EP2396009A1

EP2396009A1 - Compositions for the treatment of aphthous stomatitis

Info

Publication number: EP2396009A1
Application number: EP10708593A
Authority: EP
Inventors: Monica Bonucci
Original assignee: Individual
Current assignee: Individual
Priority date: 2009-02-12
Filing date: 2010-02-10
Publication date: 2011-12-21
Also published as: ITBO20090070A1; WO2010092534A1

Abstract

Compositions for the treatment of aphthous stomatitis are described comprising a) a zinc salt of a polyhydroxy acid and b) a magnesium salt of a polyhydroxy acid, wherein the components a) and b) are in a v/v ratio of 10:1 to 1 :10. In particular, said compositions have proved to be remarkably effective not only for the surprising swiftness to which the aphthous stomatitis heals, but also for the significant reduction in their subsequent recurrence in time.

Description

COMPOSITIONS FOR THE TREATMENT OF APHTHOUS STOMATITIS

Field of the invention

The present invention relates to compositions for the treatment of aphthous stomatitis. In particular, said compositions have proved to be remarkably effective not only for the surprising swiftness to which aphthous stomatitis recedes, but also for the significant reduction in occurrence of the same over time. State of the art

Aphthous stomatitis is an affection of the oral cavity involving the formation of one or more ulcers. They can even persist for several weeks, leave a scar after healing and can relapse in a few years or can recur continuously, with new lesions appearing before the previous ones have healed. This latter case is referred to as recurrent aphthous stomatitis whose occurrence frequency can lead to extreme cases wherein the affection becomes chronic. Aphthous stomatitis affects both sexes and, while observable at any age, it is more often seen in children and young people. Aphthous stomatitis is hence a specific pathology which presents with swelling, painful ulcers from puπctiform to 2.5crτhsized in diameter, localized on the lips, cheeks, gums, palate and oral cavity floor. Three forms are known: minor, major and herpetiform. The minor form presents with small, painful, round and well-defined recurring ulcers, with raised margins surrounded by a reddened halo and a shallow necrotic central part. The major form is similar to the minor form but the ulcers are larger and deeper, often leaving scars, and can last for several weeks or months. The herpetiform form is the least common and is characterized by small and several ulcers.

The etiology of aphthous stomatitis is currently unknown, while the existence of factors favouring the onset thereof is known, such as conditions of nutrient deficiency, specifically vitamin B12, folic acid and iron, and of stress, local trauma, menstrual periods, hormonal dysfunction, gastrointestinal disturbances, celiac disease, drug taking, intestinal parasites, gastric and/or intestinal malabsorption, physical and mental tiredness, allergies, fever and use of amalgam in dental treatments. For the treatment of aphthous stomatitis, it is known to take analgesics for relieving pain and to undergo a cortisone therapy for controlling inflammation. These therapies, however, are unable to intervene in the causes that trigger aphthous stomatitis, being rather limited to prevent the inflammation from getting any worse. Moreover, cortisone drug administration cannot be continued for long periods particularly in cases where the affected individuals are children, and after it has ceased the ulcers unavoidably reoccur.

Also known are products in spray form for local topical application which form a protective layer on individual ulcers so that the same are isolated to hence facilitate their resorption. Alternatively, patches are known which &re to be applied onto the ulcers and, similarly to the spray, isolate them from contact with food and liquids. Even in this case, the aphthous stomatitis is treated after its onset to avoid contamination and prevent the inflammation from getting any worse. Therefore, the contraindications of cortisone therapy are overcome but only one ulcer per time is treated, simply by physically covering it.

In attempting to intervene at the problem underlying the aphthous stomatitis onset, it was also envisaged to use vitamins able to reduce inflammation. However, known vitamin complexes and food supplements have been also proved to be unsatisfactory as they minimize worsening of the ulcers, but are unable to heal them effectively and rapidly; nor are they able to prevent or even limit their further onset over time, either in terms of number of simultaneous aphthae or in terms of occurrence frequency.

It is therefore an object of the present invention to find a remedy for the treatment of aphthous stomatitis which is rapidly effective, well tolerated by the body, particularly in case of children, such as to limit as far as possible any unwanted side effects, and is able to reduce the number of aphthae and their recurrence over time.

Summary of the invention The above object has been achieved by a solution comprising: a) a zinc salt of a polyhydroxy acid having n carbon atoms, and b) a magnesium salt of a polyhydroxy acid having m carbon atoms, wherein n and m are, independently of each other, an integer from 3 to 10 and the components a) and b) are in a v/v ratio of 10:1 to 1:10. For the purposes of the present invention, with the term "polyhydroxy acid" it is meant an acid substituted by 1 to 9 hydroxy! groups, and with the term Vv ratio of

10:1 to 1 :10" it is meant a ratio based on a volume unit which varies from 10 volumes of component a) per 1 volume of component b) to 1 volume of component a) per 10 volumes of component b).

In another aspect, the invention concerns a pharmaceutical formulation comprising said solution.

In a further aspect, the invention concerns a homeopathic product comprising said solution.

In a yet further aspect, the invention relates to the use of the solution for the treatment of aphthous stomatitis.

The characteristics and advantages of the present invention will be evident from the following detailed description and from the working examples given for illustrating and non-limiting purposes.

Detailed description of the invention

The subject of the invention is therefore a solution comprising: a) a zinc salt of a polyhydroxy acid having n carbon atoms, and b) a magnesium salt of a polyhydroxy acid having m carbon atoms, wherein n and m are, independently of each other, an integer from 3 to 10 and the components a) and b) are in a v/v ratio of 10:1 to 1 :10.

In this respect, it has been surprisingly found that the combination of zinc and magnesium, when vehicled in the form of a salt of polyhydroxy acid having 3 to10 carbon atom, is able to relieve the pain caused by aphthae in an extremely and advantageously short time period, even only a few hours after consumption, and is able to substantially reduce a further onset over time. In fact, it has been observed that the rate of recurrence of aphthous stomatitis is significantly reduced, up to two or three fold, compared to untreated aphthous stomatitis. Moreover, said recurrence is progressively reduced, meaning that the frequency, both in time and in number, of each event diminishes by two or three fold compared to the frequency both in time and in number of the previous event. By way of illustration only, and as will be seen from the following examples, it was found that individuals who manifested a plurality of aphthae about every 15 days, noted after treatment with the solution of the invention that the aphthae reappeared surprisingly after not less than about two months and were fewer in number; after a subsequent treatment with the solution of the invention, the aphthae surprisingly reappeared after not less than about six months and were even fewer in number. Preferably, the components a) and b) are in a v/v ratio of 5;1 to 1 :5. More preferably, the components a) and b) are in a v/v ratio of 2:1 to 1 : 2. Even more preferably, the components a) and b) are in a v/v ratio of 1 :1. Suitable polyhydroxy acids are:

• 2-hydroxypropanoic acid

• 3-hydroχypropanoic acid

• 2-hydroxybutanoic acid

• 3-hydroxybutanoic acid

• 4-hydroxybutanoic acid

• 2-hydroxypentanoic acid

• 3-hydroxypentanoic acid

• 4-hydroxypentanoic acid

• 5-hydroxypentanoic acid

• 3,5-dihydroxypentanoic acid

• 4,5-dihydroxypentaπoic acid

• 3,4-dihydroχypentanoic acid

• 2,3,4-trihydroxypentanoic acid

• 2,3,4,5-tetrahydroxypentanoic acid

• 2-hydroxyhexanoic acid

• 3-hydroxyhexanoic acid

• 4-hydroxyhexanoic acid

• 5-hydroxyhexanoic acid

• 6-hydroχyhexanoic acid

• 2,2-dihydroxyheχanoic acid

• 3,5-dihydroxyhexanoic acid

• 4,5-dihydroxyhexanoic acid

• 3,5,6-trihydroχyhexanoic acid

• 4,5,6-trihydroxyhexanoic acid • 2,3,4,5,6-pentahydroxyheχanoic acid

• 2-hydroxyheptanoic acid

• 3-hydroxyheptanoic acid

• 4-hydroxyheptanoic acid » 5-hydroxyheptanoic acid

• 6-hydroxyheptanoic acid

• 7-hydroxyheptanoic acid

• 3,5-dihydroxyheptanoic acid

• 3,5,7-trihydroxyheptanoic acid

• 2,3, 4,5,6, 7-hexahydroxyheptanoic acid - 2-hydrαxyαctanoic acid

• 3-hydroxyoctanoic acid

• 4-hydroxyαctanoic acid

• 5-hydroxyoctanoic acid

• 6-hydroxyoctanoic acid

• 7-hydroxyoctanoic acid

• 8-hydroxyoctanoic acid

• 2,8-dihydroxyoctanoic acid

^• 6,8-dihydroxyoctanoic acid

• 4,5,6,7,8-pentahydroxyoctanoic acid

• 2,4,5,6,7-pentahydroxyoctanoic acid

• 2,4,5, 6,7,8-hexahydrσxyoctanoic acid

• 2,3,4,5,6,7,8-heptahydroxyoctaπoic acid

Preferably, in said polyhydroxy acids having π or m carbon atoms, n and m are, independently of each other, an integer from 5 to 8. More preferably, π and m are equal to each other. Even more preferably, both n and m are 6.

According to a preferred embodiment, said solution further comprises at least one inorganic magnesium salt and at least one inorganic zinc salt. According to a more preferred embodiment, said at least one inorganic magnesium salt and at least one inorganic zinc salt are, independently of each other, a chloride, sulphide or carbonate.

Preferably said solution is an alcoholic solution. More preferably, said solution is a 30% alcoholic solution. Even more preferably said solution is a 30% ethano) solution.

In another aspect, the solution of the invention is used as a medicament. In particular, said solution is used in the treatment of aphthous stomatitis. As will be seen from the examples that follow, the selection and suitable combination of the components a) and b) has proved to be particularly effective not only in relieving the pain caused by the aphthae within an extremely and advantageously short time period, even only a few hours after consumption, but also in substantially reducing healing time, as well as subsequent onset in time both in terms of the number of simultaneous aphthae and their recurrence over time. Moreover, the faster the administration of solution of the invention after appearance of the aphthae, the more remarkable the advantages attained.

Preferably, said solution is to be administered sublingualis In this respect, it has been observed that this administration route enables aphthae healing times to be further shortened, thus more rapidly relieving the pain caused thereby. The solution is contacted with the mucous membrane and diffuses through the epithelium under the tongue, a region dense with blood vessels, and enters the circulation i.e. into the blood, more rapidly than for example by oral administration, while conveniently by-passing the stomach. In this sense, the possibility of avoiding the passage through the stomach is appreciable not only in consideration of the vulnerability of the gastric mucosa, which is particularly delicate in very young and elderly subjects, but is also extremely desirable in cases of gastric malabsorption. This latter, as aforesaid, is one of the factors promoting onset of aphthous stomatitis, but is at the same time an obstacle to drug assimilation and hence also to any assimilation of the components of the solution of the invention, thus unavoidably compromising its effectiveness.

In the case of sublingual administration, absorption is of indirect type and the mechanism is passive diffusion. Compared to other administration routes, it is more advantageous as it also allows self-administration. Besides being rapid, the effect is also greater, as there is no loss of the components a) and b) before entering the bloodstream. In a further aspect, the present invention relates to a sublingual formulation comprising the solution as above described and suitable pharmaceutically acceptable vehicles.

In a yet further aspect, the present invention relates to the use of the solution as above described for preparing a homeopathic product for treating aphthous stomatitis. As will be seen from the following examples, the solution of the invention has also proved to be suitable for preparations according to homeopathic practice. Preferably, said homeopathic product is to be administered sublingualis Indeed, similarly to the aforesaid, this administration route enables aphtha healing times to be further shortened for homeopathic products as well, thus more rapidly relieving the pain caused thereby. Moreover, it has been surprisingly observed that said homeopathic product is also suitable for treating aphthous stomatitis in the paediatric field, i.e. when administered to children suffering therewith.

In another aspect, the present invention concerns a sublingual homeopathic product comprising the above described solution and suitable homeopathically acceptable vehicles. Preferably, in said solution the components a) and b) are present independently of each other in homeopathic dilutions from 2 CH to 7 CH. According to homeopathic practice, several types of dilutions are employed. The Hahnemannian centesimal dilutions (CH) indicate a 1 :100 ratio. They are prepared by adding one part of active substance to 99 parts of solvent. The mixture is subjected to vigorous succession, namely "dynamization", by a vibrating apparatus; in this manner the first Hahnemannian centesimal is produced, i.e. 1CH. One part of the 1CH dilution, mixed in a fresh flask with 99 parts of solvent then dynamized, constitutes the 2CH and so forth until the 30CH as the maximum limit. The Hahnemmanian decimal dilutions (DH) are dilutions in a 1 :10 ratio, prepared by following exactly the same method as for Hahnemannian centesimals.

It should be noted that at the dilutions selected above the combination of components a) and b) is conveniently effective, being at the same time advantageously extremely safe and tolerable in view of the significantly reduced quantities of said components. In accordance with a preferred embodiment, said solution in said homeopathic product further comprises at least one inorganic magnesium salt and at least one inorganic zinc salt, each independently of the other in homeopathic dilutions from

5 DH to 10 CH.

Indeed, said inorganic salts potentiate the synergy, and hence efficacy, observed for the combination of components a) and b) conveniently in said dilutions, i.e. at advantageously very low concentrations.

Preferably, in said solution the components a) and b) are salts of a polyhydroxy acid having 6 carbon atoms. More preferably, said solution is an alcoholic solution comprising components a) and b) in a 1 :1 v/v ratio, double calcium magnesium carbonate, and zinc sulphide. As will be seen from the following examples, said selection of compounds enables optimal results to be obtained under all considered viewpoints.

Particularly preferred is the homeopathic product wherein said solution is an alcoholic solution comprising a Zn salt of 2,3,4,5,6-pentahydroxyhexanoic acid

3CH and a Mg salt of 2,3,4,5,6-pentahydroxyheχanoic acid 3CH in a 1 :1 v/v ratio, double magnesium calcium carbonate 8CH, and zinc sulphide 8DH.

In addition, said homeopathic product is particularly suitable for the treatment of aphthous stomatitis in the paediatric field, i.e. when administered to children suffering therewith.

Working examples of the present invention are hereinafter given for illustrating and non-limiting purposes.

EXAMPLES

Examples 1-7

Preparation of formulations according to the present invention

The component a) was prepared by mixing 1 g of a zinc salt of a polyhydroxy acid and optionally 10 g of an inorganic zinc salt in 30% ethyl alcohol to obtain a total solution of 100 ml.

The component b) was prepared by mixing 1 g of a magnesium salt of a polyhydroxy acid and optionally 0.1 g of an inorganic magnesium salt in 30% ethyl alcohol to obtain a total solution of 100 ml.

The solution according to the present invention was obtained by mixing component a) and component b). Examples of said solutions of the invention obtained according to the above process are given in the following table:

Examples 8-14

Preparation of homeopathic products according to the present invention

The component a) was prepared by mixing 8 ml of a zinc salt of a polyhydroxy acid and optionally 7 ml of an inorganic zinc salt in 30% ethyl alcohol to obtain a total solution of 100 ml.

The component a) was prepared by mixing 8 ml of a magnesium salt of a polyhydroxy acid and optionally 7 ml of an inorganic magnesium salt in 30% ethyl alcohol to obtain a total solution of 100 ml.

The solution according to the present invention was obtained by mixing component a) and component b).

Examples of said solutions of the invention obtained according to the aforesaid process are given in the following table:

Example 15

Evaluation of the results obtained by sublingual administration of the homeopathic product of Example 14 in adult individuals

Although all the formulations and homeopathic products prepared above were shown to be effective in the treatment of aphthous stomatitis, it was chosen to report the results attained with the homeopathic product of Example 14 as it enabled optimal results to be obtained according to all the considered viewpoints,

A panel of 20 adult individuals affected by recurrent aphthous stomatitis were selected for whom the treatment with neither the known supplements also containing Zn and Mg nor treatment with a Zn salt of 2,3,4,5,6- peπtahydroxyhexaπoic acid and a Mg salt of 2,3,4,5,6-pentahydroxyhexanoic acid taken alone and separately gave results of any kind.

To these 20 adult individuals 20 drops of the homeopathic product of Example 14 were administered sublingual^ 3 times a day for 5 days.

4-6 hours after the first consumption, 80% of said individuals noted a relief of pain caused by the aphthae and the ulcer healing beginning. After 1 day, 100% of said individuals no longer felt any pain, while in 70% of them the aphthae had already completely healed.

One year after starting the treatment with the homeopathic product of Example 14 as above described, recurrence was significantly reduced in so far as in over 90% of individuals, ulcer recurrence in both number and frequency was halved with respect to the personal average of each individual. In fact, those who manifested a plurality of aphthae about every 15 days, noted after treatment with the solution of the invention that they reappeared surprisingly after not less than about two months and were fewer in number; after a subsequent treatment with the solution of the invention the aphthae surprisingly reappeared after not less than about six months and were even fewer in number.

Hence, the homeopathic product of the invention has proved to be particularly indicated in the treatment of aphthous stomatitis, enabling pain to be rapidly mitigated and above all to heal aphthae and reduce their onset in terms of number and frequency with an efficacy never before noted, neither with known supplements nor with the components a) and b) consumed singly.

Moreover, it was found that the above indicated dosages also proved to be suitable for children aged 5 and upwards, demonstrating the optimal tolerability of the homeopathic product of the invention as well as its confirmed effectiveness.

Example 16

Evaluation of the results obtained by sublingual administration of the homeopathic product of Example 14 in children

Although all the formulations and homeopathic products prepared above were shown to be effective in the paediatric treatment of aphthous stomatitis, it was chosen to report the results attained with the homeopathic product of Example 14 as it enabled optimal results to be obtained according to all the considered viewpoints.

A panel of 20 children aged between 2 and 5 years affected by recurrent aphthous stomatitis were selected for whom the treatment with neither the known supplements also containing Zn and Mg nor treatment with a Zn salt of 2,3,4,5,6- pentahydroxyhexanoic acid and a Mg salt of 2,3,4,5, 6-ρentahydroxyhexanoic acid taken alone and separately gave results of any kind. To these 20 children 10 drops of the homeopathic product of Example 14 were administered sublingually 3 times a day for 5 days.

4-6 hours after the first consumption, 85% of said children noted a relief of pain caused by the aphthae and the ulcer healing beginning.

After 1 day, 100% of said children no longer felt any pain, while in 75% the aphthae had already completely healed.

One year after starting the treatment with the homeopathic product of Example 14 as above described, recurrence was significantly reduced in so far as in over 95% of the children, ulcer recurrence in both number and frequency was halved with respect to the personal average of each child. In fact, those children who manifested a plurality of aphthae about every 15 days, noted after treatment with the solution of the invention that they reappeared surprisingly after not less than about two months and were fewer in number; after a subsequent treatment with the solution of the invention the aphthae surprisingly reappeared after not less than about six months and were even fewer in number.

Hence, the homeopathic product of the invention has proved to be particularly indicated in the paediatric treatment of aphthous stomatitis, enabling pain to be rapidly mitigated in children and above all to heal aphthae and reduce their onset in terms of number and frequency with an efficacy never before noted, neither with known supplements nor with components a) and b) consumed singly. From the detailed description and from the given working examples, the advantages achieved by the described solution, obtained according to the present invention, are evident. In particular, in the case of both adults and children the synergy of the two components has enabled the disadvantages associated with the products of the known art to be overcome, as well as to effectively and rapidly heal the ulcers, thus significantly reducing their subsequent onset over time both in terms of the number of simultaneous aphthae and their occurrence frequency. A remedy has therefore been found for healing aphthous stomatitis which is well tolerated by the body to the extent that it can be used in both adults and children.

Claims

1. A solution comprising: a) a zinc salt of a polyhydroxy acid having π carbon atoms, and b) a magnesium salt of a polyhydroxy acid having m carbon atoms, wherein n and m are, independently of each other, an integer from 3 to 10 and the components a) and b) are in a v/v ratio of 10:1 to 1 :10.

2. The solution according to claim 1 , wherein the components a) and b) are in a v/v ratio of 5:1 to 1 :5.

3. The solution according to claim 2, wherein the components a) and b) are in a v/v ratio of 2:1 to 1 :2.

4. The solution according to claim 3, wherein the components a) and b) are in a v/v ratio of 1 :1 ,

5. The solution according to any one of claims 1-4, wherein n and m are, independently of each other, an integer from 5 to 8.

6. The solution according to any one of claims 1-5, wherein n and m are equal to each other.

7. The solution according to claim 6, wherein both n and m are 6.

8. The solution according to any one of claims 1-7, further comprising at least one inorganic magnesium salt and at least one inorganic zinc salt.

9. The solution of claim 8, wherein said at least one inorganic magnesium salt and at least one inorganic zinc salt are, independently of each other, chloride, sulphide or carbonate.

10. The solution according to any one of claims 1-9, in the form of an alcoholic solution.

11. The solution according to any one of claims 1-10 for use as a medicament.

12. Use of the solution according to any one of claims 1-10 for preparing a medicament for the treatment of aphthous stomatitis.

13. The use according to claim 12, wherein said medicament is to be administered sublingually.

14. A sublingual formulation comprising the solution according to any one of claims 1-10 and suitable pharmaceutically acceptable vehicles.

15. Use of the solution according to any one of claims 1-10 for preparing a homeopathic product for the treatment of aphthous stomatitis.

16. The use according to claim 15, wherein said homeopathic product is to be administered sublingually.

17. The use according to claim 15 or 16, wherein said homeopathic product is for the paediatric treatment of aphthous stomatitis.

18. A sublingual homeopathic product comprising the solution according to any one of claims 1-10 and suitable homeopathically acceptable vehicles.

19. The sublingual homeopathic product according to claim 18, wherein in said solution the components a) and b) are present independently of each other in homeopathic dilutions from 2 CH to 7CH.

20. The sublingual homeopathic product according to claim 19, wherein said solution additionally comprises at least one inorganic magnesium salt and at least one inorganic zinc salt, each independently of each other in homeopathic dilutions from 5 DH to 10 CH.

21. The sublingual homeopathic product according to any one of claims 18-20, wherein in said solution the components a) and b) are salts of a polyhydroxy acid having 6 carbon atoms.

22. The sublingual homeopathic product according to claim 21, wherein said solution is an alcoholic solution comprising the components a) and b) in a v/v ratio of 1 :1 , double magnesium calcium carbonate, and zinc sulphide.

23. The sublingual homeopathic product according to claim 22, wherein said solution is an alcoholic solution comprising a Zn salt of 2,3,4,5,6- pentahydroxyhexanoic acid 3CH and a Mg salt of 2,3,4,5,6-pentahydroxyhexanoic acid 3CH in a 1 :1 v/v ratio, double magnesium calcium carbonate 8CH, and zinc sulphide 8DH.

24. The sublingual homeopathic product according to any one of claims 18-23, for the paediatric treatment of aphthous stomatitis.