COMPOSITIONS AND METHODS FOR TREATMENT OF ORAL ULCERATION AND ORAL MUCOSITIS

Abstract

An oral rinse including ionic silver as silver citrate complex and acemannan is useful for the treatment of oral ulceration and oral mucositis. The oral rinse has shown effectiveness against fungal and bacteria species such as Candida species, Staphylococcus aureus and Streptococcus pyogenes.

Claims

1. An oral rinse for the treatment of oral ulceration and oral mucositis comprising: (a) silver citrate complex, wherein the silver citrate complex comprises a concentration of ionic silver of about 10 ppm; (b) acemannan, wherein the acemannan has a concentration of about 0.4 w/w %; (c) disodium EDTA; (d) polyvinylpyrrolidone; (e) hyaluronic acid; (f) tris(hydroxymethyl)aminomethane, wherein the tris(hydroxymethyl)aminomethane has a concentration sufficient to produce a pH of about 6 to about 6.6 in the oral rinse.

2. The oral rinse of claim 1, further comprising flavoring agents.

3. The oral rinse of claim 1, further comprising purified water.

4. The oral rinse of claim 1, wherein the oral rinse comprises about 5 to about 10 μg/mL silver citrate complex and about 3 to about 4 mg/mL acemannan.

5. The oral rinse of claim 1, wherein the oral rinse comprises about 3 μg/mL silver citrate complex to about 15 μg/mL and about 1 mg/mL acemannan to about 10 mg/mL acemannan.

6. The oral rinse of claim 1, wherein the oral rinse comprises about 5 mg/mL disodium EDTA, about 2 mg/mL polyvinylpyrrolidone, and about 0.1 mg/mL hyaluronic acid.

7. A method for treating oral ulceration and oral mucositis in an oral cavity of a patient, comprising: contacting the oral cavity of the patient with an amount of the oral rinse of claim 1 for a period of time.

8. The method of claim 7, wherein the amount of the oral rinse is about 10 mL.

9. The method of claim 7, wherein the period of time is about 30 seconds.

10. A method for reducing pain and time to heal in a patient affected by oral ulceration or oral mucositis, comprising: contacting the oral cavity of the patient with an amount of the oral rinse of claim 1 for a period of time.

11. The method of claim 10, wherein the amount of the oral rinse is about 10 mL.

12. The method of claim 10, wherein the period of time is about 30 seconds.

13. A method for treating oral ulceration and oral mucositis in an oral cavity of a patient, comprising: contacting the oral cavity of the patient with an amount of an oral rinse for a period of time, wherein the oral rinse comprises about 3 to about 15 μg/mL silver citrate complex, about 1 to about 10 mg/mL acemannan, disodium EDTA, polyvinylpyrrolidone, hyaluronic acid, and tris(hydroxymethyl)aminomethane.

14. The method of claim 13, wherein the oral rinse comprises about 5 mg/mL disodium EDTA, about 2 mg/mL polyvinylpyrrolidone, and about 0.1 mg/mL hyaluronic acid.

15. The method of claim 13, wherein the oral rinse comprises about 10 μg/mL silver citrate complex and about 4 mg/mL acemannan.

16. The method of claim 13, wherein the oral rinse further comprises a flavoring agents and purified water.

17. The method of claim 13, wherein the amount of the oral rinse is about 10 mL.

18. The method of claim 13, wherein the period of time is about 30 seconds.

19. A method for reducing pain and time to heal in a patient affected by oral ulceration or oral mucositis, comprising: contacting the oral cavity of the patient with an amount of an oral rinse for a period of time, wherein the oral rinse comprises about 3 to about 15 μg/mL silver citrate complex, about 1 to about 10 mg/mL acemannan, disodium EDTA, polyvinylpyrrolidone, hyaluronic acid, and tris(hydroxymethyl)aminomethane.

20. The method of claim 19, wherein the oral rinse comprises about 5 mg/mL disodium EDTA, about 2 mg/mL polyvinylpyrrolidone, and about 0.1 mg/mL hyaluronic acid.

21. The method of claim 19, wherein the oral rinse comprises about 10 μg/mL silver citrate complex and about 4 mg/mL acemannan.

22. The method of claim 19, wherein the oral rinse further comprises a flavoring agents and purified water.

23. The method of claim 19, wherein the amount of the oral rinse is about 10 mL.

24. The method of claim 19, wherein the period of time is about 30 seconds.

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] The current compositions and methods relate to the treatment of oral ulceration and oral mucositis.

[0021] In preferred embodiments, the present compositions include ionic silver at about 10 ppm as a silver citrate complex salt and acemannan at about 0.4 w/w %. Additional excipients include Disodium EDTA, Hyaluronic acid, Polyvinylpyrrolidone (PVP), purified water, a flavoring agent, and a buffer such as tris(hydroxymethyl)aminomethane to bring the pH of the composition to about 6 to 6.7. The pH of the oral mucosae found in literature is between 6.28-7.34 with the mean of 6.78. The compositions coat the oral mucosae exposing bacteria and yeast to ionic silver while also reducing inflammation, pain and discomfort allowing for mucosal healing.

[0022] In additional preferred embodiments, the compositions include silver citrate complex at about 5 to about 10 μg/mL, and acemannan at about 3 to about 5 mg/mL. In further preferred embodiments the compositions may include about 3 μg/mL silver citrate complex to about 15 μg/mL and about 1 mg/mL acemannan to about 10 mg/ml.

[0023] Silver citrate complex as used herein is a silver salt that is a stable mixture of citric acid monohydrate and silver dihydrogen citrate monohydrate providing for the stabilized silver citrate complex. Silver citrate complex is a broad-spectrum antimicrobial silver salt that has been demonstrated to have effect against gram-positive and gram-negative bacteria as well as against yeast and molds and its safety has been described in Health and Consumer Protection Directorate-General Report SCCP/1196/08. The use of silver citrate salts in compositions containing acemannan for treating wounds or lesions have been described in U.S. Pat. Nos. 9,327,029 and 10,272,108, and European Patent Number 2704729. The entire contents of the patent is hereby incorporated by reference. The use of silver citrate complex as a component in the present compositions is for its effect against Candida sp. as well as its broad spectrum anti-bacterial effects.

[0024] Disodium ethylenediaminetetraacetic acid (disodium EDTA) is included in the compositions as a stabilizer. A second stabilizer and dispersant that can be included in the composition is polyvinylpyrrolidone (PVP). Hyaluronic acid can be included as a mucosal coating agent. Further excipients that are present in preferred embodiments include flavoring agents, purified water, and a buffer such as tris(hydroxymethyl)aminomethane. These excipients are all known to be safe for oral administration. In one preferred embodiment, the composition includes 5 mg/mL Disodium EDTA, 0.1 mg/mL Hyaluronic acid, 2 mg/mL PVP, purified water, and sufficient tris(hydroxymethyl)aminomethane to adjust the pH to about 6 to 6.6.

[0025] In order to prepare the compositions there are several methods that would be acceptable to one knowledgeable and skilled in the art. One such method would consist of creating an acemannan phase followed by addition of the silver salt phase. Using a phased approach for composition preparation, the acemannan phase can be compounded at a level sufficient to provide the desired concentration of the final product.

[0026] In preferred embodiments, the compositions are administered orally by swishing in the oral cavity for about 30 seconds and then expectorating the material. This may be repeated on multiple occasions throughout the day, preferably about 4 times, including after meals and at bedtime. The treatment may be extended for a number of days and in certain preferred embodiments lasts for 14 days. In preferred embodiments, a dose of about 10 mL (or 2 tsp) is administered, which contains 100 μg of silver and 40 mg of acemannan.

Example 1

[0027] In the examples below, ATCC means American Type Culture Collection, (Manassas, Va.), CAMHB means Cation-adjusted Mueller-Hinton Broth, and LHB means lysed horse blood.

[0028] The purpose of this experiment was to determine the potency of one embodiment of the oral rinse on different Candida species, namely Candida albicans.sub.ATCC 10231 and ATCC 24433, Candida glabrata.sub.ATCC 15126, Candida krusei (Issechenkia orientalis).sub.ATCC 6258, Candida parapsilosis.sub.ATCC 22019, and Candida tropicalis.sub.ATCC 1369, to determine the minimum inhibitory concentration (MIC) of the oral rinse on each species. The oral rinse was compared to current antifungal treatments on the market.

[0029] The embodiment of the oral rinse 150528 tested in this experiment included 10 μg/mL silver citrate complex, 3 mg/mL acemannan, 5 mg/mL Disodium EDTA, 0.1 mg/mL Hyaluronic acid, 2 mg/mL PVP, 3.5 mg/ml of masking and cherry flavor, purified water, pH adjustment with tris(hydroxymethyl)aminomethane to a pH of 6.59. The current antifungal treatments that were tested and compared were Fluconazole (Sigma-Aldrich, Cat: PHR1160-1G, Lot LRAA6502) a Nystatin suspension (Sigma-Aldrich, Cat: N6261-SMU, Lot 020M13491V), and Gentian Violet (1% Humco, Cat: NDC 0395-1003-92, Lot547845).

[0030] The antimicrobial activity of the oral rinse solution as described above, Example 1, was tested using the micro-tube dilution method described in the Method for Determination of Broth Dilution MICs of Antifungal agents for fermentative yeasts, published by the European Committee for Antimicrobial Susceptibility Testing (EUCAST). This method was used to determine the minimal inhibitory concentrations (MICs) for the antimicrobial agents listed in Table 1 below. In brief, a standard inoculum of each microorganism was prepared by diluting a 0.5 MacFarland turbidity standard of the microorganism 1:100 in RPMI media without sodium bicarbonate plus 2% glucose. Then, 100 μL of the standard inoculum was added to equal volumes of two-fold serial dilutions of the oral rinse solution or controls, and the plates were incubated at 35° C. for 48 hours. MICs were determined photometrically as the lowest antimicrobial agent concentration (last well in the dilution series) that inhibited OD530 absorbance at least 50%. Each experiment was performed three times, with each antimicrobial agent tested in duplicate or triplicate.

[0031] Table 1 below shows the average MIC for each of four tested products—oral rinse, Fluconazole, Nystatin, and Gentian Violet, against each of five different Candida species.

TABLE-US-00001 TABLE 1 Standard MIC (mg/L) Mean Deviation Candida albicans Fluconazole 1.2 0.4 N = 6 ATCC 10231 Nystatin 3.9 1.7 N = 9 Gentian Violet 0.3 0.0 N = 6 Oral rinse 150528 0.0007 0.0003 N = 9 Candida albicans Fluconazole 0.5 0.0 N = 6 ATCC 24433 Nystatin 4.8 1.6 N = 9 Gentian Violet 0.3 0.0 N = 6 Oral rinse 150528 .002 .001 N = 9 Candida glabrata Fluconazole 7.3 1.6 N = 6 ATCC 15126 Nystatin 2.7 0.7 N = 9 Gentian Violet 1.02 .32 N = 6 Oral rinse 150528 0.0008 0.0002 N = 9 Issatchenkia Fluconazole 24 9 N = 6 orientalis Nystatin 5.4 1.3 N = 9 ATCC 6258 Gentian Violet 0.3 0.0 N = 6 (formerly known as Oral rinse 150528 0.03 0.01 N = 9 Candida krusei) Candida Fluconazole 1.2 .4 N = 6 parapsilosis Nystatin 2.7 0.7 N = 9 ATCC 22019 Gentian Violet 0.2 0.0 N = 6 Oral rinse 150528 0.03 0.03 N = 9 Candida Fluconazole 0.5 0.0 N = 6 tropicalis Nystatin 2.2 0.8 N = 9 ATCC 1369 Gentian Violet 0.3 0.2 N = 6 Oral rinse 150528 0.14 0.03 N = 9

[0032] Results show that the oral rinse has antifungal activity against five common Candida species. The oral rinse was three to several thousand times more potent than Fluconazole and fifteen to several thousand times more potent than Nystatin.

Example 2

[0033] This experiment tested two examples of the oral rinse in the treatment of three different Candida organisms associated with oral mucositis. The embodiments of the Oral Rinses tested in this experiment were: [0034] Oral Rinse 170915-10 μg/mL silver citrate complex, 4 mg/mL acemannan, 5 mg/mL Disodium EDTA, 0.1 mg/mL Hyaluronic acid, 2 mg/mL PVP, 5.75 mg/ml of masking and cherry flavor, purified water, pH adjustment with tris(hydroxymethyl)aminomethane to a pH of 6.36. [0035] Oral Rinse 170719-8 μg/mL silver citrate complex, 3.9 mg/mL acemannan, 5 mg/mL Disodium EDTA, 0.1 mg/mL Hyaluronic acid, 2 mg/mL PVP, 5.75 mg/ml of masking agent and cherry flavor, purified water, pH adjustment with tris(hydroxymethyl)aminomethane to a pH of 6.38.

[0036] The antimicrobial activity of two oral rinse solutions as described above, Example 2, was tested using the microtube dilution method described in the Clinical and Laboratory Standards Institute (CLSI) Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts, M27-4. This method was used to determine the minimal inhibitory concentrations (MICs) for the antimicrobial agents listed in the Table below. In brief, a standard inoculum of each microorganism was prepared by diluting a 0.5 MacFarland turbidity standard of the microorganism 1:100 in RPMI media without sodium bicarbonate. Then, 100 μL of the standard inoculum was added to equal volumes of two-fold serial dilutions of the silver API (active pharmaceutical ingredient, silver citrate complex), controls, or the oral rinse solution, and the plates were incubated at 35° C. for 24 hours. MICs were determined photometrically as the lowest antimicrobial agent concentration (last well in the dilution series) that inhibited OD.sub.530 absorbance at least 50%. Each experiment was performed three times, with each antimicrobial agent tested in duplicate or triplicate.

[0037] Table 2 below shows the average MIC for each of five tested products, two controls, two oral rinses and the API silver citrate complex alone, against each of three different Candida species.

TABLE-US-00002 TABLE 2 Standard MIC (mg/L) Mean Deviation Candida albicans Silver citrate complex 0.234 0.000 N = 6 ATCC 24433 Fluconazole 0.583 0.714 N = 6 Flucytosine 0.250 0.137 N = 6 Oral rinse 170915 0.001 0.001 N = 9 Oral rinse 170719 0.002 0.001 N = 9 Candida Silver citrate complex 0.088 0.032 N = 6 parapsilosis Fluconazole 1.667 0.516 N = 6 ATCC 22019 (Control Range- 0.5-4.0) Flucytosine 0.063 0.000 N = 6 (Control Range- 0.06-0.25) Oral rinse 170915 0.002 0.001 N = 9 Oral rinse 170719 0.003 0.001 N = 9 Issatchenkia Silver citrate complex 0.117 0.000 N = 6 orientalis Fluconazole 14.667 3.266 N = 6 ATCC 5258 (Control Range- (formerly known as 8-64) Candida krusei) Flucytosine 3.667 0.816 N = 6 (Control Range- 4-16) Oral rinse 170915 0.003 0.002 N = 9 Oral rinse 170719 0.004 0.001 N = 9

Example 3

[0038] This experiment tested an example of the oral rinse in the treatment of Group A Strep that can be associated with oral mucositis. The embodiment of the Oral Rinse 141106 tested in this experiment included 10 μg/mL silver citrate complex, 4 mg/mL acemannan, 5 mg/mL Disodium EDTA, 0.1 mg/mL Hyaluronic acid, 2 mg/mL PVP, 5.75 mg/ml of masking and cherry flavor, purified water, pH adjustment with tris(hydroxymethyl)aminomethane to a pH of 6.38.

[0039] The antimicrobial activity of an oral rinse as described herein in Example 3, was tested using the microtube dilution method for determining minimal inhibitory concentrations (MIC) listed in the chart below. In brief, a standard inoculum of each microorganism was prepared by diluting a 0.5 MacFarland turbidity standard of the microorganism 1:100 in standard growth media. Then, 100 μL of the standard inoculum was added to equal volumes of two-fold serial dilutions of the oral rinse solution, and the plates were incubated at 35° C. for 48 hours. MICs were determined visually as the lowest antimicrobial agent concentration (last well in the dilution series) that inhibited growth. Each experiment was performed five times, with each organism tested in replicates of six. Mixtures demonstrating no growth remained clear while mixtures exhibiting growth turned cloudy.

[0040] Table 3 below shows the average MIC for oral rinse 141106 against Group A Strep and Candida spp.

TABLE-US-00003 TABLE 3 MIC (mg/L) Oral Rinse Mean SD Streptococcus pyogenes Oral rinse-141106 0.235 .080 (Grp A Strep) N = 30 Candida spp (Control) 0.282 .064

Example 4

[0041] This experiment tested an example of the oral rinse in the treatment of oral mucositis. The embodiment of the oral rinse 150528 tested in this experiment included 10 μg/mL silver citrate complex, 3 mg/mL acemannan, 5 mg/mL Disodium EDTA, 0.1 mg/mL Hyaluronic acid, 2 mg/mL PVP, 3.5 mg/ml of masking and cherry flavor, purified water, pH adjustment with tris(hydroxymethyl)aminomethane to a pH of 6.59.

[0042] The subject was a 69-year-old white female with diabetes and a 6-year history of reoccurring oral mucositis and candidiasis. She was eventually evaluated by an EENT and a biopsy was completed of her cheek and tongue. She was diagnosed with mucosal erosion, hyperparakeratosis, chronic mucositis and chronic candidiasis in 2011. Patient used dexamethasone rinse (0.5 mg/ml) two times per day for 6 years as needed for pain and inflammation and used chlorhexidine rinse as needed as well. She had also been treated for oral candidiasis with fluconazole twice. Patient could not eat anything spicy, crunchy, or carbonated during this time and could only use Biotene toothpaste. Her gums and tongue were swollen from blisters, and she was in considerable pain. Patient rated her pain on a scale from 1-10, with 10 being the worst, as an 8-10 at various times before using a rinse. Also, before using the oral rinse, the patient had blisters on the inside of her mouth, white streaks running from her gums to her lips, and her tongue was swollen and erythematous.

[0043] The patient's treatment regimen with the oral rinse was to swish and spit 10 milliliters three times a day for 7 days. However, after a couple days of treatment, patient reduced it to only twice a day to conserve what was left of the product. After treatment with the oral wash, patient experienced a 90% reduction in swelling and lesions. All of the patient's symptoms (blisters, swelling, and erythematous) resolved except the white streaks on her gums Immediately upon the first use of oral rinse, patient's pain reduced to a 5 where previously it was at an 8-10. Patient stated that she experienced more relief with the oral rinse than she had with any other previous treatment.

Example 5

[0044] This experiment tested an example of the oral rinse in the treatment of recurrent oral ulceration. The embodiment of the oral rinse 141201 tested in this experiment included 5 μg/mL silver citrate complex, 3 mg/mL acemannan, 5 mg/mL Disodium EDTA, 0.1 mg/mL Hyaluronic acid, 2 mg/mL PVP, 3.5 mg/ml of masking and peppermint flavor, purified water, pH adjustment with tris(hydroxymethyl)aminomethane to a pH of 6.48.

[0045] The subject was a 52-year-old white female with a chronic history of reoccurring mouth ulcers. She was evaluated by her dentist and diagnosed with a dormant viral infection with outbreaks associated with stress and immune suppression. Patient used various treatments including steroids, antivirals and coating and protecting agents. Duration of ulcers usually persist for 7-10 days prior to clearing.

[0046] The patient's treatment regimen with the oral rinse was to swish and expectorate 10 milliliters three times a day for 2-3 days. The patient reported that ulcers cleared rapidly with reduction in inflammation and pain. On a pain scale of 0-10 with 10 being the most severe, the patient reported that pre-use pain was at a 5 and following use decreased to a 0-1 providing for excellent pain relief.

Example 6

[0047] The purpose of this experiment was to determine the potency of one embodiment of the oral rinse on three common gram-positive cocci species tested: Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes by determining the minimal inhibitory concentrations (MIC) of the oral rinse on each species. The oral rinse was compared to vancomycin, a common antibiotic used to treat various infections.

[0048] The embodiment of the oral rinses (170915 and 171003) tested in this experiment included 10 ug/mL silver citrate complex, 4 mg/mL acemannan, 5 mg/mL Disodium EDTA, 0.1 mg/mL Hyaluronic acid, 2 mg/mL PVP, 3.5 mg/ml of masking and cherry flavor, purified water, and pH adjustment with tris(hydroxymethyl)aminomethane to a pH of 6.36 and pH of 6.40, respectively. The vancomycin control (Sigma-Aldrich, Cat: PHR1160-1G, Lot LRAA9717, 5120 ppm) was reconstituted 20.5 mg/4 mL RO water.

[0049] The antimicrobial activity of this embodiment of the oral rinse solution was tested using the microtube dilution method for determining minimal inhibitory concentrations (MIC) described in the Clinical and Laboratory Standards (CLSI) Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, M07, 11th ed, Approved January 2018. In brief, a standard inoculum (125 μL of a 1:150 dilution of a 0.5 MacFarland turbidity standard) of each microorganism was prepared in the growth media recommended by CLSI M07 and added to equal volumes of two-fold serial dilutions of CelaCare OR, and the vancomycin control. MICs were determined visually and turbidometrically at OD530 nm as the highest dilution of CelaCare OR, or vancomycin (control) that showed at least half the turbidity, or 50% OD530 of the no drug control. Each experiment was performed three times, with each antimicrobial agent tested in triplicate. The MIC dilution was converted to μg/mL by multiplying the neat drug (Ag.sup.+) concentration by the dilution appropriate dilution factor. The results are shown in Table 4 below.

TABLE-US-00004 TABLE 4 MIC (mg/L) - CelaCare Oral Rinse and Vancomycin (Control) Organism Device Mean SD Staphylococcus aureus N = 3 × 3 (9) ATCC 29213 OR - 170915 1.3 0.0 Media - CAMHB OR - 171003 1.2 0.0 No LHB Vancomycin (Control 0.5-2.0) 0.7 0.2 Streptococcus N = 3 × 3 (9) pneumoniae OR - 170915 1.25 0.0 ATCC 49619 OR - 171003 0.81 0.48 Media - CAMHB + LHB Vancomycin (Control 0.06-0.5) 0.13 0.04 Streptococcus N = 3 × 3 (9) pyogenes OR - 170915 0.2 0.1 ATCC 12384 OR - 171003 0.2 0.1 Media - CAMHB + LHB Vancomycin 0.7 0.2

[0050] This example demonstrates that the oral rinses containing silver-citrate complex and acemannan (OR 170915 and 171003) demonstrate antibacterial activity against three common gram-positive cocci species tested: Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes. These oral rinses are 3.5× more effective than vancomycin (control) in its antimicrobial activity against Streptococcus pyogenes (the cause of strep throat).

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