Stable mouth-dissolving formulations based on s-adenosyl methionine

Abstract

The invention relates to edible mouth-dissolving formulations based on S-adenosyl methionine, anhydrous sodium or potassium carbonate, and optionally other active ingredients and excipients.

Description

[0001] STABLE MOUTH-DISSOLVING FORMULATIONS BASED ON S-ADENOSYL METHIONINE

[0002] The invention relates to edible mouth-dissolving formulations based on S-adenosyl methionine.

[0003] Background of the invention

[0004] S-adenosyl-L-methionine (SAMe) is a cofactor present in all living organisms, which is essential for methylation processes in cell metabolism. A deficiency of said substance in the human body contributes to the onset of numerous disorders; for example, it is associated with the development of osteoarthritis, cirrhosis of the liver, cystic fibrosis, depressive states, and aging-associated diseases such as Alzheimer’s disease and Parkinson’s disease. Moreover, low levels of SAMe are correlated with the development of cardiovascular disorders. SAMe in injectable form is a medicament approved in many European countries, while the oral form is used as a diet supplement.

[0005] SAMe is characterised by a high level of chemical instability; it degrades rapidly, isomerising to (R5 SAMe and giving rise to other degradation products, identifiable by HPLC analysis, as reported in EP2742943. The degradation is accompanied by a change of colour and the formation of an unpleasant odour.

[0006] SAMe is more stable in salified form with an acid; for example, EP2945959 describes the preparation of the salt with 3-indolylpropionic acid. Salts with 1,4-butanedisulphuric acid, with a mixture of sulphuric and p-toluenesulphonic acids, and with phytic acid, are present on the market; the salified form with the mixture of sulphuric / p-toluenesulphonic acids (SAMe Pates) is the most common.

[0007] SAMe salts are hygroscopic, and therefore unstable following water absorption, which triggers the degradation processes. Formulations containing SAMe salts must therefore be prepared in premises with relative humidity levels below 20%.

[0008] To increase the stability of SAMe and the salts thereof, excipients able to slow its degradation have been proposed, such as casein (EP2742943) and inositol (EP1971370). The use of desiccants such as calcium chloride, calcium oxide, magnesium sulphate and magnesium oxide is also widespread. The use of excipients obviously reduces the amount of active ingredient which can be included in an oral administration form.

[0009] SAMe is mainly used for its beneficial effects on the central nervous system (antidepressant effect) or for the treatment of osteoarthritis. When administered orally, SAMe is subject to a hepatic first-pass effect, which involves problems of low therapeutic efficacy. A buccal absorption formulation can partly solve this problem; for example, EP2370062 describes the preparation of chewing-gums containing SAMe. Formulations in mouth-dissolving or effervescent tablets, in addition to a carbonate or bicarbonate, contain a stabilising / desiccant excipient such as casein (EP2393475), magnesium oxide (EP2393475) or calcium oxide (EP2189154).

[0010] A further problem with mouth-dissolving formulations is associated with the unpleasant flavour of SAMe and the salts thereof, in particular of the Pates salt; the flavour of the sulphuric and p-toluenesulphonic acid mixture is disliked by most people, even when it is corrected with sweeteners and flavourings. Moreover, SAMe Pates is strongly acid, and can irritate the buccal mucosa. To improve the flavour and simultaneously reduce the acidity of the formulation, the addition of arginine base has been proposed, as described in EP2370062. However, the blend with arginine requires the use of desiccants and / or stabilisers to prevent the degradation of the active ingredient.

[0011] Description of the invention

[0012] It has surprisingly been observed that the palatability and stability of edible formulations of SAMe or the salts thereof are improved by the addition of anhydrous sodium or potassium carbonate. The combination of SAMe or the salts thereof with anhydrous sodium or potassium carbonate can be used as a preformulate in the preparation of orodispersible formulations such as mouth-dissolving tablets, chewable tablets, sublingual tablets, sachets and the like. Due to their better flavour and lower acidity, orodispersible formulations can be produced with a minimal amount of other excipients. In this way a formulation with a high active ingredient content is obtained; orodispersible tablets offer the further advantage of smaller size, leading to improved acceptability by the patient. The improved palatability leads to a longer residence time in the oral cavity, due to the reduced swallowing impulse.

[0013] In a first aspect thereof, the invention therefore relates to mouth-dissolving formulations comprising S-adenosyl methionine or the salts thereof as active ingredient, and at least one excipient comprising or consisting of anhydrous sodium carbonate or anhydrous potassium carbonate, preferably anhydrous sodium carbonate.

[0014] The specifications of the anhydrous sodium carbonate advantageously usable according to the invention are reported in the sodium carbonate monograph in the Food Chemicals Codex. The amount of anhydrous sodium carbonate as a percentage of the total weight of the formulation ranges between 10% and 70%, preferably between 15% and 60%, and more preferably between 20 and 35% of the total weight of the composition.

[0015] The preferred salts of S-adenosyl methionine are para toluenesulphonate / sulphate, butanedi sulphonate and phytate. Para-toluenesulphonate / sulphate (SAMe Pates) is particularly preferred. The amount of SAMe or a salt thereof as a percentage of the total weight of the formulation ranges between 5 and 95%, preferably between 40 and 85%.

[0016] The formulations according to the invention can include other excipients such as diluents, lubricants, antiaggregants, disintegrants, film-forming agents, colourings, sweeteners, flavouring agents and antioxidants. In addition to SAMe or the salts thereof, the formulations can also contain other active ingredients, in particular vitamin K, preferably menaquinone-7.

[0017] The total weight of a formulation typically ranges between 10 mg and 1500 mg, preferably between 100 mg and 1300 mg.

[0018] According to a further aspect, the invention relates to a process for the preparation of a granulate useful for the preparation of the formulations according to the invention. The process comprises mixing of SAMe or a salt thereof with an excipient having a low melting point, for example less than 70°C, and granulation of the melted blend (melt granulation). Examples of low-melting-point excipients comprise stearic acid, palmitic acid, mono- and diglycerides of fatty acids or mixtures thereof. Stearic acid or a mixture of stearic acid and palmitic acid is preferred. Stearic acid preferably meets the specifications reported in the USP monograph, identified as additive E-570 by the European Pharmacopoeia.

[0019] Alternatively, a mixture containing stearic acid and palmitic acid obtained from fats or oils of plant or animal origin can be used.

[0020] In detail, the process comprises the following steps: mixing the active ingredient and the excipients in the process chamber of a thermostated granulator such as a high-shear mixer; increasing the temperature of the process chamber until the granulating excipient melts; optionally, producing a vacuum in the process chamber to eliminate the residual moisture retained by the blend of ingredients; at the end of mixing, reducing the thermostating temperature to below the melting point of the excipient or blend of excipients; optionally, using a granulating mill fitted with a grid to sieve the granulate to the desired size.

[0021] The end result is a granulate that guarantees greater manageability of the raw material, as well as protecting the active ingredient against contact with environmental moisture.

[0022] Said granulate is a further subject of the invention.

[0023] The melt granulation process can be used to obtain formulates also comprising other excipients and other active ingredients. The process is preferably conducted under vacuum to obtain a granulate with lower moisture than the mixture of ingredients used at the start of the process, despite the strongly hygroscopic nature of S-adenosyl methionine.

[0024] The invention is illustrated in greater detail in the examples below.

[0025] EXAMPLE 1 - Drying of SAMe granulate obtained by melt granulation

[0026] The blend to be dried was prepared by mixing the ingredients in the following proportions: a) 93% of powdered S-adenosyl methionine sulphate / p-toluenesulphonate (SAMe Pates) with a SAMe-ion content of about 52%, b) 7% stearic acid.

[0027] The blend then underwent a granulation process, setting the temperature of the thermostated jacket to 80°C. When the melting point of the excipient had been reached, a vacuum was induced in the granulation chamber.

[0028] To evaluate the true impact of the drying process applied to the granulation process, 4 aliquots of the product were taken up at the following times:

[0029] - time 0: blend (SAMe + stearic acid) not yet granulated;

[0030] 10 min: the blend is dried under high vacuum;

[0031] 30 min: the blend after 20 minutes’ drying;

[0032] 40 min: the blend after 30 minutes’ drying.

[0033] The samples undergo analysis of the residual water by Karl -Fischer titration. The results are set out in Table 1 :

[0034] Table 1:

[0035] Table 1: drying of blend by melt granulation under vacuum.

[0036] The data set out in Table 1 demonstrate that the residual water content of the blend falls significantly in proportion to the duration of the drying process.

[0037] EXAMPLE 2 - Stability evaluation of SAMe and SAMe granulate

[0038] The stability of powdered SAMe Pates and the SAMe granulate obtained as described in Example 1 was evaluated with an accelerated test. The samples were stored in a thermostatic stove at +53°C, placing the sample in a closed low-density polyethylene (PE-LD) bag, which in turn was inserted into an aluminium bag placed under vacuum, and heat-sealed. At set times, the content of SAMe-ion and the correlated impurities was evaluated by HPLC analysis. The results are set out in Table 2.

[0039] Table 2: stability data at 53°C for 15 days

[0040] The results demonstrate that at the end of the test, the SAMe Pates and stearic acid granulate maintained 95% of its initial assay value, while the SAMe Pates maintained 89% thereof; the drying process therefore improved the stability of the active ingredient.

[0041] EXAMPLE 3 - Evaluation of stability of combinations of SAMe + sodium carbonate

[0042] Sodium carbonate, a common excipient in food products, is normally on the market with a moisture content of about 10%, which is incompatible with the chemical stability of SAMe. The compatibility between SAMe Pates and two types of excipient was evaluated: standard quality (loss on drying = 11.50%) and anhydrous sodium carbonate (loss on drying = 0.16%). The tests were conducted as described in Example 2 by preparing single-dose sachets containing 200 mg of SAMe ion, containing the following blends: a) 68% SAMe Pates + 32% anhydrous sodium carbonate (KF=1.05%) b) 68% SAMe Pates + 32% standard sodium carbonate (KF = 4.03%)

[0043] The samples were stored in a thermostatic stove at +53°C, placing the sample in a closed PE-LD bag, which in turn was inserted into an aluminium bag placed under vacuum, and heat- sealed.

[0044] The results are set out in Table 3.

[0045] Table 3: stability data at 53°C for 15 days

[0046] The results demonstrate that at the end of the stability test, the blend with anhydrous sodium carbonate has a recovery of 79%, whereas the blend with standard-quality sodium carbonate has a recovery of 34%.

[0047] EXAMPLE 4 - Evaluation of stability of SAMe + sodium carbonate combinations at different percentages.

[0048] The compatibility between SAMe Pates and anhydrous sodium carbonate in proportions ranging from 15 to 60% was evaluated under the same conditions as described for Examples 2 and 3. The following blend were used:

[0049] 85% SAMe Pates + 15% anhydrous sodium carbonate (KF=1.47%)

[0050] 40% SAMe Pates + 60% anhydrous sodium carbonate (KF=0.73%).

[0051] The results are set out in Table 4.

[0052] Table 4: Stability data at 53°C for 15 days

[0053] The results demonstrate that at the end of the stability test at 53°C, both the blend with 15% anhydrous sodium carbonate and the blend with 60% anhydrous sodium carbonate have a recovery of 86% after 15 days, not exhibiting any differences.

[0054] EXAMPLE 5 - Evaluation of stability of SAMe blends and tablets and SAMe + sodium carbonate granulate

[0055] The stability of formulations of powdered SAMe Pates and the SAMe granulate described in Example 1, each mixed with anhydrous sodium carbonate, was evaluated. The powders were packaged in single-dose sachets containing 200 mg of SAMe ion, and tablets with the same dose were prepared by adding the minimum amount of excipients technologically necessary.

[0056] Stability was evaluated under the same conditions as described for the preceding examples.

[0057] Powders, blend A: SAMe (68%) + anhydrous sodium carbonate (32%)

[0058] Powders, blend B: SAMe granulate (69%) + anhydrous sodium carbonate (31%)

[0059] Tablet A (560 mg): SAMe (68%) + anhydrous sodium carbonate (31%) + magnesium stearate (1%) + silica (0.30%)

[0060] Tablet B (600 mg): SAMe granulate (69%) + anhydrous sodium carbonate (31%) + silica (0.30%)

[0061] The tablets listed above were obtained with a round convex punch die having a diameter of 11 mm.

[0062] Said tablets were obtained by a process comprising the following steps:

[0063] - preparing the blend after weighing and sieving of each ingredient, and mixing thereof;

[0064] - loading the powder into the hopper of the tablet press and setting said press to obtain tablets of the desired weight, thickness, hardness and friability;

[0065] - optimising the rotation speed of the turret and of the forced loading system to ensure the homogeneity of each tablet;

[0066] - packaging and labelling the resulting tablets.

[0067] The tablets were also stored in a thermostatic stove at +53°C, placing the sample in a closed PE-LD bag, which in turn was inserted into aluminium bag, placed under vacuum and heat-sealed.

[0068] The results are set out in Table 5 and Table 6.

[0069] Table 5: stability data of blends at 53°C for 15 days

[0070] Table 6: stability data of tablets at 53°C for 15 days

[0071] EXAMPLE 6 - Evaluation of stability of combinations of SAMe + potassium carbonate The compatibility between SAMe Pates and potassium carbonate (L0D=1.18%) was evaluated.

[0072] The stability of the SAMe Pates and potassium carbonate tablets was evaluated with an accelerated test. 11 mm diameter tablets were prepared with a dose of 200 mg ion per tablet. SAMe Pates with a 52.8% SAMe ion content was used for the preparation, operating as described in Example 5, but replacing anhydrous sodium carbonate (TABLET A) with anhydrous potassium carbonate. The tablets were also stored in a thermostatic stove at +53 °C for 15 days, placing the sample in a closed PE-LD bag, which in turn was inserted into an aluminium bag placed under vacuum and heat-sealed. At set times, the content of SAMe-ion and the correlated impurities was evaluated by HPLC analysis. The results are set out in Table 7.

[0073] Table 7: Stability data at 53°C for 15 days

[0074] EXAMPLE 7 - Examples of formulations

[0075] The following compositions were prepared: 1) Mouth-dissolving tablet containing 200 mg of S-adenosyl-L-methionine ion

[0076] 2) Mouth-dissolving tablet containing 100 mg of S-adenosyl-L-methionine ion 3) Mouth-dissolving tablet containing 200 mg of S-adenosyl-L-methionine ion.

[0077] A granulate of S-adenosyl methionine, stearic acid and palmitic acid, prepared as described in Example 1, is used. 4) Chewable tablet containing 200 mg of S-adenosyl-L-methionine ion

[0078] 5) Chewable tablet containing 200 mg of S-adenosyl-L-methionine ion and 100 mcg of vitamin K2.

[0079] A preparation of vitamin K2-MK7 on maltodextrins with a 10,000 ppm vitamin content is used.

[0080] 6) Chewable tablet containing 200 mg of S-adenosyl-L-methionine ion (in the form of SAMe granulate) and 100 mcg of vitamin K2.

[0081] A preparation of vitamin K2-MK7 on maltodextrins with a 10,000 ppm vitamin content is used. 7) Chewable tablet containing 400 mg of S-adenosyl-L-methionine ion

[0082] 8) Chewable tablet containing 200 mg of S-adenosyl-L-methionine ion (in the form of SAMe granulate) 9) Mouth-dissolving stick containing 200 mg of S-adenosyl-L-methionine ion

[0083]

[0084] 10) Mouth-dissolving stick containing 200 mg of S-adenosyl-L-methionine ion (in the form of SAMe granulate) 11) Mouth-dissolving stick containing 200 mg of S-adenosyl-L-methionine ion and 400 mcg of 5-methyltetrahydrofolic acid (5-MTHF) glucosamine salt. 12) Mouth-dissolving stick containing 200 mg of S-adenosyl-L-methionine ion and 400 mcg of 5-MTHF (in the form of calcium salt)

[0085] EXAMPLE 8 - Preparation of tablets used for sensory evaluation. To evaluate the palatability of the invention, the following experimental test was set up by combining the active ingredient SAMe Pates with various buffering agents in a stoichiometric amount.

[0086] 11 mm diameter tablets with a dose of 200 mg ion per tablet were prepared for use in the sensory analyses described in Example 9. SAMe Pates with a 52.8% SAMe ion content was used for the preparation, operating as described in Example 5.

[0087] Table 8: composition of tablets used for sensory evaluation The tablets are identical in terms of diameter and colour, and almost identical in terms of weight.

[0088] EXAMPLE 9 - Sensory evaluation of SAMe in the presence of various buffering agents.

[0089] The tablets described in Example 8 were evaluated by a panel of 10 members, previously trained as tasters according to standard ISO 8586 / 1.

[0090] The test was conducted with an objective sensory analysis approach to determine the profile used to describe the succession of sensory perceptions during and after dissolution of the tablet in the mouth.

[0091] Prior to the test, preliminary sessions were held wherein the tasting procedures and the attributes to be evaluated during the test were defined:

[0092] - Tasting procedures: keep the sample still on the tongue for 20 seconds (Attack), then start moving it in the mouth until it has completely dissolved, without chewing it (Evolution). A minute after complete dissolution, terminate the evaluation (Finishing).

[0093] - The panel were asked to indicate which of the attributes evaluated during the test was prevalent at the specified time throughout the tasting test for each formulation, according to the following description:

[0094] Table 9: Attributes evaluated in the tasting test

[0095] In a number of consecutive sessions the judges, using an electronic system, evaluated the sensory attribute described as dominant moment by moment throughout the tasting period. Each judge tasted a single tablet per day, not knowing the composition of the tablet, and each formulation was tasted twice (replications) by each judge. The formulations tested exhibited widely differing dynamic profiles, and can be grouped into two macrocategories: - Formulations P30020-3 and P30020-4 exhibited a dynamic profile characterised by the dominance of acidity and the tactile sensation of astringency

[0096] - Formulations P30020-1, P30020-2, P30020-5 and P30020-6 exhibited a dynamic profile wherein bitterness completely masks the acid flavour. The products can also be broken down into two further subcategories:

[0097] P30020-1, P30020-2 and P30020-6, with a dynamic profile characterised by effervescence, especially in the initial part, and by bitterness, which was more balanced in the aftertaste part (finishing)

[0098] P30020-5, with a profile mainly characterised by the dominance of bitterness at both the initial and final stages.

[0099] In conclusion, the test demonstrates that formulations P30020-1, P30020-2 and P30020- 6 have an acceptable flavour, confirming their palatability. Flavourings or sweeteners can optionally be added to said compositions to obtain formulations with an acceptable flavour and a high concentration of active ingredient.

Claims

CLAIMS1. Mouth-dissolving formulations comprising S-adenosyl methionine or the salts thereof as active ingredient, and at least one excipient comprising or consisting of anhydrous sodium carbonate or anhydrous potassium carbonate.

2. Formulations according to claim 1, wherein the S-adenosyl methionine is in the form of para toluenesulphonate / sulphate, butanesulphonate or phytate.

3. Formulations according to claim 1 or 2 wherein the excipient comprises or consists of anhydrous sodium carbonate.

4. Formulations according to one or more of claims 1 to 3, characterised by a weight ranging from 10 mg to 1500 mg, preferably from 100 mg to 1300 mg.

5. Formulations according to one or more of claims 1 to 4 wherein the excipients comprise diluents, lubricants, antiaggregants, disintegrants, film-forming agents, colourings, sweeteners, flavouring agents or antioxidants.

6. Formulations according to claim 3 wherein the amount of anhydrous sodium carbonate as a percentage of the total weight of the formulation ranges between 10% and 70%, preferably between 15% and 60%.

7. Formulations according to one or more of claims 1 to 6 wherein the amount of active ingredient as a percentage of the total weight of the formulation ranges between 5 and 95%, preferably between 40 and 85%.

8. Formulations according to one or more of claims 1 to 7 in the form of solid formulations selected from orodispersible tablets, sublingual tablets, chewable tablets, powders and / or granulates in sticks or sachets.

9. Formulations according to any one of the preceding claims comprising vitamin K, preferably menaquinone-7.

10. A process for preparing a granulate of SAMe or a salt thereof useful for preparing the formulations of claims 1-9, comprising mixing SAMe or a salt thereof with a low-melting-point excipient and granulating the melted blend.

11. A process according to claim 10 wherein the low-melting-point excipients comprise stearic acid, palmitic acid, mono- / diglycerides of fatty acids or blends thereof.

12. A process according to claim 10 or 11 wherein the granulation is carried out under vacuum.

13. Granulate of SAMe or a salt thereof with low-melting-point excipients selected from stearic acid, palmitic acid, mono- / diglycerides of fatty acids or blends thereof.

14. Granulate according to claim 13 obtainable by the process according to claims 10-13.