WO2009115280A1

WO2009115280A1 - Remineralizing saliva substitute and method for the production thereof

Info

Publication number: WO2009115280A1
Application number: PCT/EP2009/001928
Authority: WO
Inventors: Dirk Wiedemann
Original assignee: Nova Dentalia Zahnpflege Gmbh
Priority date: 2008-03-16
Filing date: 2009-03-16
Publication date: 2009-09-24
Also published as: DE102008014227A1

Abstract

The invention relates to a method for producing a remineralizing saliva substitute, comprising the steps: f) complete dissolution of at least one organic calcium salt, selected from the group of physiologically acceptable organic acids, in warm water at 35-80 °C; g) concentrating the solution under reduced pressure at a hot bath temperature of 50-150 °C; h) expanding to standard pressure and then adding at least one organic acid at constant temperature; i) concentrating the solution under reduced pressure at a hot bath temperature of 50-150 °C; j) expanding the hot, free-flowing calcium salt hydrate melt to standard pressure; aa) producing a base saliva substitute compound comprising: 55 - 97,8 weight % water; 1 - 15 weight % humectant agent; 0.2 - 10 weight % binding and thickening agent; bb) producing a mixture of the base saliva substitute compound while heating to a temperature range from 40 to 70 °C; cc) adding the calcium salt hydrate melt to the base compound tempered to 40 to 70 °C and stirring until a homogenous saliva substitute mixture is produced, wherein the proportion of the calcium salt hydrate melt relative to the total weight of the saliva substitute mixture is between 1 and 20 weight %, and the sum of the amounts of the components from step aa) adds up to 100 %. dd) cooling the saliva substitute mixture.

Description

Remineralising saliva substitutes and methods of making them

The present invention relates to remineralizing saliva substitutes and methods for their preparation.

Dry mouth (xerostomia) can have various causes. Often it is a concomitant in radiation patients in which the salivary production of salivary glands is severely limited due to the irradiation, the dry mouth is often noticed only at a reduced by 50% saliva production. The dry mouth is particularly problematic because the lack of saliva dry out the mucous membranes and thus become more susceptible to infections caused by bacteria, viruses, fungi and other germs.

Various saliva substitutes in the form of sprays and gels are known in the prior art. As a recent study by Tschoppe et al. however, these substitutes have been shown to regularly demineralize dental hard tissues since they have a pH <6.5 below which dentine is already demineralized and below pH 5.7 the enamel.

As a rule, acids, preferably citric acid, are added to these saliva substitutes, on the one hand, because the acidic taste stimulates the salivary glands and, on the other hand, because this covers the bland taste of the saliva substitutes. Basically, this is not a problem. However, since natural salivation is reduced or absent in persons affected by xerostomia, the natural remineralization of the hard tooth substance by saliva is also impaired in the case of acid-related tooth damage.

The object of the present invention is therefore to provide a saliva substitute which allows a remineralization of hard tooth substances and to provide a method for its preparation.

The above objects are achieved according to the features of the independent claims.

BESTATIGUNGSKOPIE In the remineralizing effect experiments it was surprisingly found that a saliva substitute after addition of an acidic, freshly prepared, dehydrated under reduced pressure calcium salt hydrate melt with a residual water content in the range of 5 wt .-% - 25 wt .-%, preferably of 10 wt. % -20% by weight, in contrast to the saliva substitutes known on the market, causes a significant reminalization of the teeth despite the short residence time in the oral cavity which is typical for these agents.

In addition, the production of saliva is stimulated by the acids added to the melt in patients who are still partially intact salivary glands.

The preparation of the salt hydrate melt was carried out on the basis of calcium salts of physiologically acceptable, organic acids, although mixtures of different acids could be used.

Preferably, the melt has been prepared with at least one organic acid selected from the group consisting of lactic acid, citric acid and gluconic acid, this composition providing improved distribution and wetting of all teeth in the oral cavity. It has surprisingly been found that the use of citric acid does not adversely affect the efficacy of the enamel remineralization compositions despite the known calcium complexing properties.

More preferably, a salt hydrate melt containing a combination of lactic acid and citric acid is used.

The calcium salt used is preferably calcium lactate, calcium citrate and calcium gluconate. As a further acid, preference is given to using lactic acid or citric acid and gluconic acid, the acid added being particularly preferably the acid corresponding to the acid anion.

The inventors assume that dimers and oligomers (anhydrides) of the added acids are also proportionally formed by the preparation of the melt at reduced pressure in the freshly prepared calcium salt melt, whereby mixed anhydrides may also be present. With the simultaneously occurring during mixing rehydration reaction, the surprising advantages of the presented with fresh melt saliva substitutes can be explained, such as the high Remineralisierungswirkung by a lowered pH longer period of time, which allows the diffusion of calcium ions into the hard tooth substance, before these with increasing pH can be immobilized by precipitation of insoluble salts.

Further advantages will become apparent from the following explanation and the embodiments.

According to the invention, the calcium salt hydrate melts are freshly recovered from an aqueous mixture of at least one organic calcium salt and one or more organic acids by removal of water under reduced pressure and elevated temperature and subsequent cooling. The molten salt is obtained as a ductile, macroscopically homogeneous mass. In this case, the melt has a close order in domains. The domains are in turn distributed chaotically distributed, so that only uncharacteristic, extremely broad and diffuse diffraction signals are visible in the X-ray diffractogram. This is evidenced by a X-ray amorphous, non-crystalline arrangement of the domains having the above-described order of proximity in the solid.

The preparation of such a melt on a laboratory scale comprises the steps:

a) complete dissolution of at least one organic calcium salt in warm water (T = 35-8O ° C); b) concentration of the solution under reduced pressure and elevated temperature (heating bath 50-150 ⁰ C); c) depressurization to normal pressure and subsequent addition of the at least one organic acid at a constant temperature; d) concentration of the solution under reduced pressure and elevated temperature (heating bath 50-150 ⁰ C); e) depressurization to normal pressure of the hot, flowable melt. The fluidity has the advantage that the melt can be processed directly into the further production process of the saliva substitute by stirring into the matrix or can be poured into thin slices, which are granulated or ground after solidification, so that a high surface to volume ratio the particle is achieved, which facilitates the further processing, especially the redissolution.

Advantageously, the first concentration in step b) removes 10-88%, preferably 25-85%, more preferably 45-80% and most preferably 80% of the amount of water initially charged.

Advantageously, the organic acid before step c) up to 25 wt .-%. preferably 2 to 20% by weight, more preferably 3 to 10% by weight, and most preferably 4.6% by weight of water, based on the total mass of the calcium salts added.

Most preferably, the acid is heated to the temperature of the salt solution submitted prior to addition.

Advantageously, during concentration in step d), a further 5 to 12% of the amount of water initially introduced in step a, preferably 7 to 10%, particularly preferably 8.5%, are removed.

Advantageously, the melt contains a calcium content of 1.5-3 mol per 1 kg of melt, based on elemental calcium, which corresponds to a proportion of 6% by weight to 12% by weight.

Embodiment 1

In a 1-1 cup 0.5 1 of water is heated to 60 ° and stirring and more

Heat gradually added 172.28 g (0.559 mol) of calcium lactate pentahydrate and simultaneously 43.58 g (0.097 mol) of calcium gluconate and stirred until a clear solution is formed.

The clear solution is transferred to the distillation flask and 0.40 1 of water at a

Heating bath temperature of 130 ⁰ C distilled off under reduced pressure. After the defined amount of water has been transferred, the heating is interrupted and the system is decompressed to normal pressure.

In the meantime, 21.89 g (0.194 mol) of lactic acid (80%) is heated in a second beaker with 10 ml of water to about 60 ⁰ C and with stirring 18.68 g (0.0972 mol) of citric acid so that a clear solution is formed. This solution is added to the distillation batch and the distillation continued under reduced pressure (0.4 bar) until another 0.1 1 of water have passed.

The distillation flask remains an only slightly colored mass of syrupy consistency, which remains liquid and pourable when cooled to about 80 ° and can be further processed directly.

According to the invention, the addition of the inventive salt hydrate melt is carried out by the steps:

aa) presenting a saliva substitute base composition comprising:

- 55 - 97.8 wt .-% water;

- 1 - 15 wt .-% humectant;

- 0.2 - 10 wt .-% binding and thickening agents;

bb) Heating the base composition with stirring to a temperature range of 40

- 70 ⁰ C until a homogeneous mixture is formed;

cc) adding the granulated calcium salt hydrate melt to the tempered at 40 - 70 ⁰ C basic composition with subsequent stirring until a homogeneous saliva substitute mixture is formed, wherein the proportion of calcium salt hydrate melt to the total mixture between 1 and 20 wt .-% and the sum of the amounts of the ingredients from Step aa) add up to 100%.

dd) cooling the mixture.

In an alternative preparation method, the melt according to the above-mentioned proportions dissolved in water while heating to 40-70 ⁰ C, humectants, preferably xylitol, is added, wherein the solution is cooled. Then binder, preferably hydroxyethyl cellulose, is stirred into the solution and allowed to rest for 12 h. Preferably, the saliva substitute base composition further contains physiologically acceptable sodium, magnesium and calcium salts, surfactants, preservatives, dyes and / or color pigments and / or flavorings.

Preferably, the preservative is selected from the group consisting of ascorbic acid, vitamin E and benzoic acid.

Preferred binders and thickeners are hydroxyethylcellulose (HEC), hydroxyalkylcelluloses, carboxymethylcellulose, alginates, gelatin or derivatives thereof and physiologically acceptable salts, and other binders known in the art, with binders having mucoadhesive properties being preferred.

Preferably, the saliva substitute base composition additionally contains a buffer system for pH adjustment, preferably a phosphate buffer.

Surprisingly, it has been found that the presence of citric acid or citrates in the calcium salt hydrate melt, which also gives the composition a pleasant taste and promotes salivation, does not affect the remineralizing effect of the present composition.

In a further preferred embodiment, the saliva replacement composition contains a fluoride or a fluorine compound, preferably in encapsulated form, wherein the capsules have mucoadhesive properties and first disintegrate in the oral cavity and release the active ingredient with a time delay, so that the remineralization is additionally forced by fluoride.

The maximum proportion of fluoride in the total composition is 1500 ppm (1.5 g / kg), preferably the proportion of fluoride is 1500 to 100 ppm, more preferably 1400 to 300 ppm, most preferably 500 ppm.

A preferred embodiment of the saliva substitute contains at least one binder, at least one humectant, water and a proportion of the calcium salt hydrate melt according to the invention. Exemplary embodiment 2:

2 g of the melt of Example 1 according to the invention are dissolved with heating in 91.9 g of water and added 5 g of xylitol, wherein the solution cools strongly. Subsequently, 1.1 g of carboxymethylcellulose sodium salt are added and stirred.

The compositions of the invention thus prepared have a good resistance to segregation, a homogeneous, fine distribution of the ingredients and a consistent composition until the end of consumption.

Due to the high proportion of available calcium ions in the compositions at a low pH optimal remineralization of the hard tooth substance is achieved, whereby due to the mediated by the thickening agent adhesion to the oral mucosa and the teeth a sufficiently long exposure time of the composition is achieved.

In a preferred embodiment, the saliva substitute is present as a two-component preparation, wherein the first component provides a fluoride for attachment of fluoride, for example as amine fluoride, on the teeth and the second component has a calcium salt in a high concentration in the form of the inventive Salzhydratschmelze, so that over conventional saliva substitutes a remineralizing effect begins and calcium is incorporated into the enamel.

In a particularly preferred embodiment, at least the calcium salt component is present in microencapsulated or nano-encapsulated form, which delays the release of the salt during use, so that first a fluoride layer is applied to the tooth before the calcium is liberated. In this way, the premature precipitation of fluorspar is prevented, the calcium content is no longer available for the remineralization due to the poor solubility of the compound and reaches a maximum accelerated remineralization.

In a further embodiment, the fluoride component is encapsulated, so that an initial remineralization by the calcium takes place first and a long-term remineralization by the subsequently released and adhering to the teeth fluoride occurs in conjunction with the liberated from the artificial saliva calcium ions. Another preferred embodiment provides for encapsulation of fluoride and calcium components so that they are alternately released in at least three sequential steps to ensure optimal remineralization.

Another embodiment comprises a microencapsulated acid or an acid anhydride, which are released with a time delay, so that over a longer period of time required for the remineralization low pH value is maintained in the oral cavity. The microcapsules preferably have mucoadhesive properties for this purpose, so that an optimal pH range for remineralizing the tooth hard substance is maintained even after completion of oral care.

In a further preferred embodiment, the saliva substitute is a gel or a hydrocolloid that is applied to the oral mucosa, wherein the consistency of the saliva substitute can be adjusted by the type and amount of the binder.

A further preferred embodiment provides that the saliva substitute is enclosed in a gel capsule or a candy and released by biting after ingestion, wherein the saliva substitute may be formed both as a liquid and as a gel.

Also provided is the execution of the saliva substitute as a sprayable solution.

Claims

claims

1. A method for producing a remineralizing saliva substitute, comprising the steps of: a) complete dissolution of at least an organic calcium salt selected from the group of physiologically acceptable organic acids, in warm water at 35- 80 ⁰ C b) concentrating the solution under reduced pressure at a heating bath temperature of 50- 150 ⁰ C; c) depressurization to atmospheric pressure and subsequent addition of at least one organic acid at a constant temperature; d) concentrating the solution under reduced pressure at a heating bath temperature of 50-150 ° C; e) depressurizing the hot, flowable calcium salt hydrate melt to atmospheric pressure;

aa) providing a saliva substitute base composition comprising: 55-97.8% by weight of water; 1 to 15% by weight of humectant; 0.2-10% by weight of binder and thickener;

bb) producing a mixture of the saliva substitute base composition while heating to a temperature range of 40 to 70 ⁰ C;

cc) adding the calcium salt hydrate to at 40 to 70 ⁰ C temperature-controlled base composition has been created followed by stirring until a homogeneous saliva substitute mixture, wherein the proportion of the calcium salt hydrate based on the total weight of the ^'saliva substitute mixture is between 1 and 20 wt .-% and the sum of the quantities the ingredients from step aa) adds up to 100%.

dd) cooling the saliva substitute mixture.

2. A method of making a remineralizing saliva substitute comprising the steps of: a) complete dissolution of at least one organic calcium salt, selected from the group of physiologically acceptable organic acids, in warm water at 35-80 ° C. b) concentration of the solution under reduced pressure at a bath temperature of 50-150 ° C.; c) depressurization to atmospheric pressure and subsequent addition of at least one organic acid at a constant temperature; d) Concentration of the solution under reduced pressure at a heating bath temperature of 50-150

⁰ C; e) depressurizing the hot, flowable calcium salt hydrate melt to atmospheric pressure;

aal) presentation of 25-45 wt .-% water and dissolving the calcium salt hydrate melt at 40 to 70 ⁰ C, wherein the proportion of the calcium salt hydrate melt based on the total weight of the saliva substitute mixture between 1 and 20 wt .-% and the sum of the amounts of the ingredients from step aal) add up to 100%.

bbl) addition of 1 to 15% by weight of humectant, preferably xylitol, with cooling of the solution;

ccl) addition of 0.2-10% by weight of binder and thickener.

3. The method according to any one of the preceding claims, characterized in that the saliva substitute base composition contains at least one further component selected from the group consisting of physiologically acceptable sodium, magnesium and calcium salts, surfactants, preservatives, dyes, color pigments and flavorings.

4. The method according to any one of the preceding claims, characterized in that the binding and thickening agent contains at least one component selected from the group consisting of hydroxyethylcelluloses, carboxymethylcelluloses, alginates, and gelatin and derivatives thereof and physiologically acceptable salts.

5. The method according to any one of the preceding claims, characterized in that the saliva substitute base composition additionally contains a buffer system, preferably a phosphate buffer.

6. The method according to any one of the preceding claims, characterized in that the saliva substitute composition contains a fluoride, wherein the fluoride concentration based on the total mass of the finished saliva substitute mixture does not exceed 1500 ppm.

7. The method according to any one of the preceding claims, characterized in that the freshly prepared Cacliumsalzhydratschmelze a residual water content in the range of 5 - 25 wt .-%, preferably 10 - 20 wt .-%, having.

8. The method according to any one of the preceding claims, characterized in that the melt is prepared with at least one organic acid selected from the group consisting of lactic acid, citric acid and gluconic acid, wherein a combination of lactic acid and citric acid is particularly preferred.

9. The method according to any one of the preceding claims, characterized in that the calcium salt is selected from the group consisting of calcium lactate, calcium citrate and calcium gluconate, particularly preferred that the calcium salt is selected with acid anions corresponding to the acid added.

10. The method according to any one of the preceding claims, characterized in that the melt contains a calcium content of 1.5 to 3 mol based on 1 kg of melt based on elemental calcium, preferably from 2 to 2.8 mol ..

11. The method according to any one of the preceding claims, characterized in that the calcium salt hydrate melt is introduced liquid by stirring in the process or that the solid calcium salt hydrate melt is introduced particulate with a defined surface-to-volume ratio of the particles in the process.

12. A method of making a remineralizing saliva substitute comprising the steps of: a) water is heated to 60 ° and gradually added with stirring and further heating calcium lactate pentahydrate and simultaneously calcium gluconate and stirred, wherein the Gewichtsverhätnis water: calcium lactate pentahydrate: calcium gluconate 500: 172: 44;

b) the clear solution is transferred to the distillation flask and distilled off a volume fraction of water 0.4 / 0.5 based on the original amount of water at a heating bath temperature of 130 ⁰ C under reduced pressure;

c) in a container, lactic acid (80%) is heated with water to 60 ° C and added with stirring with citric acid, wherein the weight ratio of lactic acid: water: citric acid 22: 10: 19, and then to the mixture obtained in b) added;

d) the distillation is continued under reduced pressure at 0.4 bar until, in total, in all distillation steps, an amount of water equal to the amount of water introduced under a) has passed over.

13. A method for granulating a calcium salt hydrate melt, characterized in that a liquid salt hydrate melt is solidified by cooling and then processed into particles having a defined surface-to-volume ratio.

14. Salivary replacement agent comprising:

From 55 to 97.5% by weight of water;

1 to 20% by weight of calcium salt hydrate melt according to one of the preceding process claims;

1 to 15% by weight of humectant;

- 0.2 to 10 wt .-% binding and thickening agents; where the sum of the weight% information adds up to 100%.

15. Salivary replacement agent comprising:

- 91, 9 wt .-% water;

2% by weight of calcium salt hydrate melt according to one of the preceding process claims; 5% by weight of humectant, preferably xylitol;

1.1 wt.% Binding and thickening agent, preferably sodium carboxymethylcellulose;

where the sum of the weight% information adds up to 100%.

16. saliva substitute according to one of the two preceding claims, characterized in that in addition a fluoride-containing compound is contained, wherein the fluoride content based on the total mass of the saliva substitute does not exceed 1500 ppm.

17. Salivary replacement agent according to the preceding claim, characterized in that the saliva substitute as a two-component preparation, a first component containing a fluoride compound for attachment of fluoride to the tooth hard substance, and a second component containing a calcium salt hydrate melt in a high concentration, prepared according to one of the preceding method claims , contains.

18. saliva substitute according to the preceding claim, characterized in that at least one of the two components is present at least partially in encapsulated form.

19. Saliva substitute according to one of the six preceding claims, characterized in that the saliva substitute contains an at least partially encapsulated acid and / or acid anhydride.

20. saliva substitute according to the preceding claim, characterized in that the encapsulation is made mucoadhesive.

21. Saliva substitute according to the preceding claim, characterized in that the binder is selected from the group of mucoadhesive polymers.

22. Saliva substitute according to one of the preceding claims, characterized in that it is prepared as a spray, gel, filled gel capsule or as a candy.

23. Saliva substitute, producible according to one of the preceding method claims.

24. Use of a saliva substitute according to one of the preceding claims for the preventive and therapeutic treatment of xerostomia.