Stable oral dissolving formulation based on s-adenosylmethionine

Abstract

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

Description

[0001] This invention relates to edible oral dissolving formulations based on S-adenosylmethionine. BACKGROUND

[0003] S-Adenosyl-L-methionine (SAMe) is a cofactor present in all living organisms and is essential for methylation processes in cellular metabolism. Deficiency of this substance in the human body leads to the onset of many diseases; for example, it is associated with osteoarthritis, cirrhosis, cystic fibrosis, depressive states, and age-related diseases such as Alzheimer's and Parkinson's. Furthermore, low levels of SAMe are also associated with the development of cardiovascular diseases. Injectable forms of SAMe are approved as medicines in many European countries, while oral forms are used as dietary supplements.

[0004] SAMe is characterized by a high level of chemical instability; it degrades rapidly and isomerizes into (R... S SAMe and other degradation products are produced, which can be confirmed by HPLC analysis, as reported in EP2742943. Degradation is accompanied by color changes and the formation of an unpleasant odor.

[0005] SAMe is more stable in its acid-salt forms; for example, EP2945959 describes the preparation of salts with 3-indolylpropionic acid. Salts with 1,4-butanedisulfonic acid, salts with a mixture of sulfuric acid and p-toluenesulfonic acid, and salts with phytic acid are available on the market; the salt form (SAMe Pates) formed with a mixture of sulfuric acid / p-toluenesulfonic acid is the most common.

[0006] SAMe salts are hygroscopic and therefore unstable after absorbing water, which triggers a degradation process. Therefore, formulations containing SAMe salts must be prepared under conditions where the relative humidity is below 20%.

[0007] To increase the stability of SAMe and its salts, excipients capable of slowing their degradation have been proposed, such as casein (EP2742943) and inositol (EP1971370). Desiccants such as calcium chloride, calcium oxide, magnesium sulfate, and magnesium oxide are also widely used. The use of excipients significantly reduces the amount of active ingredient that can be included in oral administration.

[0008] SAMe is primarily used for its beneficial effects on the central nervous system (antidepressant effect) or for the treatment of osteoarthritis. When administered orally, SAMe undergoes a first-pass effect in the liver, which involves the problem of low therapeutic efficacy. Orally absorbed formulations can partially solve this problem; for example, EP2370062 describes the preparation of chewable gum containing SAMe. In addition to carbonates or bicarbonates, formulations in orally dissolving or effervescent tablets also contain stabilizer / drying excipients such as casein (EP2393475), magnesium oxide (EP2393475), or calcium oxide (EP2189154).

[0009] Another problem with oral dissolving formulations relates to the unpleasant taste of SAMe and its salts, particularly Pates salt; even with sweeteners and flavoring agents, most people dislike the taste of a mixture of sulfuric acid and p-toluenesulfonic acid. Furthermore, SAMe Pates are highly acidic and can irritate the oral mucosa. To improve flavor while simultaneously reducing the acidity of the formulation, the addition of arginine bases has been proposed, as described in EP2370062. However, blends with arginine require the use of desiccants and / or stabilizers to prevent the degradation of the active ingredient.

[0010] SUMMARY

[0011] Surprisingly, it has been observed that the palatability and stability of edible formulations of SAMe or its salts are improved by the addition of anhydrous sodium carbonate or potassium carbonate. Combinations of SAMe or its salts with anhydrous sodium carbonate or potassium carbonate can be used as pre-formulations for the preparation of orally dispersible formulations, such as orally dissolving tablets, chewable tablets, sublingual tablets, sachets, etc. Due to their improved flavor and lower acidity, orally dispersible formulations can be produced with minimal amounts of other excipients. In this way, formulations with high active ingredient content are obtained; orally dispersible tablets offer the further advantage of smaller size, improving patient acceptability. Improved palatability results in a longer residence time in the oral cavity due to reduced swallowing impulse.

[0012] Therefore, in a first aspect, the present invention relates to an oral dissolving preparation comprising S-adenosylmethionine or a salt thereof as an active ingredient and at least one excipient comprising anhydrous sodium carbonate or anhydrous potassium carbonate, preferably anhydrous sodium carbonate, or composed thereof.

[0013] Specifications of anhydrous sodium carbonate that can be advantageously used according to the present invention are reported in the monograph on sodium carbonate in Food Chemicals Codex. The amount of anhydrous sodium carbonate as a percentage of the total weight of the formulation ranges from 10% to 70%, preferably 15% to 60%, and more preferably 20% to 35% of the total weight of the composition.

[0014] Preferred S-adenosylmethionine salts are p-toluenesulfonate / sulfate, succinate, and phytate. P-toluenesulfonate / sulfate (SAMe Pates) are particularly preferred. The amount of SAMe or its salts as a percentage of the total weight of the formulation ranges from 5% to 95%, preferably from 40% to 85%.

[0015] The formulations of the present invention may include other excipients, such as diluents, lubricants, anti-aggregating agents, disintegrants, film-forming agents, colorants, sweeteners, flavoring agents, and antioxidants. In addition to SAMe or its salts, the formulations may also contain other active ingredients, particularly vitamin K, preferably methylnaphthoquinone-7.

[0016] The total weight of the formulation is typically from 10 mg to 1500 mg, preferably in the range of 100 mg to 1300 mg.

[0017] According to another aspect, the present invention relates to a method for preparing granules that can be used to prepare formulations of the present invention. The method comprises mixing SAMe or a salt thereof with an excipient having a low melting point, for example, below 70°C, and granulating the melt blend (melt granulation). Examples of low-melting-point excipients include 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. Preferably, stearic acid conforms to the specifications reported in the USP monograph, which is identified in the European Pharmacopoeia as additive E-570.

[0018] Alternatively, a mixture containing stearic acid and palmitic acid can be used, obtained from fats or oils of plant or animal origin.

[0019] Specifically, the method includes the following steps:

[0020] - The active ingredients and excipients are mixed in the processing chamber of a thermostatic granulator, such as a high-shear mixer;

[0021] - Increase the temperature of the processing chamber until the granulation excipient melts;

[0022] - Optionally, a vacuum is created in the processing chamber to eliminate residual moisture retained by the component blend;

[0023] - At the end of the mixing process, the isothermal temperature is lowered below the melting point of the excipient or excipient blend;

[0024] - Optionally, use a granulator equipped with a grid to sieve the granules to the desired size.

[0025] The final result is granules, which ensure greater workability of the raw materials and protect the active ingredients from contact with environmental moisture.

[0026] The particles are another subject of this invention.

[0027] Melt granulation can be used to obtain formulations that also contain other excipients and other active ingredients.

[0028] This method is preferably carried out under vacuum to obtain particles with a moisture content lower than that of the component mixture used at the beginning of the method, despite the strong hygroscopicity of S-adenosylmethionine.

[0029] The invention is explained and described in more detail in the following embodiments.

[0030] Example 1 - Drying of SAMe particles obtained by melt granulation

[0031] A blend to be dried was prepared by mixing the components in the following proportions:

[0032] a) 93% powdered S-adenosylmethionine sulfate / p-toluenesulfonate (SAMe Pates), with an SAMe ion content of approximately 52%.

[0033] b) 7% stearic acid.

[0034] The mixture is then subjected to a granulation process, with the temperature of the thermostatic jacket set at 80°C. When the melting point of the excipient is reached, a vacuum is induced in the granulation chamber.

[0035] To evaluate the true impact of the drying process on the granulation process, four equal samples of the product were taken at the following times:

[0036] - 0 time: Ungranulated blend (SAMe + stearic acid);

[0037] - 10 minutes: The blend is dried under high vacuum;

[0038] - 30 minutes: The blend after drying for 20 minutes;

[0039] - 40 minutes: The blend after drying for 30 minutes.

[0040] The samples were analyzed for residual water by Karl-Fischer titration. The results are listed in Table 1:

[0041]

[0042] The data listed in Table 1 show that the residual water content of the blends decreased significantly in proportion to the duration of the drying process.

[0043] Example 2 - Stability evaluation of SAMe and SAMe particles

[0044] The stability of powdered SAMe Pates and SAMe particles obtained as described in Example 1 was evaluated using accelerated testing. Samples were stored in a constant-temperature oven at +53°C, placed in sealed low-density polyethylene (PE-LD) bags, then inserted into vacuum-sealed aluminum bags and heat-sealed. The content of SAMe ions and related impurities was evaluated by HPLC analysis at set time intervals.

[0045] The results are listed in Table 2.

[0046]

[0047] The results showed that at the end of the experiment, SAMe Pates and stearic acid particles retained 95% of their initial measured values, while SAMe Pates retained 89%; therefore, the drying process improved the stability of the active ingredients.

[0048] Example 3 - Stability evaluation of the combination of SAMe and sodium carbonate

[0049] Sodium carbonate, a commonly used excipient in food, typically has a water content of about 10% in the market, which is incompatible with the chemical stability of SAMe. The compatibility of SAMe Pates with two types of excipients was evaluated: standard mass (loss on drying = 11.50%) and anhydrous sodium carbonate (loss on drying = 0.16%). Testing was conducted by preparing single-dose sachets containing 200 mg of SAMe ions as described in Example 2, the sachets containing the following blend:

[0050] a) 68% SAMe Pates + 32% anhydrous sodium carbonate (KF = 1.05%)

[0051] b) 68% SAMe Pates + 32% Standard Sodium Carbonate (KF = 4.03%)

[0052] The sample was stored in a constant temperature oven at +53°C. The sample was placed in a sealed PE-LD bag, then inserted into an aluminum bag placed under vacuum, and heat-sealed.

[0053] The results are listed in Table 3.

[0054]

[0055] The results showed that at the end of the stability test, the blend containing anhydrous sodium carbonate had a recovery rate of 79%, while the blend containing standard mass sodium carbonate had a recovery rate of 34%.

[0056] Example 4 - Stability evaluation of SAMe + sodium carbonate combinations with different percentages

[0057] Compatibility between SAMe Pates in proportions ranging from 15% to 60% and anhydrous sodium carbonate was evaluated under the same conditions as described in Examples 2 and 3. The following blends were used:

[0058] 85% SAMe Pates + 15% Anhydrous Sodium Carbonate (KF = 1.47%)

[0059] 40% SAMe Pates + 60% anhydrous sodium carbonate (KF = 0.73%).

[0060] The results are listed in Table 4.

[0061]

[0062] The results showed that at the end of the 53℃ stability test, the blend containing 15% anhydrous sodium carbonate and the blend containing 60% anhydrous sodium carbonate both had a recovery rate of 86% after 15 days, showing no difference.

[0063] Example 5 – Stability evaluation of SAMe blends and tablets, as well as SAMe + sodium carbonate granules

[0064] The stability of the powdered SAMe Pates and SAMe granules formulations described in Example 1, each mixed with anhydrous sodium carbonate, was evaluated. The powders were packaged into single-dose capsules containing 200 mg of SAMe ions, and tablets of the same dosage were prepared by adding the minimum amount of excipients technically necessary.

[0065] Stability was evaluated under the same conditions as described in the foregoing embodiments.

[0066] Powder, blend A: SAMe (68%) + anhydrous sodium carbonate (32%)

[0067] Powder, Blend B: SAMe granules (69%) + anhydrous sodium carbonate (31%)

[0068] Tablet A (560 mg): SAMe (68%) + anhydrous sodium carbonate (31%) + magnesium stearate (1%) + silicon dioxide (0.30%)

[0069] Tablet B (600 mg): SAMe granules (69%) + anhydrous sodium carbonate (31%) + silica (0.30%)

[0070] The tablets listed above were obtained using a circular punch with a diameter of 11 mm.

[0071] The tablet is obtained by a method comprising the following steps:

[0072] - Weigh, sieve and mix the components to make a blend;

[0073] - The powder is loaded into the tablet press hopper, and the tablet press is set to obtain tablets with the desired weight, thickness, hardness and brittleness;

[0074] - Optimize the rotation speed of the turntable and forced feeding system to ensure the uniformity of each tablet;

[0075] - Package and label the resulting tablets.

[0076] The tablets were also stored in a constant temperature oven at +53°C. The samples were placed in sealed PE-LD bags, then inserted into aluminum bags, placed under vacuum, and heat-sealed.

[0077] The results are listed in Tables 5 and 6.

[0078]

[0079]

[0080] Example 6 - Stability evaluation of the SAMe + potassium carbonate combination

[0081] The compatibility between SAMe Pates and potassium carbonate (LOD = 1.18%) was evaluated.

[0082] Accelerated testing was used to evaluate the stability of SAMe Pates and potassium carbonate tablets. Tablets with an 11 mm diameter were prepared, each containing 200 mg of ions. SAMe Pates with a SAMe ion content of 52.8% were used, following the procedure described in Example 5, but with anhydrous potassium carbonate instead of anhydrous sodium carbonate (tablet A).

[0083]

[0084] The tablets were also stored in a constant temperature oven at +53°C for 15 days. The samples were placed in sealed PE-LD bags, then inserted into aluminum bags, placed under vacuum, and heat-sealed. At the set time, the content of SAMe ions and related impurities was evaluated by HPLC analysis.

[0085] The results are listed in Table 7.

[0086]

[0087] Example 7 - Formulation Example

[0088] Prepare the following compositions:

[0089] 1) Orally dissolving tablets containing 200mg of S-adenosine-L-methionine ions

[0090]

[0091] 2) Orally dissolving tablets containing 100 mg of S-adenosine-L-methionine ions

[0092]

[0093] 3) Orally dissolving tablets containing 200 mg of S-adenosine-L-methionine ions

[0094] Particles of S-adenosylmethionine, stearic acid, and palmitic acid prepared as described in Example 1 were used.

[0095]

[0096] 4) Chewable tablets containing 200mg of S-adenosine-L-methionine ions

[0097]

[0098] 5) Chewable tablets containing 200 mg S-adenosine-L-methionine ions and 100 mcg vitamin K2

[0099] The vitamin K2-MK7 formulation used on maltodextrin contains 10,000 ppm of vitamin K2.

[0100]

[0101] 6) Chewable tablets containing 200 mg S-adenosine-L-methionine ions (in SAMe granule form) and 100 mcg vitamin K2.

[0102] The vitamin K2-MK7 formulation used on maltodextrin contains 10,000 ppm of vitamin K2.

[0103]

[0104] 7) Chewable tablets containing 400 mg of S-adenosine-L-methionine ions

[0105]

[0106] 8) Chewable tablets containing 200 mg of S-adenosine-L-methionine ions (in SAMe particle form)

[0107]

[0108] 9) Oral dissolving stick containing 200mg S-adenosine-L-methionine ions

[0109]

[0110] 10) Oral dissolving sticks containing 200mg S-adenosine-L-methionine ions (in the form of SAMe particles)

[0111]

[0112] 11) Oral dissolving stick containing 200 mg S-adenosyl-L-methionine ions and 400 mcg 5-methyltetrahydrofolate (5-MTHF) glucosamine salt

[0113]

[0114] 12) Oral dissolving sticks containing 200 mg S-adenosyl-L-methionine ions and 400 mcg 5-MTHF (calcium salt form).

[0115]

[0116] Example 8 - Preparation of tablets for sensory evaluation

[0117] To evaluate the palatability of the present invention, the following experimental tests were conducted by mixing the active ingredient SAMe Pates with various stoichiometric buffers.

[0118] Tablets with a diameter of 11 mm and a dose of 200 mg ions per tablet were prepared for the sensory analysis described in Example 9.

[0119] SAMe Pates with a SAMe ion content of 52.8% were used for preparation, as described in Example 5.

[0120]

[0121] The tablets are identical in diameter and color, and almost identical in weight.

[0122] Example 9 - Sensory evaluation of SAMe in the presence of various buffers

[0123] The tablets described in Example 8 were evaluated by a panel of 10 members who had been trained beforehand as tasters according to standard ISO 8586 / 1.

[0124] The test was conducted using objective sensory analysis methods to determine the characteristics used to describe the continuous sensory perception during and after the tablet dissolves in the mouth.

[0125] Prior to the trial, a preliminary trial was conducted to determine the tasting procedures and the attributes to be evaluated during the trial:

[0126] - Tasting procedure: Hold the sample still on the tongue for 20 seconds (attack), then begin moving it around in the mouth until it is completely dissolved without chewing (progression). Stop evaluation one minute after complete dissolution (complete).

[0127] - The panel is required to identify which attributes evaluated during the testing period were prevalent at specified times throughout the entire tasting test for each formulation, based on the following description:

[0128]

[0129] In multiple consecutive sessions, judges used an electronic system to assess the dominant sensory properties described at each moment throughout the tasting period. Each judge tasted one tablet per day, unaware of the tablet's composition, and each judge tasted each formulation twice (repeatedly). The tested formulations exhibited a wide range of dynamic characteristics and could be divided into two main categories:

[0130] - Formulations P30020-3 and P30020-4 exhibited dynamic characteristics primarily characterized by acidity and astringent feel.

[0131] Formulations P30020-1, P30020-2, P30020-5, and P30020-6 exhibit a dynamic characteristic where bitterness completely masks sourness. The products can also be further subdivided into two subcategories:

[0132] - P30020-1, P30020-2, and P30020-6 have dynamic characteristics characterized by effervescence (especially in the initial phase) and bitterness (which is more balanced in the aftertaste).

[0133] - P30020-5 is characterized by a predominantly bitter taste in both the beginning and the end stages.

[0134] In summary, this test demonstrates that formulations P30020-1, P30020-2, and P30020-6 possess acceptable flavors, confirming their palatability. Flavoring agents or sweeteners may optionally be added to the compositions to obtain formulations with acceptable flavors and high concentrations of active ingredients.

Claims

1. An oral dissolving preparation comprising S-adenosylmethionine or a salt thereof as an active ingredient and at least one excipient comprising or composed of anhydrous sodium carbonate or anhydrous potassium carbonate.

2. The formulation according to claim 1, wherein S-adenosylmethionine is in the form of toluenesulfonate / sulfate, butyrate, or phytate.

3. The formulation according to claim 1 or 2, wherein the excipient comprises or is composed of anhydrous sodium carbonate.

4. The formulation according to one or more of claims 1 to 3, characterized in that... The weight ranges from 10 mg to 1500 mg, preferably from 100 mg to 1300 mg.

5. The formulation according to one or more of claims 1 to 4, wherein the excipient comprises a diluent, a lubricant, an anti-aggregating agent, a disintegrant, a film-forming agent, a colorant, a sweetener, a flavoring agent, or an antioxidant.

6. The formulation according to claim 3, wherein the amount of anhydrous sodium carbonate as a percentage of the total weight of the formulation is in the range of 10% to 70%, preferably 15% to 60%.

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

8. A formulation according to one or more of claims 1 to 7, wherein it is in the form of a solid dosage form selected from oral dispersible tablets, sublingual tablets, chewable tablets, sticks or pouches of powder and / or granules.

9. The formulation according to any one of the preceding claims, comprising vitamin K, preferably methylnaphthoquinone-7.

10. A method for preparing granules of SAMe or a salt thereof for use in the preparation of formulations of claims 1-9, the method comprising mixing SAMe or a salt thereof with a low-melting-point excipient and granulating the molten blend.

11. The method of claim 10, wherein the low-melting-point excipient comprises stearic acid, palmitic acid, fatty acid mono / diglycerides, or blends thereof.

12. The method of claim 10 or 11, wherein the granulation is performed under vacuum.

13. SAMe or its salts and particles of a low-melting-point excipient selected from stearic acid, palmitic acid, fatty acid monoglycerides / diglycerides or blends thereof.

14. The particles according to claim 13, which can be obtained by the method of claims 10-13.

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