CA2539003A1

CA2539003A1 - Compositions and methods for topical treatment of skin infection

Info

Publication number: CA2539003A1
Application number: CA002539003A
Authority: CA
Inventors: Win L. Chiou
Original assignee: Chiou Consulting Inc.; Win L. Chiou
Current assignee: Chiou Consulting Inc
Priority date: 2003-12-04
Filing date: 2004-11-30
Publication date: 2005-06-23
Also published as: WO2005055927A3; US20050123620A1; TW200520762A; GB0612417D0; GB2426454A; JP2007513162A; CN101262871A; WO2005055927A2; KR20070000393A; US20080020059A1; US7258875B2

Abstract

The present invention describes an extremely effective, simple, novel, inexpensive, safe and quick method to treat both acne and warts, each with a different etiology and different clinical symptoms, by topically applying an effective and safe amount of one or more polyvalent metal compounds. The present invention can also be used for prophylaxis of acne. The polyvalent metal compounds include, but are not limited to, bismuth compounds, zinc compounds, magnesium compounds, aluminum compounds, calcium compounds, copper compounds, titanium compounds, manganese compounds, chromium compounds, barium compounds, selenium compounds and iron compounds. The present invention can also be applied to the treatment of rosacea. The present invention can also be employed to prevent scarring and to facilitate healing or elimination of the scars once formed, and to be useful in depigmentation. The present invention can also be used for the prophylaxis and treatment of periodontitis and tooth mobility, as well as for promoting healthy growth of oral mucous membranes and tissues.

Description

COMPOSITIONS AND METHODS

This application is being filed as a PCT International Patent application in the name of Chiou Consulting Inc., a U.S. national corporation, applicant for the designation of all countries except the US, and Win L. Chiou, a U.S. citizen, applicant for the designation of the US only, and claims priority to U.S.
Application Serial No. 10/727,376, filed December 4, 2003.
Field of the Invention The present invention relates to treating acne and warts with a topical application containing one or more polyvalent metal compounds, and also relates to prevention and healing or sloughing of scars or depigmentation on the skin, as well as for the prophylaxis and treatment of periodontitis and tooth mobility.
Background of the Invention Skin infection is commonly treated with antimicrobial agents orally and/orv topically. Topical treatment is preferred because it can minimize any potential systemic adverse effects of drugs and it is also less expensive. Acne, mainly caused by P. acnes, and warts (i.e., verruca) caused by human papillomavirus, are two common, potentially serious skin infectious diseases ("Current Medical Diagnosis and Treatment" by L. M. Tierney, Jr. et al., Lange Medical Books, NY, 2004, pp.
111-113 and 123-125; "Andrews' Diseases of the Skin, Clinical Dermatology" by R.
B. Odom et al., Philadelphia, 2000, pp. 284-306 and 509-519.) Topical acne treatment commonly includes prescription-required antibiotics (such as erythromycin and clindamycin) and potent retinoids. The effectiveness of the above treatment method does not appear to be satisfactory since many weeks or months of continuous daily treatment are generally required. In one study, for example, only about 50% of patients showed satisfactory responses after 12 weelcs of erythromycin or clindamycin treatment (J.J. Leyden, et al., J. Am. Acad. Dermatol. 1987;
16:822-827). Topical nonprescription drugs such as sulfur and salicylic acid are considered less effective. For topical treatment of warts, probably with the exception of salicylic acid, drugs such as bleomycin, 5-fluorouracil, podophyllin and imiquimod require a physician's prescription. Furthermore, at least two or three months of sustained treatment are generally required. Potential serious adverse effects of topical or systemic treatment for both acne and warts are well known.
Furthermore, unsightly "permanent" scars are often present after completion of the treatment.
It is important to emphasize here that many reported antimicrobial compounds can kill the microorganisms and "cure" the diseases but often inhibit wound healing (U.S. Patent 5,567,716 by Della Valle et al., October 22, 1996).
Furthermore, healing or treatment of a disease, a lesion or a wound may also result in the formation of an unsightly, undesirable scar on the skin ("Webster's New World Dictionary," edited by D. B. Garalnik, Prentice Hall Press, 1986, pp.
1271) as exemplified in the conventional treatment of acne, warts and herpes simplex.
The above brief review clearly indicates that there is an urgent need to develop a new, novel, simple, rapid, highly safe, highly effective topical treatment of acne and warts without leaving scars behind after the treatment. Ideally, the new drug treatment may not require a prescription, and the same drug can be used to treat both diseases. The present invention is aimed to achieve the above objectives.
SummarYof the Invention The present invention relates to the surprising discovery that topical application of mixtures containing one or more polyvalent metal compounds can effectively heal the acne and warts in humans when applied from an appropriate dosage form. Thus, for example, for papular inflammatory acne, complete healing without any scars left behind (Examples I and II) was found in several subjects within one day after only one single application. For pustular inflammatory acne, virtually complete healing was found in just about one to two days of treatment (Examples I to III). For very severe chronic, multiple-lesion acne, a dramatic effect was observed in 6 days (Example IV). For warts, a crust was formed and healing was found to begin shortly after one application. Near healing was found in about one week. A complete healing without any scar left was achieved in about two weeks. The speed of healing and the absence of permanent scars left (Examples I to V) after topical administration of a composition of the present invention was extremely dramatic and surprising compared to the conventional methods of treatment that usually take many weeks or months to heal with or without permanent scars left behind. Furthermore, no adverse effects were found in most the studies (Examples I to V). With a proper adjustment in dosage strength or with use of different metal salts, practically no significant adverse effects are expected.
Accordingly, the present invention provides an extremely effective, efficacious, simple, rapid, novel, safe, inexpensive method for treating both acne and warts by topically applying an effective and safe amount of one or more polyvalent metal compounds in a suitable dosage form to the area of lesion of the acne or warts.
Extremely rapid healing without any significant side effects and without any scar left behind is in most dramatic contrast with the conventional treatment methods discussed above.

In view of the early success for treating aphthous ulcers and herpes simplex described in PCT International Patent Application No. PCT/LJS02/18223, the present invention may also be applied to effectively treat other superficial skin diseases caused by other microorganisms including viruses, fungi and yeasts;
one such disease is rosacea which is often treated topically using similar drugs as for acne, and requires five to eight weeks of treatment for significant response.
The present invention also provides a very surprising and highly effective method for preventing and minimization of scar formation as well as for rapid healing or sloughing of the scar once formed in any skin lesions caused by a disease such as acne and warts or caused following drug treatment, laser treatment, cryotherapy and surgery ("Current Medical Diagnosis and Treatment" by L. M.
Tierney, Jr. et al., Lange Medical Boolcs, NY 2004, pp. 111-113 and 123-125;
"Andrews' Diseases of the Skin, Clinical Pharmacology" by R. B. Odom et al., Philadelphia, 2000, pp. 16, 284-306 and 509-519) by a topical application to the area of the scar containing an effective amount of one or more polyvalent metal compotmds in a suitable dosage form; the method is effective for depigmentation.
Applicant also surprisingly finds that use of one or more safe polyvalent metal compounds in an appropriate dosage form is effective for the prophylaxis and treatment of periodontitis and tooth mobility (Example VI). For periodontitis conventional drug therapy usually employs oral administration of antibiotics that require a prescription and has the implication of developing drug resistance.
For tooth mobility it seems that there is no effective drug treatment and the disease is generally considered to be irreversible. Thus, the present invention in the above dental care represents a major unprecedented advance in dentistry. The present method can also be used for promoting health of oral mucous membranes and tissues by regular use of tooth paste, mouth wash, gel or paste that contains an effective and safe amount of a magnesium compound.
Detailed Description of the Invention As used herein, the word "treatment" or "treating" includes ameliorating the symptoms of, curing or healing, and preventing the development of a given disease such as acne and warts. The phrase "effective amount" refers to that amount of a compound which is sufficient to effect safe treatment when administered to a mammal in need of such treatment or prevention. The word "prevention" refers to prophylaxis. The word "scar" refers to a mark left on the skin after a wound, burn, ulcer, pustule, lesion, etc. has healed. The words "healing or sloughing" as they relate to scar provide regenerating a new slcin tissue to replace the scarred tissue.

As used herein, the phrase "polyvalent metal compound" refers to any organic or inorganic polyvalent compound that has the beneficial therapeutic properties described herein. Polyvalent metal compounds include, but are not limited to, aluminum compounds, magnesium compounds, zinc compounds, calcium compounds, bismuth compounds, titanium compounds, copper compounds, manganese compounds, iron compounds, chromium compounds, selenium compound, and barium compounds. A polyvalent compound can be an inorganic or organic salt, an oxide or a complex. Ideally the counter ion to a metal or the ligand moiety to a metal is also therapeutically active or can enhance the therapeutic activity of the metal moiety. One such example may be magnesium salicylate since salicylate is known to have an anti-inflammatory property. Any polyvalent metal compound known to date to have effective therapeutic properties described in this invention is excluded from the present invention.
Suitable dosage forms of one or more polyvalent metal compounds include, but are not limited to, a liquid solution or mixture with various viscosity, a suspension, a gel, a cream, a lotion, an emulsion, a paste, a spray, and a medicated bandage or patch. Pure fine powders or diluted fine powders can also be applied to the open lesion area. The method to prepare a dosage form is based on the standard principles and methods described in various pharmaceutical literature.
It is impossible to list all of the potential polyvalent metal compounds that may be useful in the present invention. Virtually all of the examples of polyvalent metal compounds described below are listed in standard references ("Martindale, The Extra Pharmacopoeia", edited by J.E.F. Reynolds, The Pharmaceutical Press, London, 1989; "Martindale, the Complete Drug Reference," edited by K. Parfitt, Pharmaceutical Press, London, 1999; "The Merclc Index", Merck & Co., Inc., Whitehouse Station, New Jersey, 2001). Complexes of a polyvalent metal compound with various amino acids are also included in this invention.
W one embodiment of the invention, the therapeutically effective compound is selected from the group consisting of bismuth subsalicylate, bismuth chloride, bismuth oxide, bismuth subcarbonate, bismuth subgallate, bismuth subnitrate, bismuth phosphate, bismuth aluminate, bismuth salicylate, bismuth tribromophenate, bismuth dipropylacetate, bismuth citrate, bismuth subcitrate, bismuth ascorbate, bismuth subcarbonate, bismuth tartrate, colloidal bismuth subcitrate, and other bismuth-containing compounds.
In another embodiment of the invention, the therapeutically effective compound is selected from the group consisting of zinc sulfate, zinc acetate, zinc gluconate, zinc chloride, zinc carbonate, zinc oxide, zinc oleate, zinc stearate, zinc propionate, zinc salicylate, zinc undecenoate, and other zinc-containing compounds.

In another embodiment of the invention, the therapeutically effective compound is selected from the group consisting of magnesium acetate, magnesium ascorbate, magnesium carbonate, magnesium chloride, magnesium citrate, magnesium stearate, magnesium gluconate, magnesium hydroxide, magnesium salicylate, magnesium sulfate, magnesium lactate, magnesium oxide, and other magnesium-containing compounds. .
In another embodiment of the invention, the therapeutically effective compound is selected from the group consisting of aluminum acetate, aluminum carbonate, aluminum chloride, aluminum potassium sulfate, aluminum glycinate, aluminum hydroxide, aluminum lactate, aluminum oxide, aluminum subacetate, aluminum sulfate, aluminum salicylate, aluminum ammonium sulfate, aluminum phosphate, and other aluminum-containing compound.
In another embodiment of the invention, the therapeutically effective compound is selected from the group consisting of calcium acetate, calcium alginate, calcium benzoate, calcium carbonate, calcium chloride, calcium citrate, calcium gluconate, calcium hydroxide, calcium lactate, calcium phosphate, calcium stearate, calcium sulfate, calcium salicylate calcium oxide, and other calcium-containing compounds.
In another embodiment of the invention, the therapeutically effective compound is selected from the group consisting of copper gluconate, copper salicylate, copper sulfate, and other copper-containing compounds.
In one embodiment of the invention, the therapeutically effective compound is selected from the group consisting of titanium dioxide, titanium peroxide, titanium salicylate, titanium tannate, and other titanium-containing compounds.
In another embodiment of the invention, the therapeutically effective compound is selected from the group consisting of ferric chloride, fernc citrate, fernc oxide, fernc sulfate, ferrous ascorbate, ferrous carbonate, ferrous sulfate, ferrous gluconate, ferrous fumarate, ferrous glycine, and ferrous lactate, and other ferrous- or ferric-containing compounds.
In another embodiment of the invention, the therapeutically active compound is selected from the group consisting of manganese acetate, manganese benzoate, manganese borate, manganese carbonate, manganese salicylate, manganese bromide, manganese iodide and manganese diiodide, and other manganese-containing compounds.
In another embodiment of the invention, the therapeutically active compound is selected from the group consisting of chromium potassium sulfate, chromium sulfate, chromium trichloride, chromium piconilate and chromium trioxide, and other chromium-containing compounds.

In another embodiment of the invention, the therapeutically active compound is selected from the group of barium sulfate, barium hydroxide, barium chloride, barium carbonate and barium sulphide, and other barium-containing compounds.
Generally, the concentration of a polyvalent metal compound for the treatment of acne, warts and rosacea and for the prevention of scar formation, for depigmentation (Example I) or for the healing or elimination of the scar formed or for the prophylaxis and treatment of periodontitic and tooth mobility in a dosage form will be about 0.001 % to about 50% by weight. Other embodiments contain about 0.1% to about 40%, about 0.5% to about 30%, or about 1.0% to about 10%
by weight of polyvalent metal compounds. An effective amount of one or more polyvalent metal compounds may also be applied daily to vulnerable skin areas for prophylactic purpose in acne management or to the gum and teeth for prevention of periodontitis and tooth mobility, as well as for promoting healthy growth of oral tissue. Also, any compound or compounds that may further enhance the efficacy of the polyvalent compounds in the treatment of acne, warts, periodontitis or tooth mobility as well as in the promotion of health of oral mucous membranes and tissues can also be incorporated into the dosage form; this may include an anti-inflammatory compound. Skin-peeling compounds such as lactic acid, citric acid and salicylic acid as well as other absorption enhancers such as glycyrrhizin may also be added to increase the absorption through the skin. The present invention is also useful for prevention and treatment of scar and for depigmentation.
The present invention~is illustrated by the following non-limiting examples.
The percentages of ingredients are by weight.
Example I
An Adueous Glycerin Solution Containing 10% Aluminum Potassium Sulfate, 8% Magnesium Sulfate and 1 % Zinc Gluconate for Acne Treatment and for Depigmentation The above solution containing about 70% of glycerin was topically applied a once to three adults with an inflammatory papular acne on the face. The papule in two adults was found to disappear the following day with no flare-ups in the following weeks. The third adult had the redness and bump of a papule markedly reduced the following day. Without any additional treatment the redness and bump were completely gone after about ten days.
The fourth adult applied the solution to the area of lesion with an inflammatory papule three times a day. The next day there was a dry dark crust (about 0.4 cm in diameter) formed, and no pain was noted upon~touch. The crust sloughed off in about four days without any scar left.

The fifth adult applied the solution about twice a day to the lesion after squeezing out the typical pus from a pustular acne. A dry dark crust (about 0.5 cm in diameter) was formed the next day and no pain was noted afterwards. The acne might be considered "healed" on the second day in this adult although it took about one week to have the scar completely sloughed off; this kind of rapid healing without scarring also occurred in a sixth subject. The solution was applied to a subject with a facial scar (about 0.25 cm in diameter) due to the earlier acne. The scar completely disappeared after about 3 weeks of application. Thus, the solution is effective for depigmentation.
Example II
A Glycerin Solution Containing 10% Aluminum Potassium Sulfate and 10% Magnesium Sulfate for Treatment of Acne The above solution was applied once prior to bedtime to each of the four small inflammatory papular acnes on the forehead of a female adult. The acnes were found to completely disappear the following morning, indicating complete cure in about eight hours just after one treatment. The above solution was simply prepared by dissolving the two metal compounds in glycerin.
Example III
Aluminum Potassium Sulfate for Acne Treatment A small amount of a 20% aqueous paste of aluminum potassium sulfate prepared with 5% hydroxypropylmethylcellulose as a thickening agent was applied to the area of acne lesion on the face of a male adult after squeezing out the pus from a pustular acne. On the second day, the area of lesion was dry and the previous redness was much reduced. After two more applications, on the second day, the lesion was found to completely heal without any scar left on the third day. In another adult a mixture containing 15% aluminum potassium sulfate, 10% water and 75% glycerin was found to be lughly effective in reducing acne lesions when applied about once daily for several days.
Example IV
Magnesium Chloride for Severe Acne A solution containing 30% magnesium chloride hexahydrate, 10% water and 60% glycerin was applied twice daily to a male adult with a chronic severe acne problem (about 40 acnes on one side of the face) for 6 days. A major dramatic effect was observed in terms of reduction in size and number of pustular acnes and redness (inflammation) of the skin. Shin irntation was observed using this medicament. A less-irritating magnesium sulfate is recommended for future use.
Alternatively, the strength of magnesium chloride could be reduced.
Example V
A Polyvalent Metal Sus ep nsion for Treatment of Warts A male adult developed a typical wart with bleeding on his right side of the face for a few weeks. A small amount of a suspension containing about 10%
aluminum potassium sulfate, 10% magnesium sulfate and 2% zinc acetate in glycerin was applied to the area of lesion and covered with a bandage. The following day a hanging dark brown tissue was removed. The metal suspension was applied three times on that day and the lesion was found to begin to dry and to heal.
The suspension was applied two times the following day without a bandage. The area of the lesion got smaller every day and in about one week only a small needle-size bump was present. A 10% aluminum potassium sulfate in glycerin-water mixture was later tried for three days and the lesion was completely healed without any scar left in a few days.
Example VI
Treatment for Periodontitis and Tooth Mobility W one adult with a chronic periodontitis (dull pain felt upon application of pressure or biting the teeth or eating) and a severe tooth mobility, an aqueous gel containing 1.5% of magnesium sulfate was applied to the lesion several times a day.
Dull pain completely disappeared in about one week and tooth mobility improved significantly after about two weelcs of treatment, presumably due to some tissue re-generation and elimination of infection by magnesium sulfate; the gum also appeared much healthier. On another occasion, a minor tooth tenderness was nearly completely relieved after two applications. A significant improvement in periodontitis and tooth mobility was also observed in another subject after one week of treatment.
It is to be understood that the above descriptions are intended to be illustrative, and not restrictive. One skilled in the art will be able to ascertain, without anymore routine experimentation, marry equivalents to the specific embodiments described herein. This is particularly true with the use of other polyvalent metal compounds since a large variety of salts, oxides or complexes not specifically mentioned in this application can be synthesized or perhaps obtained commercially. These equivalents are intended to be encompassed by the following claims.

Claims

1. The use of an effective and safe amount of a salt, oxide or complex of one or more safe polyvalent metal compounds in a suitable topical dosage form for the prophylaxis and treatment of acne in a mammal wherein a percutaneous absorption enhancer and/or a conventional anti-inflammatory compound may also be incorporated.

2. The use of an effective and safe amount of a salt, oxide or complex of one or more safe polyvalent metal compounds in a suitable topical dosage form for the treatment of warts in a mammal wherein a percutaneous absorption enhancer and/or a conventional anti-inflammatory compound may also be incorporated.

3. The use of an effective and safe amount of a salt, oxide or complex of one or more safe polyvalent metal compounds in a suitable topical dosage form for the prophylaxis and treatment of rosacea in a mammal wherein a percutaneous absorption enhancer and/or a conventional anti-inflammatory compound may also be incorporated.

4. The use of an effective and safe amount of a salt, oxide or complex of one or more safe polyvalent metal compounds in a suitable topical dosage form for the prophylaxis and treatment of periodontitis in a mammal wherein a mucous-membrane absorption enhancer and/or anti-inflammatory compound may also be incorporated.

5. The use of an effective and safe amount of a salt, oxide or complex of one or more safe polyvalent metal compounds in a suitable topical dosage form for preventing scar formation or for healing, or sloughing of the scar once found in a mammal or for depigmentation, wherein a percutaneous absorption enhancer and/or a conventional anti-inflammatory compound may also be incorporated.

6. The use of an effective and safe amount of a salt, oxide or complex of one or more safe polyvalent metal compounds in a suitable topical dosage form for the prophylaxis and treatment of tooth mobility in a mammal wherein a mucous-membrane absorption enhancer and/or anti-inflammatory compound may also be incorporated.

7. The use of claims 1, 2, 3, 4, 5 or 6 wherein the salt, oxide or complex is a bismuth compound, zinc compound, magnesium compound, aluminum compound, calcium compound, titanicum compound, iron compound, copper compound, selenium compound, barium compound, manganese compound or chromium compound.

8. The use of claim 7, wherein a bismuth compound is selected from the group consisting of bismuth subsalicylate, bismuth chloride, bismuth oxide, bismuth subcarbonate, bismuth subgallate, bismuth subnitrate, bismuth phosphate, bismuth aluminate, bismuth salicylate, bismuth tribromophenate, bismuth dipropylacetate, bismuth citrate, bismuth subcitrate, bismuth ascorbate, bismuth subcarbonate, bismuth tartrate and colloidal bismuth subcitrate, and other bismuth-containing compounds.

9. The use of claim 7, wherein a zinc compound is selected from the group consisting of zinc sulfate, zinc acetate, zinc gluconate, zinc chloride, zinc carbonate, zinc oxide, zinc oleate, zinc stearate, zinc propionate, zinc salicylate, zinc undecenoate, and other zinc-containing compounds.

10. The use of claim 7, wherein a magnesium compound is selected from the group consisting of magnesium acetate, magnesium ascorbate, magnesium carbonate, magnesium chloride, magnesium citrate, magnesium stearate, magnesium gluconate; magnesium hydroxide, magnesium salicylate, magnesium sulfate magnesium salicylate, magnesium lactate, magnesium oxide, and other magnesium-containing compounds.

11. The use of claim 7, wherein an aluminum compound is selected from the group consisting of aluminum acetate, aluminum carbonate, aluminum chloride, aluminum potassium sulfate, aluminum glycinate, aluminum hydroxide, aluminum lactate, aluminum oxide, aluminum subacetate, aluminum sulfate, aluminum salicylate, aluminum ammonium sulfate, aluminum phosphate, and other aluminum-containing compounds.

12. The use of claim 7, wherein a calcium compound is selected from the group consisting of calcium acetate, calcium alginate, calcium benzoate, calcium carbonate, calcium chloride, calcium citrate, calcium gluconate, calcium hydroxide, calcium lactate, calcium phosphate, calcium stearate, calcium sulfate, calcium salicylate, calcium oxide, and other calcium-containing compounds.

13. The use of claim 7, wherein a copper compound is selected from the group consisting of copper gluconate, copper salicylate, copper sulfate, and other copper-containing compounds.

14. The use of claim 7, wherein a titanium compound is selected from the group consisting of titanium dioxide, titanium peroxide, titanium salicylate, titanium tannate, and other titanium-containing compounds.

15. The use of claim 7, wherein an iron compound is selected from a group consisting of ferric chloride, ferric citrate, ferric oxide, ferric sulfate, ferrous ascorbate, ferrous carbonate, ferrous sulfate, ferrous gluconate, ferrous fumarate, ferrous glycine, ferrous salicylate, ferrous lactate, and other iron-containing compounds.

16. The use of claim 7, wherein a manganese compound is selected from the group consisting of manganese acetate, manganese benzoate, manganese borate, manganese carbonate, manganese salicylate, manganese bromide, manganese iodide, manganese diiodide, and other manganese-containing compounds.

17. The use of claim 7, wherein a barium compound is selected from the group consisting of barium sulfate, barium hydroxide, barium chloride, barium carbonate, barium sulphide, and other barium-containing compounds.

18. The use of claim 7, wherein the polyvalent metal compound is selected from chromium potassium sulfate, chromium trichloride, chromium piconilate, chromium trioxide, and other chromium-containing compounds.

19. The use of claim 7, wherein the polyvalent metal compound is selected from aluminum potassium sulfate, aluminum sulfate, aluminum acetate, aluminum chloride, aluminum lactate, aluminum salicylate, aluminum ammonium sulfate, magnesium sulfate, magnesium lactate, magnesium gluconate, magnesium chloride, magnesium acetate, magnesium salicylate, zinc sulfate, zinc acetate, zinc chloride, and zinc gluconate.

20. The use of all of the above claims, wherein the polyvalent metal compounds can range in concentration from about 0.001% to about 50% w/w, the dosage forms include paste, cream, spray, ointment, gel, liquid mixture, lotion, medicated bandage and patch and powders, and comfort to the mammal is provided.

21. The use of an effective and safe amount of a salt; oxide or complex of magnesium in a suitable dosage form for promoting health of oral mucous membranes and tissues and for treating periodontitis and tooth mobility of a mammal wherein the dosage form includes a gel, paste, ointment, suspension, liquid mixture, powder, spray or toothpaste.