a test tube.
A volume of the mouthwash described in Example 1 was added to each tube such that the concentration of ~ 19 -llZ7970 ZnSO4 7H2O and ascorbic acid were both 0.5 percent by weight/volume. In another set of experiments, the mouth-wash of Example 1 was diluted with water 1:1 such that the concentration of the zinc sulfate and acid wa~ half of that described above.
The concentration of the bacteria was then de-termined after 30 sec and after 1, 2, 5 and 30 minutes.
The results are reported in Table III below.
Table III
30 sec 1 min 2 min 5 min 30 min Mouthwash from Example 1 Concentrated Staphylococcus NG* NG NG ~G NG
Streptococcus 3X106 NG NG NG NG
Diluted 1:1 Staphylococcus 3x105 4xlO5 9x104 6x104 lx103 Streptococcus 1.5x106 2.9x105 2.3x105 NG NG
*No Growth Example 12 Culture media were prepared with ZnSO4 7H2O or ascorbic acid or a combination thereof in Tryplic Soy Broth as described in Example 10. These broths were then inocu-lated with 0.1 ml of an inoculum containing 8 x 108 cells/ml of Escherichia coli ~TCC-25922 or 5 x 1o8 cells/ml of Pseudomonas aeruginosa. The results are reported in Table IV
- 2~ -~ 9111 below wherein and throughout the following examples the symbol H~ indicates that there was heavy growth, M+
moderate growth, S~ scant growth and NG that there was no growth.
Table IV
Concentration percent by weight/volume 0.25 0.5 1.0 2.0 4.0 8.0 Control ZnSO 7~1 O
E. coli - H+ NG NG NG NG H+
P. aeruginosa - H+ S+ S+ S+ S+ H+
Ascorbic a_id E. coli - S+ H+ NG NG NG H+
P. aeruginosa - H+ M+ S+ NG NG R~
-Combination ænso 7H2O and asco~bic acid E. coli H+ M+ S~ NG N~, - H+
P. aeruginosa S+ S+ NG NG NG - H+
~ .
The effectiveness of the-mout.hwash described in Example l was tested for its antimicrobial effect on Strep~ococcus mutans, ATCC No. 25175, Actinomyce~ viscosus, ATCC No. 19246 and Candida albicans, ATCC No. 18804. It was found effective in inhibiting the growth of all of the test organisms.
~127~70 _xample 14 The effectiveness of zinc salts, ascorbic acid and a combination thereof ~ras tried in an amount below that necessary for a syner~istic combination. ~lore par-ticularly, ZnS04~7~120, ascor~ic acid and combinations thereof were tested at the o.t, 0.2, 0.3 and 0.4 percent by weight/volume level for its antimicrobial effect against alpha Streptococcus, Streptococcus mutans, Staphylococcus aureus, Staphylococcus epidermidis, ~ctinomyces israeli and Actinomyces viscosus. All samples showed heavy growth with zinc alone, ascorbic acid alone or their 1:1 combina-tion at the 0.1, 0.2, 0.3 and 0.4 concentrations.
Example 15 The effectiveness of the mouthwash described in - 15 Example 1 in the presence of biological fluids such as sterile animal serum was tested for its antimicrobial ef-fect on alpha Streptococci and Staphylococcus epidermidis.
It was found that the mouthwash was effective against these organisms in the presence of the serum.
Exam~le 16 Ascor~ic acid when dissolved in water tends to oxidize and is not stable for a long period of time. ~ow-ever, when ZnS04 7~l20 is added to an ascorbic acid solu-tion, it become~ more stable. Stability can be extended to one year by adding 1000 I~ U. Vitamin E per liter of 2.~W 9111 ~lZ7970 solution containing 0.5 percent by weight/volume of ZnSO4-7~l2O and of ascorbic acid. The results of these tests are reported in Table V below.
Table V
-Active Ascorbic Acid 0 1 month 3 months 6 months1 year 2% Ascorbic acid 20 16.6 15.4 12.2 10.1 2% Ascorbic acid and ZnS4-7H2 20 20 19.8 18.7 17.6 Mouthwash Example 1 20 20 20 19.6 18~4 Mouthwash Example 18 20 20 20 20 19.5 From the above, it is seen that TWEEN*also in-crease~ the stability of the vitamin C.
In view of the above, lt will be seen that the several objects of the invention are achieved and other advantageous results attained. As various changes could be made in the above compoait$ons and methods without de-parting from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense.
The invention accordingly comprises the composition~ and methods hereinbefore described, the scope of the invention being indicated by the subjoined claims.
*Trade Mark for polyoxyethylene sorbitan monooleate
Claims (7)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A therapeutic composition for topical oral administration for stimulating production of collagen consisting essentially of about 0.5 to about 2.0 percent by weight/volume of a pharmaceutically acceptable, water soluble zinc; salt and about 0.5 to about 2.0 percent by weight/volume of one of ascorbic acid and sodium ascorbate.
2. The composition according to claim 1 wherein the ratio of the zinc salt to said one of ascorbic acid and sodium ascorbate is substantially 1 to 1 by weight.
3. The composition according to claim 2 wherein the zinc salt is ZnSO4 7H2O.
4. The composition according to claim 3 wherein the pH is from about 4 to about 5.
5. A method of producing a therapeutic composition for use in oral hygiene comprising admixing essentially about 0.5 to about 2.0 percent by weight/volume of a pharmaceutically acceptable, water soluble zinc salt with about 0.5 to about 2.0 percent by weight/volume of one of ascorbic acid and sodium ascorbate.
6. The method according to claim 5 wherein said zinc salt is ZnSO4 7H2O, said salt is admixed with sodium ascorbate and the admixture has a pH from about 4 to about 5.
7. The method according to claim 6 wherein the ratio of the ZnSO4 7H2O to the sodium ascorbate is substantially 1 to 1 by weight.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US935,247 | 1978-08-21 | ||
| US05/935,247 US4229430A (en) | 1978-08-21 | 1978-08-21 | Oral composition for improving oral health |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1127970A true CA1127970A (en) | 1982-07-20 |
Family
ID=25466777
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA334,067A Expired CA1127970A (en) | 1978-08-21 | 1979-08-20 | Oral composition for improving oral health |
Country Status (2)
| Country | Link |
|---|---|
| US (1) | US4229430A (en) |
| CA (1) | CA1127970A (en) |
Families Citing this family (42)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4289754A (en) * | 1980-11-03 | 1981-09-15 | Richardson-Vicks Inc. | Zinc derivatives and their use in mouthwash compositions |
| US4289755A (en) * | 1980-11-03 | 1981-09-15 | Richardson-Vicks Inc. | Stable mouthwash compositions containing zinc and fluoride compounds |
| SE8206250L (en) * | 1982-11-03 | 1984-05-04 | Chemical Dynamics Sweden Ab | REGULATION OF GAS MICROFLORA |
| US4515771A (en) * | 1983-04-11 | 1985-05-07 | Fine Daniel H | Composition and method for the preventative treatment of dental disease and apparatus for dispensing said composition |
| US4711780A (en) * | 1984-06-11 | 1987-12-08 | Fahim Mostafa S | Composition and process for promoting epithelial regeneration |
| CA1291034C (en) * | 1987-10-19 | 1991-10-22 | Mostafa S. Fahim | Composition for promoting epithelial regeneration |
| US4895727A (en) * | 1985-05-03 | 1990-01-23 | Chemex Pharmaceuticals, Inc. | Pharmaceutical vehicles for exhancing penetration and retention in the skin |
| US4996232A (en) * | 1985-10-25 | 1991-02-26 | Cadbury Schweppes Proprietary Limited | Reducing bacterial content in water |
| US4704280A (en) * | 1986-12-19 | 1987-11-03 | Bates Harry L | Cosmetic lotion |
| US4983382A (en) * | 1987-01-27 | 1991-01-08 | Avon Products, Inc. | Cosmetic preparation incorporating stabilized ascorbic acid |
| FR2617709B1 (en) * | 1987-07-06 | 1991-04-26 | Roch Romeo | TOOTHPASTE WITH BRUSHING TIME INDICATOR |
| GB8922594D0 (en) * | 1989-10-06 | 1989-11-22 | Unilever Plc | Oral compositions |
| US5308621A (en) * | 1991-02-18 | 1994-05-03 | Commonwealth Scientific And Industrial Research Organisation | Ascorbic acid composition and transdermal administration method |
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| ATE310497T1 (en) * | 2002-06-20 | 2005-12-15 | Oreal | COSMETIC AND/OR DERMATOLOGICAL USE OF A COMPOSITION CONTAINING AT LEAST ONE OXIDATION SENSITIVE HYDROPHILE ACTIVE INGREDIENTS STABILIZED BY AT LEAST ONE POLYMER OR COPOLYMER OF MALEIC ANHYDRIDE |
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| RU2619848C2 (en) * | 2015-11-10 | 2017-05-18 | федеральное государственное бюджетное учреждение "Центральный научно-исследовательский институт стоматологии и челюстно-лицевой хирургии" Министерства здравоохранения Российской Федерации | Paste for periodontal diseases treatment for patients with diabetes mellitus |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US1488097A (en) * | 1922-03-09 | 1924-03-25 | Henry N Creger | Dentifrice |
| US2470906A (en) * | 1946-07-31 | 1949-05-24 | Taylor Ralph | Dentifrice |
| US3065139A (en) * | 1953-11-12 | 1962-11-20 | Astra Ab | Anti-infectant topical preparations |
| CH568758A5 (en) * | 1971-02-10 | 1975-11-14 | Unilever Nv | Dentifrice contg. moderately water-soluble zinc salt - of an acid, to increase activity against tartar and plaque |
| SE369036B (en) * | 1972-06-30 | 1974-08-05 | Astra Laekemedel Ab | |
| US3888976A (en) * | 1972-09-21 | 1975-06-10 | William P Mlkvy | Zinc and strontium ion containing effervescent mouthwash tablet |
| US3772431A (en) * | 1972-09-21 | 1973-11-13 | W Mlkvy | Effervescent mouthwash tablet |
| US4022880A (en) * | 1973-09-26 | 1977-05-10 | Lever Brothers Company | Anticalculus composition |
-
1978
- 1978-08-21 US US05/935,247 patent/US4229430A/en not_active Expired - Lifetime
-
1979
- 1979-08-20 CA CA334,067A patent/CA1127970A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| US4229430A (en) | 1980-10-21 |
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