GB2354441A - Composition for treating dentine hypersensitivity - Google Patents

Abstract

A composition is provided for treating dentine hypersensitivity, the composition containing a potassium salt and the amino acid L-arginine. The composition may be a dentifrice, which may be in the form of a paste, a gel or a liquid.

Description

2354441 COMPOSITION FOR TREATING DENTINE HYPERSENSITIVITY The present

invention relates to a composition for treating dentine hypersensitivity. In particular, but not exclusively, the invention relates to a dentifrice.

Dentifrices containing potassium salts, such as potassium chloride or nitrate, have been demonstrated under controlled conditions to be effective in the home treatment of the common dental condition known as dentine sensitivity or dentine hypersensitivity. Teeth become sensitive when the enamel surface is lost, for whatever reason, or when gums recede exposing the inner tooth surface known as dentine. Processes known as tubules connect the exposed dentine surface with the inner structures within the vicinity of the pulp. The endings of nerves which conduct pain are located within these inner regions at the distal ends of the tubules. Numerous clinical studies attest to the efficacy of potassium-containing dentiffices in treating the pain of dentine hypersensitivity. These observations appear entirely consistent with the ability of potassium ions to block conduction in a nerve when the potassium ions make direct contact with the nerve.

However, this experimental observation bears little semblance to the clinical reality.

Intuitively, many workers have reasoned that the barriers imposed upon the diffusion of potassium ions along dentinal tubules are too great to allow for accumulation at distant sites. Moreover, any increase in potassium ion concentration would only be transient. Importantly, if potassium ions could accumulate deep within the tooth then it would appear that when tubules are exposed, the tooth could become a "trash can" for all manner of diffusible ions which made contact with the exposed surfaces.

Recently, the diffusion of potassium ions in dentinal tubules was modelled mathematically. From this model it was concluded that the barriers to diffusion, notably that of the outward movement of tubular fluid were formidable. Any accumulation, at best, would be transient, and in any case would not be tolerated by the dynamic environment which exists within the regions of the nerve fibres; that is, rapidly-activated homeostatic mechanisms would act so as to oppose and dilute any accurnulation of ions which resulted in a disturbance of the natural enviromnent. In considering these and other difficulties associated with the "diffusion model", recent findings now allow us to 2 propose a more plausible explanation for the analgesic effect of potassium ions. In this new model, it is the odontoblast, a cellular process extending throughout the dentinal tubule, that occupies a key role as mediating the effects of potassium.

Two findings have led to our new understanding. Firstly, the odontoblast has the capacity to synthesise the analgesic radical, nitric oxide. Secondly, potassium ions can activate the production of nitric oxide.

The odontoblast produces nitric oxide by the catalytic effects of the enzyme, nitric oxide synthase (NOS) upon the amino acid L-arginine, which occurs naturally in saliva and dentinal fluid. However, it was not previously understood how potassium ions could affect this process. Recently, it has been reported that potassium ions can increase the uptake of L-arginine by cellular processes in pulmonary artery endothelial cells.

On the basis of these findings a priori we conclude that the addition of L-arginine to a potassium-containing dentifrice, whether paste, gel or liquid, will result in a greater availability of the substrate L-arginine for conversion by the NOS-containing odontoblasts to produce nitric oxide. Whereas currently-available potassium-containing dentiffices (e.g. the toothpaste sold under the trade mark Sensodyne F) take several weeks to produce benefit in the treatment of dentine hypersensitivity, we believe our invention will result in a faster onset of analgesic relief.

According to the present invention there is provided a composition for treating dentine hypersensitivity that contains a potassium salt and the amino acid L- arginine.

The potassium salt stimulates the production of nitric oxide in the odontoblast, whilst the provision of L-arginine results in a greater availability of that amino acid for conversion into nitric acid. The quantity and rate of production of nitric oxide is therefore increased, providing more rapid and effective analgesic relief.

The composition may be a dentifrice, which may be in the form of a paste, a gel or a liquid. Alternatively, it may be in any other form, for example a mouthwash, a treatment applied to the teeth, or a chewing gum.

3 The composition may also include other substances for strengthening, cleaning, brightening or protecting the teeth, for example fluoride (sodium monofluorophosphate), calcium (calcium glycerophosphate) and an antibacterial agent (for example, that sold under the trade mark Triclosan).

The potassium salt may be potassium chloride, tripotassiurn citrate monchydrate or potassium nitrate, which may be provided at concentrations of 1.8%-7.5%, preferably 3.75%, w/w potassium chloride; 2.6%-10.7%, preferably 5.3 5% w/w tripotassiurn citrate monohydrate; or 2.5%-l 0. 1%, preferably 5.05%, w/w potassium nitrate.

The L-arginine may be included in the basic salt form, such as arginine hydrochloride, which may be provided at a concentration of 7.5%-3 0%, preferablyl 5.0%, w/w.

Alternatively, the L-arginine is provided in the form of an L-arginine precursor: for example, the L-arginine may be incorporated within a peptide. Alternatively, the L arginine may be provided in the form of a protamine.

Advantageously, the composition comprises a toothpaste or tooth gel that contains per 50g portion of the composition a quantity of potassium chloride in the range 4-1 00mg, preferably 10-40mg, more preferably approximately 20mg, and a quantity of arginine hydrochloride in the range 15-300mg, preferably 40-150mg, more preferably approximately 75mg.

Advantageously, the composition comprises a mouthwash that contains per 20g portion of the composition a quantity of potassium chloride in the range 4- 1 00mg, preferably 10 40mg, more preferably approximately 20mg, and a quantity of arginine hydrochloride in the range 15-300mg, preferably 40-150mg, more preferably approximately 75mg.

By way of example, embodiments of the invention will now be described.

The composition may be in the form of a toothpaste or a gel having the following ingredients: calcium carbonate; water; sorbitol; glycerin; sodium lauryl sulfate; hydrated silica; sodium monofluorophosphate; arginine hydrochloride; potassium chloride; calcium glycerophosphate; sodium hydroxide and an antibacterial agent.

4 Alternatively, the composition may be in the form of a liquid, for example a mouthwash, having the following ingredients: water; alcohol; sorbitol; glycerin; sodium lauryl sulfate; sodium fluoride; arginine hydrochloride; potassium chloride; sodium saccharin; polysorbate; sodium benzoate; disodium phosphate; cetylpyridinium chloride and an 5 antibacterial agent.

Further alternative formulations are of course possible: for example, the composition may be in the form of a gel or liquid that is painted onto the teeth to remain in place semipermanently, or a chewing gum.

In each case, the composition contains the amino acid L-arginine, for example in a basic salt form, such as arginine hydrochloride, and a potassium salt, for example potassium chloride, which serves as a source of potassium ions (K'). The precise quantity of each of these two substances is thought not to be critical, but in the case of a dentifrice that is designed to be used once or twice per day, the concentration is preferably designed to provide a dose per use in the following ranges:

arginine hydrochloride: 7.5%-30% w/w, preferablyl5.0% w/w.

potassium chloride: 1.8%-7.5% w/w, preferably 3.75% w/w.

For example, the composition may be in the form of a toothpaste, in which 1 OOg of the product contains 4g potassium chloride (4% w/w) and 15g arginine hydrochloride (15 % w/w). A typical 500mg portion of the toothpaste will therefore contain 20mg potassium chloride and 75mg arginine hydrochloride.

The preferred ranges for these active ingredients, per 500mg dose of toothpaste are as follows:

Substance A B C potassium chloride 4-1 00mg 10-40mg 20mg potassium chloride (concentration) 0.8-20% 2-8% 4% arginine hydrochloride 15-300mg 40-150mg 75mg arginine hydrochloride (concentration) 3-60% 8-30% 15% In the above table, A is the preferred range, B is the more preferred range and C is the most preferred value.

As a second example, the composition may be in the form of a mouthwash, in which 400ml (400g) of the product contains 0.4g potassium chloride (0.1% w/w) and 1.5g arginine hydrochloride (0.375% w/w). A typical 20ml (20g) portion of the mouthwash will therefore contain 20mg potassium chloride and 75mg arginine hydrochloride.

The preferred ranges for these active ingredients, per 500mg dose of toothpaste are as follows:

Substance A B C potassium chloride 4-100mg 10-40mg 20mg potassium chloride (concentration) 0.02-0.5% 0.05-0.2% 0.1% arginine hydrochloride 15-300mg 40-150mg 75mg arginine hydrochloride (concentration) 0.075-1.5% 0.2-0.75% 0.375% As in the previous table, A is the preferred range, B is the more preferred range and C is the most preferred value.

Without wishing to be bound by theory, the mechanism through which the composition relieves dentine hypersensitivity is thought to be as follows. The L-arginine in the composition supplements that found naturally in saliva and dentinal fluid. The potassium ions encourage the take-up of L-arginine by the odontoblast in the dentinal tubules. Once inside the odontoblast, the L-arginine is acted upon by the enzyme nitric oxide synthase, which acts as a catalyst, stimulating the production of nitric oxide. The nitric oxide diffuses readily through the dentinal fluid to the nerve endings at the inner ends of the tubules, where it has an analgesic effect, thereby providing rapid relief from dentine hypersensitivity.

The L-arginine may be provided either in its basic form or in the form of an L-arginine precursor. The L-arginine may, for example, be incorporated within a peptide (a molecule composed of amino acids in series), particularly a small peptide of, for 6 example, 2 to 4 amino acid units. The naturally-occurring enzyme salivary arginase can degrade the peptide to release or "split-out" the L-arginine.

Alternatively, the L-arginine may be delivered via small basic proteins, known as protamines, which are extremely rich in arginine. Again, the Larginine residues can be 5 split off by the enzyme arginase.

7

Claims (13)

1. A composition for treating dentine hypersensitivity, said composition containing a potassium salt and the amino acid L-arginine.

2. A composition according to claim 1, wherein the composition is a dentifrice.

3. A composition according to claim 1 or claim 2, wherein the potassium salt is included in the form of either potassium chloride, tripotassium citrate monohydrate or potassium nitrate

4. A composition according to claim 3, wherein the potassium salt is included at a concentration of 1. 8%-7.5%, preferably 3.75%, w/w potassium chloride, or 2.6%10.7%, preferably 5.3 5% w/w tripotassium citrate monohydrate or 2.5%l 0. 1 %, preferably 5.05%, w/w potassium nitrate.

5. A composition according to any one of the preceding claims, wherein the L- arginine is included in a basic salt form.

6. A composition according to claim 5, wherein the L-arginine is included in the form of arginine hydrochloride.

7. A composition according to claim 6, wherein the arginine hydrochloride is provided at a concentration of 7.5 %-3 0. 0%, preferably 15. 0%, w/w.

8. A composition according to any one of claims I to 4, wherein the Larginine is included in the form of an L-arginine precursor.

9. A composition according to claim 8, wherein the L-arginine is incorporated within a peptide.

10. A composition according to any one of claims I to 4, wherein the Larginine is included in the form of a protamine.

11. A composition according to any one of claims 8 to 10, wherein the Larginine is provided at a concentration of 7.5%-30.0%, preferably 15.0% w/w.

8

12. A composition according to any one of the preceding claims, wherein the composition comprises a toothpaste or tooth gel that contains per 50g portion of the composition a quantity of potassium chloride in the range 4-100mg, preferably 10-40mg, more preferably approximately 20mg, and a quantity of arginine hydrochloride in the range 15-300mg, preferably 40150mg, more preferably approximately 75mg.

13. A composition according to any one of the preceding claims, wherein the composition comprises a mouthwash that contains per 20g portion of the composition a quantity of potassium chloride in the range 4-1 00mg, preferably 10-40mg, more preferably approximately 20mg, and a quantity of arginine hydrochloride in the range 15-300mg, preferably 40-150mg, more preferably approximately 75mg.