Oral composition

Abstract

The present invention provides a mouthwash composition comprising a heterogeneous gel, wherein said heterogeneous gel comprises at least two gelling agents and two or more active ingredients, and wherein the composition provides the differential release of the active ingredients over a period of time.

Claims

1. An edible mouthwash composition comprising a heterogeneous gel comprising two or more gels which are blended together but not homogenized, and two or more active ingredients: wherein said heterogeneous gel comprises: (i) a first gel comprising a surfactant, a first gelling agent and one or more active ingredients; and (ii) a second gel comprising a second gelling agent and one or more active ingredients, wherein the first and second gelling agents are selected from xanthan gum, gellan gum, gum arabic, guar gum, locust bean gum, methylcellulose, carboxymethyl cellulose, gelatin, carrageenan, agar and pectin; one of said active ingredients is xylitol; the other of said active ingredient(s) is selected from the group consisting of flavourants, antiseptics, antibiotics, anticaries agents, tartar control agents, oral cleaning agents, abrasive agents, desensitizing agents, sweetening agents, medicaments, pro-drugs, activating agents for activating pro-drugs, pH-buffering agents, cooling agents, herbal agents, vitamins and combinations thereof, the composition has a viscosity of from 1000 to 2000 c.p. at 20° C.; and the composition provides differential release of the active ingredients over a period of time.

2. The mouthwash composition according to claim 1, wherein said composition sequentially releases an effective amount of said surfactant and an effective amount of at least one of said one or more active ingredients over a period of time.

3. The mouthwash composition according to claim 1, wherein the composition forms a film upon contact with a buccal surface.

4. The mouthwash composition according to claim 1, wherein the heterogeneous gel comprises methylcellulose and xanthan gum, or wherein the heterogeneous gel comprises gellan gum.

5. The mouthwash composition according to claim 1, wherein said composition comprises a sweetening agent.

6. The mouthwash composition according to claim 1, wherein the heterogeneous gel contains a pro-drug and an activating agent for activating the pro-drug.

7. The mouthwash composition according to claim 1, wherein the composition is in the form of a jelly or the composition is the form of a chewable sweet having a mass of from 5 to 15 g.

8. A method of preparing a mouthwash composition in the form of a gel as claimed in claim 1, the method comprising: providing a first component; providing a second component; and mixing the first and second components together to provide a heterogeneous mixture, wherein the first and second components each comprises at least one active ingredient, and the composition comprises two or more active ingredients.

9. The method according to claim 8, wherein the first and/or second component is in the form of a gel prior to mixing.

10. The method according to claim 8, wherein the first and/or second component is in the form of a solution comprising a gelling agent.

11. The method of claim 10, further comprising adding a further gelling agent to the heterogeneous mixture prior to allowing the mixture to set.

12. The method according to claim 8, further comprising adding a colouring and/or a flavouring to the heterogeneous mixture.

13. The method according to claim 8, further comprising encapsulating the heterogeneous mixture.

14. A package comprising a single dose or unit of the mouthwash composition as claimed in claim 1.

15. A method of cleaning teeth and/or freshening breath in a subject comprising administering the mouthwash composition as claimed in claim 1.

16. The method according to claim 9, wherein providing the first and/or second components comprises dissolving a gelling agent in water with heating to form a solution and allowing the solution to cool so as to form a gel prior to mixing.

17. The method according to claim 10, wherein the method comprises a further step of allowing the heterogeneous mixture to set.

18. The method according to claim 11, further comprises dispensing the heterogeneous mixture into a mould prior to allowing the mixture to set.

19. The method according to claim 13, wherein encapsulating the heterogeneous mixture comprises injecting the heterogeneous mixture into a hollow shell.

20. The mouthwash composition according to claim 1, wherein said composition further comprises sodium fluoride and a flavorant selected from peppermint oil, menthol, eucalyptol, and thymol.

Description

(1) The invention will now be described by way of example and with reference to the following drawings in which:

(2) FIGS. 1 to 6 are electrospray ionization (ESI) profiles showing the release of molecules from mouthwash compositions in accordance with embodiments of the invention.

(3) FIG. 7 is a plot showing the release profile of glycerol from a sports-gel style mouthwash prepared according to protocol 1B.

(4) FIG. 8 is a plot showing the release profile of sorbitan monolaurate from a sports-gel style mouthwash prepared according to protocol 1B.

(5) FIG. 9 is a plot showing the release profile of xylitol from a sports-gel style mouthwash prepared according to protocol 1B.

(6) FIG. 10 is a plot showing the release profile of eucalyptol from a sports-gel style mouthwash prepared according to protocol 1B.

(7) FIG. 11 is a plot showing the release profile of thymol from a sports-gel style mouthwash prepared according to protocol 1B.

(8) FIG. 12 is a plot showing the relative release profiles of glycerol, sorbitan monolaurate, xylitol, eucalyptol and thymol from a sports-gel style mouthwash prepared according to protocol 1B.

EXAMPLES

Methodology

(9) Three different types of mouthwash were prepared: (1) a sports gel type having relatively low viscosity, (2) a jelly and (3) a lozenge.

(10) 1A. Protocol for the Production of 600 mL of Sports-Gel Style Mouthwash

(11) i. Heat 120 mL of water to 70° C. ii. Add the following components to the water to provide solution A: a. 30,000 mg of xylitol b. 9,000 mg of potassium nitrate c. 7.5 mg of sodium fluoride d. 3.6 mL of colouring—this depends on the intensity of colour desired. Couple with colouring in iv. e. 7,500 mg of methylcellulose ii. Remove solution A from heat and add 120 mL of cold water, setting aside to cool. iv. Heat 360 mL of water to 100° C. v. Add the following components to the water to provide solution B: a. 1,500 μL of sorbitan monolaurate b. 720 μL of peppermint oil—this depends on the strength of the gel desired c. 150 mg of menthol d. 72 μL of eucalyptol e. 18 mg of thymol f. 3.6 mL of food colouring—this depends on the intensity of colour desired g. 1,500 mg of xanthan vi. Remove solution B from heat and set to the side to cool. vii. Once both are cooled, mix together crudely and quantitatively add colouring and peppermint oil to adjust taste.

(12) This sports gel-style mouthwash requires gums to ensure a timely release of each of the active ingredients. Methylcellulose and xanthan gums were chosen for this application.

(13) 1B. Protocol for the Production of 600 mL of Sports-Gel Style Mouthwash

(14) i. Heat 300 mL of water to 100° C. to provide solution A. ii. Heat 300 mL of water to 100° C. to provide solution B. iii. Soak 21.88 g of leaf gelatine leaves in water at room temperature. iv. Add the following components to solution A: a. 50 g xylitol b. 15 g potassium nitrate c. 12.5 mg sodium fluoride d. 2.5 g Gellan type F v. Add the following components to solution B: a. 2.5 mL sorbitan monolaurate b. 250 mg menthol c. 30 mg thymol d. 2.5 g Gellan LT100 e. 35.5 mL of glycerol f. 7.2 mL of peppermint oil—this depends on the strength of the gel desired g. 720 μL of eucalyptol vi. Mix solution A and solution B together, maintaining the temperature at 100° C. The solution will be appear opaque and gelatinous. vii. Remove the leaf gelatine from the cold water and add this to the mixture of solutions A and B formed in step vi. The leaf gelatine should fully dissolve within 2-5 minutes. viii. Once the mixture has a uniform appearance, quantitatively add food colouring. ix. Pour the mixture into moulds and leave to cool.

(15) This sports-gel style mouthwash employs Gellans to allow the timely release of the active ingredients. Gellan Type F (low acyl) and Gellan Type LT100 (high acyl) were chosen.

(16) 2. Protocol for the Production of 600 g of a Jelly-Style Mouthwash

(17) i. Heat 300 mL of water to 100° C. ii. Add the following components to the water to provide solution A: a. 50,000 mg of xylitol b. 15,000 mg of potassium nitrate c. 12.5 mg of sodium fluoride d. 6 mL of colouring—this depends on the intensity of colour desired. Couple with colouring in iv. e. 1,000 mg of Gellan Type F iii. Remove solution A from heat. iv. Heat another 300 mL of water to 100° C. v. Add the following components to the water to provide solution B: a. 2,500 μL of sorbitan monolaurate b. 1.2 mL of peppermint oil—this depends on the strength desired c. 250 mg of menthol d. 120 μL of eucalyptol e. 30 mg of thymol f. 6 mL of food colouring—this depends on the intensity of colour desired g. 1,000 mg of Gellan Type LT100 vi. Mix solution A with solution B and immediately add 5000 mg vegetarian gelling agent. Stir until dissolved, pour into moulds and leave to cool.

(18) The jelly style mouthwash employs Gellans to allow the timely release of the active ingredients. Gellan Type F (low acyl) and Gellan Type LT100 (high acyl) were chosen.

(19) 3. Protocol for the Production of 600 mL of Wine Gum Style Mouthwash:

(20) i. Heat 120 mL of water to 70° C. ii. Add the following components to the water to provide solution A: a. 30,000 mg of xylitol b. 9,000 mg of potassium nitrate c. 7.5 mg of sodium fluoride d. 3.6 mL of colouring—this depends on the intensity of colour desired. Couple with colouring in iv. e. 7,500 mg of methylcellulose iii. Remove solution A from heat and add 120 mL of cold water, setting aside to cool. iv. Heat 360 mL of water to 100° C. Add the following components to the water to provide solution B: a. 1,500 μL of sorbitan monolaurate b. 720 μL of peppermint oil—this depends on the strength of the gel desired c. 150 mg of menthol d. 72 μL of eucalyptol e. 18 mg of thymol f. 3.6 mL of food colouring—this depends on the intensity of colour desired g. 1,500 mg of xanthan h. Remove solution B from heat and set to the side to cool. i. Once both solutions are cooled, mix together crudely and quantitatively add colouring and peppermint oil to adjust taste. j. Hollow out the centre of 600 vegetarian wine gums sufficiently to allow for the injection of 1 g of the mixture. Inject the mixture. k. Melt the unmarked side of the wine gums sufficiently to achieve a sticky surface. Attach to the injected wine gums prepared in vii and hold together for 60 seconds to ensure binding of the two wine gums is complete.

(21) The wine gum style formulation involves the injection of 1 mL of the sports gel formulation into a vegetarian wine gum.

Example Formulations

(22) TABLE-US-00001 TABLE 1 Active Ingredient Formulation of a 12 g sample of sports gel-style mouthwash Formulation per Mass fraction Component dose/mg LD.sub.50 rat (% w/w) Xylitol 600 16,500 mg/kg   5.0% Potassium nitrate 180 3,750 mg/kg   1.5% Sorbitan 30 μL 36,700 μL/kg  0.25% monolaurate Peppermint oil 24 μL 2,426 mg/kg  0.18% Menthol 3 3,300 mg/kg  0.025% Eucalyptol 1.44 μL   2,480 mg/kg  0.011% Thymol 0.36 980 mg/kg 0.0030% Sodium fluoride 0.15 52 mg/kg 0.0013%

(23) TABLE-US-00002 TABLE 2 Active Ingredient Formulation of a 4.4 g sample of jelly-style mouthwash Mass Formulation per fraction Component dose/mg LD.sub.50 rat (% w/w) Xylitol 366.67 16,500 mg/kg 8.33% Potassium nitrate 110 3,750 mg/kg 2.50% Sorbitan 18.33 μL  36,700 μL/kg 0.43% monolaurate Peppermint oil 52.8 μL 2,426 mg/kg 0.39% Menthol 1.83 3,300 mg/kg 0.042%  Eucalyptol 5.28 μL 2,480 mg/kg 0.041%  Thymol 0.22 980 mg/kg 0.0050%  Sodium fluoride 0.092 52 mg/kg 0.0021% 

(24) The concentration of peppermint oil and eucalyptol can be increased to reflect different sensitivities to peppermint.

(25) TABLE-US-00003 TABLE 3 Formulation of peppermint oil for three different strengths of sports gel-style mouthwash Formulation per Mass fraction Formulation dose/mg LD.sub.50 rat (% w/w) ‘100’ 14.4 μL 2,426 mg/kg 0.11% ‘300’   24 μL 2,426 mg/kg 0.18% ‘500’ 43.2 μL 2,426 mg/kg 0.32%

(26) TABLE-US-00004 TABLE 4 Formulation of eucalyptol for three different strengths of sports gel-style mouthwash Formulation per dose/ Mass fraction Formulation mg LD.sub.50 rat (% w/w) ‘100’ 1.44 μL 2,480 mg/kg 0.011% ‘300’  2.4 μL 2,480 mg/kg 0.018% ‘500’ 4.32 μL 2,480 mg/kg 0.033%

(27) TABLE-US-00005 TABLE 5 Formulation of peppermint oil for three different strengths of jelly-style mouthwash Mass Formulation per dose/ fraction Component mg LD.sub.50 rat (% w/w) ‘100’ 17.6 μL 2,426 mg/kg 0.35% ‘300’ 52.8 μL 2,426 mg/kg 0.39% ‘500’ 80.7 μL 2,426 mg/kg 1.65%

(28) TABLE-US-00006 TABLE 6 Formulation of eucalyptol for three different strengths of jelly-style mouthwash Mass Formulation per fraction Formulation dose/mg LD.sub.50 rat (% w/w) ‘100’ 1.76 μL 2,480 mg/kg 0.037%  ‘300’ 5.28 μL 2,480 mg/kg 0.11% ‘500’ 8.07 μL 2,480 mg/kg 0.17%

(29) TABLE-US-00007 TABLE 7 Gel Formulation for a sports gel-style mouthwash 12 g sample Mass Formulation fraction Component per dose/mg LD.sub.50 rat (% w/w) Methylcellulose 150 NA (too high)  2.0% Xanthan  30 NA (too high) 0.20% Water 10754 μL 90,000 mg/kg 89.63%  Colouring  144 μL NA 1.20%

(30) TABLE-US-00008 TABLE 8 Gel formulation for a jelly-style mouthwash based on 4.4 g sample Formulation Mass per dose/ fraction Component mg LD.sub.50 rat (% w/w) Gellan Type F (low acyl) 18.33 NA (too 0.42% (Supplier Cream Supplies) high) Gellan Type LT100 (high 18.33 NA (too 0.42% acyl) high) (Supplier Cream Supplies) Water 3116 μL  90,000 mg/kg 70.82%  Food colouring 240 μL NA 5.45% Platinum Grade Leaf 160.45  NA 3.60% Gelatin (Dr. Oetker) Glycerine (Dr. Oetker) 260 μL 12,600 mg/kg 7.45%
Dissolution Tests
Dissolution Test 1

(31) Six different mouthwash compositions (A-F) were prepared and formulated into 12 g units. Each composition contained a number of different active ingredients having a range of different molecular weights.

(32) A single preparation unit (12 g) was added to a water-based solution maintained at 30° C. and stirred. Samples were removed from the supernatant at intervals forming a time course measurement. Each sample was then subject to electrospray ionization analysis with no preceding separation column. The variation in composition was then observed over time and plotted. The temporal dissolution profile of classes of molecules, grouped by mass (0-100, 100-200 etc.), is shown in FIGS. 1 to 6.

(33) The dissolution profiles show that molecules of different mass class are released at different rates. Some have a single early phase which may be associated with surfactant and surfactant-soluble molecules; others show a later dissolution profile associated with the different phases in the gel formulation. Some mass classes show two peaks with contributions from different phases as they disperse into solution. It is believed that the composition of the film on the surface of the teeth, gum and cheek shows similar temporal dissolution behaviour as the composition of different mass classes in the mouth changes during the consumption of the gel. The film will be transient on the surface, further changing the composition time profile of the components. Any surface properties such as channels for the adsorption of K+ or oppositely charged surface groups and gel-phase species will be attracted and form an enhanced concentration-time profile. Similarly charged surface and gel-phase species will form depleted concentration-time profiles.

(34) Dissolution Test 2

(35) A sports-gel style mouthwash was prepared according to protocol 1B described above. In order to measure the release of the active ingredients from the mouthwash, it was necessary to recreate the mastication conditions of the mouth. The following protocol was employed for this purpose: i. Whilst stirring with a 3.5 cm magnetic stirrer set at the “7” rotation setting, heat 100 mL of water to 37° C. in a beaker. ii. Aspirate 1 mL of solution using a pipette to obtain a standard sample. iii. Add 10 g of the sports-gel style mouthwash prepared according to protocol 1B to the heated water. Aspirate 1 mL of the resultant solution at time intervals of t=10, 20, 40, 60, 90, 120, 150, 180, 210, 240, 270, 300, 360 and 600 seconds, ensuring that the samples are taken from the outermost rim of the beaker.

(36) Prior to mass spectrometry analysis, the samples and standards obtained were diluted 1 part in 10 in acetonitrile (ACN). All concentrations given below for the calibration are of these diluted solutions.

(37) All samples and calibration standards were injected in the following order: triplicate injections of full calibration standards from low to high concentration, triplicate injection of acetonitrile blank, triplicate injection of sample series B in timeline sequence (each with a single blank in between), single injection of full calibration standards from low to high concentration, triplicate injection of blank acetonitrile, triplicate injection of sample series B in timeline sequence (each with a single blank in between). The reason for the second, shorter, series of calibration standards was to determine if there was any significant decrease in sensitivity (indicated by decrease in peak area) during the batch.

(38) The QTOF-UHPLC analysis was conducted using a MaXis HD quadrupole electrospray time-of-flight (ESI-QTOF) mass spectrometer (Bruker Daltonik GmbH, Bremen, Germany) operated in ESI positive-ion MS mode. The QTOF was coupled to an Ultimate 3000 UHPLC (Thermo Fisher Scientific, California, USA). The capillary voltage was set to 4500 V, nebulising gas at 2 bar, drying gas at 10 L/min at 200° C. The TOF scan range was from 50-750 mass-to-charge ratio (m/z). For effective transmission of ions the ion energy was set to 1.0 eV with the collision energy for TOF MS acquisition at 2.0 eV. Liquid chromatography was performed using a Kinetex 1.7 μM, 2.1×100 mm HILIC column (Phenomenex) with a flow rate of 0.4 mL/min at 30° C. and an injection volume of 10 μL. Mobile phases A and B consisted of 50:50 ACN:H.sub.2O with 0.2% v/v formic acid and 10 mM ammonium formate, and 95:5 ACN:H.sub.2O with 0.2% v/v formic acid and 10 mM ammonium formate, respectively. Gradient elution was carried out with 100% mobile phase B until 2 min followed by a linear gradient to 0% B at 12 mins, keeping 0% B up until 15 mins, thereafter returned to 100% B until in 20 mins total run time. The MS instrument was calibrated using a range of sodium formate clusters introduced by 10 μL loop-injection prior to the chromatographic run. The mass calibrant solution consisted of 3 parts of 1 M NaOH to 97 parts of 50:50 water:isopropanol with 0.2% formic acid. The observed mass and isotope pattern perfectly matched the corresponding theoretical values as calculated from the expected elemental formula. Most of the target compounds were detected as [M+H].sup.+ and [M+Na].sup.+ ions. Data processing was performed using the Data Analysis software version 4.3 (Bruker Daltonik GmbH, Bremen, Germany). Quantification was carried out using the peak area in the extracted ion chromatogram (EIC) of the sum of the protonated and sodiated ion of the target compound. The calibration results are shown in Table 9 below.

(39) TABLE-US-00009 TABLE 9 Time injected Calibration range Ingredient (min) (μg/mL) R-squared Thymol 0.8 0-9 0.98 Xylitol 2.5  0-10 0.97 Sorbitan 0.8 0-3 0.99 monolaurate Glycerol 4.0 0-9 0.95 Eucalyptol 0.8 0-9 0.97

(40) The calibration range was in the region of the calibration curve which gave a good linear calibration, and therefore excludes points outside this range. Menthol, potassium nitrate and sodium fluoride were not detected by this method.

(41) Using the mass spectrometry data obtained, it is possible evaluate the release profiles of the active ingredients present in the sports-gel style mouthwash under simulated mastication conditions. A comparison of the individual release rate profiles for each active ingredient demonstrates the differential release profile of the mouthwash composition.

(42) FIG. 7 is a plot showing the release profile of glycerol from a sports-gel style mouthwash prepared according to protocol 1B. Referring to FIG. 7, it can be seen that glycerol immediately releases into the surrounding solution and reaches its effective concentration within seconds to provide a sweet initial flavour in the mouth of the consumer. This will mask the taste of subsequent less pleasant tasting active ingredients. This fast release is due to the low affinity of glycerol for the two gels present in the mouthwash composition, in addition to the high concentration of glycerol in the composition.

(43) FIG. 8 is a plot showing the release profile of sorbitan monolaurate, which acts as a surfactant, from a sports-gel style mouthwash prepared according to protocol 1B. Referring to FIG. 8, it can be seen that a fast release of sorbitan monolaurate occurs. The sorbitan monolaurate must be released quickly because it plays a crucial role in allowing the composition to form a film upon contact with the buccal surface. This film increases the residence time of the other active ingredients present in the mouthwash composition on the buccal surface and can also help to retain the active ingredients on the buccal surface after the majority of the composition has been swallowed. It is therefore important that the sorbitan monolaurate surfactant is released early during mastication to enable the film to be formed as soon as possible.

(44) FIG. 9 is a plot showing the release profile of xylitol, which acts as a sweetening agent, from a sports-gel style mouthwash prepared according to protocol 1B. Referring to FIG. 9, it can be seen that xylitol is released quickly from the mouthwash composition. This fast release can be explained by the low affinity of xylitol, which is negatively charged in aqueous medium, for the gelling agent Gellan type F, which is a hydrophobic polymer. The fast release of xylitol allows any unpleasant or bitter flavours originating from the potassium nitrate or menthol also present to be masked.

(45) FIG. 10 is a plot showing the release profile of eucalyptol, which acts as a flavouring, from a sports-gel style mouthwash prepared according to protocol 1B. In this particular mouthwash composition, eucalyptol is mixed with the gelling agent Gellan LT100, for which it has a relatively high affinity. Referring to FIG. 10, it can be seen that eucalyptol reaches its maximum concentration significantly later than, for example, the glycerol or sorbitan monolaurate. This slower release of eucalyptol is desirable because it allows the flavour to persist over extended periods of mastication.

(46) FIG. 11 is a plot showing the release profile of thymol, which acts as a preservative and antiseptic, from a sports-gel style mouthwash prepared according to protocol 1B. Referring to FIG. 11, it can be seen that thymol also reaches its maximum concentration at a later stage of mastication and therefore that a more gradual release of preservative occurs over time.

(47) FIG. 12 is a plot showing the relative release profiles of glycerol, sorbitan monolaurate, xylitol, eucalyptol and thymol from a sports-gel style mouthwash prepared according to protocol 1B.

(48) A comparison of each of the individual release profiles allows the differential and sequential release of effective amounts of the active ingredients to be observed over time. Thus FIG. 12 shows each of the plots of FIGS. 7-11 on a single plot after peak normalisation. Referring to FIG. 12, it can be seen that the sweetener glycerol is released immediately upon commencing mastication to provide an initial sweet taste. The surfactant sorbitan monolaurate is the next active ingredient to reach an effective concentration, thereby allowing film formation on the buccal surface to occur at an early stage. The sweetener xylitol then the flavouring eucalyptol can be seen to follow the release of the surfactant. Finally, the preservative and antiseptic thymol is the last active ingredient to release. The results therefore show that upon mastication, the mouthwash composition sequentially releases an effective amount of each of the active ingredients over a period of time.