US20090110729A1 - Solid oral compositions based on s-adenosyl methionine and/or nadh and process for obtaining them - Google Patents

Solid oral compositions based on s-adenosyl methionine and/or nadh and process for obtaining them Download PDF

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US20090110729A1
US20090110729A1 US12/240,002 US24000208A US2009110729A1 US 20090110729 A1 US20090110729 A1 US 20090110729A1 US 24000208 A US24000208 A US 24000208A US 2009110729 A1 US2009110729 A1 US 2009110729A1
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Daniele Giovannone
Carlo De Angelis
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Gnosis SpA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/282—Organic compounds, e.g. fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • SAMe S-adenosyl methionine
  • This substance therefore has a very important biological role and is essentially used in clinical practice as an antidepressant.
  • SAMe is meant both the racemic mixture and the individual diastereoisomers (RS)-(+)-S-adenosyl-L-methionine [(RS)-(+)-SAMe)] and (SS)-(+)-S-adenosyl-L-methionine [(SS)-(+)-SAMe)], as well as mixtures other than the racemic mixture.
  • S-adenosyl methionine as a drug and/or dietetic is however known because it is extremely unstable at temperatures above 0° C. or in the presence of moisture, through both degradation of the active ingredient, understood to be the sum of the two diastereoisomers, and through the conversion of active (SS)-(+)-S-adenosyl-L-methionine to inactive (RS)-(+)-S-adenosyl-L-methionine (racemisation of the substance).
  • Italian Patent no. 829906 describes a process for the preparation of pharmaceutically acceptable salts of (SS,RS)-S-adenosyl-L-methionine with quantities of inactive diastereoisomer (RS)-(+)-S-adenosyl-L-methionine of 3% or less with respect to the active diastereoisomer (SS)-(+)-S-adenosyl-L-methionine of 97% or more.
  • SS,RS diastereoisomer SS-(+)-S-adenosyl-L-methionine
  • the patent confirms that although more than 97% of active S,S diastereoisomer is obtained at ambient temperature, the racemic mixture is unstable over time, with conversion of the (SS)-(+)-S-adenosyl-L-methionine into (RS)-(+)-S-adenosyl-L-methionine in a relatively short time.
  • FIG. 1 represents a graph illustrating the water absorption capacity of several materials over time.
  • FIG. 2 illustrates the water absorbency of several materials at a varying Relative Humidity.
  • U.S. Pat. Nos. 13,627, 663,943, 98,102 and 354,263 describe a method for stabilising pharmaceutically acceptable salts of S-adenosyl methionine comprising S-adenosyl methionine paratoluene sulphonate, S-adenosyl methionine-1,4-butene disulphonate, S-adenosyl methionine sulphate, S-adenosyl methionine tosylate with a group of substances comprising chitosan, dextrin, carboxymethylcellulose, fumaric acid, azelaic acid and tryptophan.
  • the rate of racemisation of SAMe as a salt of S-adenosyl methionine paratoluene sulphonate differs from the racemisation of SAMe in the form of S-adenosyl methionine-1,4-butene disulphonate salt, or S-adenosyl methionine sulphate or as S-adenosyl methionine tosylate.
  • formulations based on S-adenosyl methionine reflect the abovementioned instability and racemisation of the active ingredient, (conversion of the active S,S diastereoisomer into the inactive R,S diastereoisomer), with obvious adverse repercussions for the preservation and storage of the material, even for short periods of time.
  • U.S. Pat. Nos. 3,954,726 and 4,057,672 describe relatively stable salts of S-adenosyl methionine, that is up to 25° C. and 45° C., respectively.
  • U.S. Pat. No. 4,465,672 also describes stable salts of S-adenosyl methionine with 5 mols of a sulphonic acid with a pK of less than 2.5.
  • the process of preparing the product comprises preparation of a concentrated aqueous solution of an impure salt of SAMe, purification of the solution and its elution with a dilute aqueous solution of the preselected sulphonic acid, titration of the resulting eluate, concentration and lyophilisation or spraying.
  • NADH is an active ingredient normally used as an energising agent and antioxidant.
  • compositions based on NADH such as those for example described in U.S. Pat. Nos. 5,332,727 and 7,034,011 are based on stabilising the active ingredient through association with other antioxidants.
  • Calcium oxide and/or hydroxide directly mixed with atomised SAMe and/or NADH powder, or with solid formulations based on SAMe and/or NADH, are successful in removing water through a chemical reaction with the powder or the preparation itself.
  • Calcium oxide is instead a natural desiccant with very high reactivity in relation to water. It reacts with it and changes to a calcium hydroxide, eliminating it permanently in preparations.
  • FIG. 1 shows the rate of absorption of H 2 O with different absorbent substances including calcium oxide.
  • FIG. 2 shows the absorption capacity for water vapour of various desiccants as the environmental humidity (RH) varies.
  • Table 1 summarises the absorbent capacities of various desiccants under different relative humidity and temperature conditions.
  • Table 2 provides moisture content values for five lots of starting material of SAMe (S-adenosyl methionine paratoluene sulphonate) with its corresponding analysis prior to mixing with calcium oxide and storage at 20° C. for 21 days, and the relative accelerated stability at 53° C. for 5 days.
  • Table 3 shows moisture content values for five lots of starting material of SAMe (S-adenosyl methionine paratoluene sulphonate) with its corresponding analysis after mixing with calcium oxide and storage at 20° C. for 21 days, and the relative accelerated stability at 53° C. for 5 days.
  • SAMe S-adenosyl methionine paratoluene sulphonate
  • Table 4 shows moisture content values for five lots of starting material of SAMe (S-adenosyl methionine-1,4-butene disulphonate) with corresponding analysis prior to mixing with calcium oxide and storage at 20° C. for 21 days, and the relative accelerated stability at 53° C. for 5 days.
  • SAMe S-adenosyl methionine-1,4-butene disulphonate
  • Table 5 shows moisture content values for five lots of starting material of SAMe (S-adenosyl methionine-1,4-butene disulphonate) with corresponding analysis after mixing with calcium oxide and storage for 23° C. for 21 days, and the relative accelerated stability at 53° C. for 5 days.
  • SAMe S-adenosyl methionine-1,4-butene disulphonate
  • Table 6 shows moisture content values for five lots of starting material of NADH with corresponding analysis prior to mixing with calcium oxide and storage at 20° C. for 21 days, and the relative accelerated stability at 53° C. for 5 days.
  • Table 7 shows moisture content values for five lots of starting material of NADH with corresponding analysis after mixing with calcium oxide and storage at 20° C. for 21 days, and the relative accelerated stability at 53° C. for 5 days.
  • one object of this invention relates to compositions comprising SAMe and/or NADH, or their salts, in association with calcium oxide and/or calcium hydroxide, and optionally pharmaceutically acceptable excipients.
  • SAMe is meant both the racemic mixture and the individual (RS)-(+)-S-adenosyl-L-methionine [(RS)-(+)-SAMe)] and (SS)-(+)-S-adenosyl-L-methionine [(SS)-(+)-SAMe)] diastereoisomers, including the mixtures other than the racemic mixture.
  • compositions according to this invention contain SAMe, or its salts, in a quantity of between 30 and 90% by weight, preferably between 50 and 85% by weight, with respect to the weight of the composition, in association with calcium oxide and/or calcium hydroxide in a quantity of between 1 and 40% by weight, preferably between 2 and 20% by weight, with respect to the weight of the composition.
  • compositions according to this invention contain NADH, or its salts, in a quantity between 1 and 90% by weight, preferably between 5 and 50% by weight, with respect to the weight of the composition, in association with calcium oxide and/or calcium hydroxide in a quantity of between 1 and 40% by weight, preferably between 2 and 20% by weight, with respect to the weight of the composition.
  • the said SAMe, or its salts is S-adenosyl methionine paratoluene sulphonate, S-adenosyl methionine-1,4-butene disulphonate, S-adenosyl methionine sulphate, S-adenosyl methionine tosylate.
  • the NADH is present in the form of its pharmaceutically acceptable salts.
  • the said calcium oxide and/or calcium hydroxide is calcium oxide alone, calcium hydroxide alone, or a mixture thereof.
  • the pharmaceutically acceptable excipients used according to this invention are preferably selected from calcium sulphate hemihydrate, magnesium oxide, malic acid, glutamic acid, glucono-delta-lactone, xylitol and/or their mixtures.
  • compositions according to this invention may optionally comprise at least one further active ingredient, preferably selected from melatonin, 1-theanine and/or 1-tryptophan and/or 5-hydroxytryptophan and/or their mixtures.
  • compositions according to this invention may be in the form of a direct mixture, tablets, capsules, granules and/or powder.
  • direct mixture is meant a mixture of atomised powder of SAMe and/or NADH, or their salts, in association with calcium oxide and/or calcium hydroxide alone, without the addition of other excipients.
  • compositions according to this invention are in the form of tablets, more preferably in the form of ordinary, coated, film-coated and/or gastroresistant tablets.
  • ordinary tablet is meant a tablet obtained by direct compression or compression after granulation without coating
  • coated tablet is meant a tablet coated with non-gastroresistant substances
  • film-coated tablet is meant a coated tablet which is further covered with water-based varnishes, which varnishes may have a gastroresistant action.
  • compositions according to this invention may be film-coated with water-based varnishes preferably selected from gum Lac (ShellacTM) and/or its salts, methacrylic acid, cellulose acetophthalates, titanium dioxide, talc, triethyl citrate, PVP K30, curcumin, lutein, hydroxypropylcellulose, hydroxypropylmethylcellulose and/or mixtures thereof.
  • gum Lac ShinyTM
  • methacrylic acid cellulose acetophthalates
  • titanium dioxide titanium dioxide
  • talc triethyl citrate
  • PVP K30 triethyl citrate
  • curcumin curcumin
  • lutein lutein
  • hydroxypropylcellulose hydroxypropylmethylcellulose and/or mixtures thereof.
  • gastroresistant tablets are meant tablets capable of passing unchanged through the gastric barrier.
  • the said film coating with varnishes when provided through ShellacTM, salts, cellulose acetophthalates and/or other coatings which are insoluble in an acid environment, may render the compositions according to the invention resistant to passage through the stomach.
  • the varnishes according to this invention may be present in a quantity varying from 1.0 to 1.98% by weight with respect to the composition.
  • compositions according to this invention have approximately 60% less moisture content (KF) than the compositions based on SAMe known hitherto and are approximately 12 times less hygroscopic than shown in Table 6 above.
  • compositions according to this invention are preferably intended for the treatment of depressive states.
  • a further object of this invention is a process for the preparation of solid compositions for oral use comprising SAMe and/or NADH, or their salts, in association with calcium oxide and/or calcium hydroxide which comprises the following stages:
  • the process according to this invention is carried out in an environment in which the relative humidity lies below 20% and the temperature is held between 18 and 25° C., preferably around 20° C.
  • Granulation according to this invention is preferably carried out using a rotating blade granulator fitted with a stainless mesh having holes of between 1.2 mm and 3.2 mm in diameter.
  • SAMe or its salts, is used in a quantity varying from 30 to 90% by weight, preferably from 50 to 85% by weight, with respect to the weight of the composition.
  • NADH or its salts
  • NADH is used in a quantity varying from 1 to 90% by weight, preferably from 5 to 50% by weight, with respect to the weight of the composition.
  • the pharmaceutically acceptable excipients used in the process according to the invention are preferably selected from calcium sulphate hemihydrate, magnesium oxide, calcium carbonate, malic acid, glutamic acid, xylitol, saccharose, anhydrous microcrystalline cellulose, hydrogenated fatty acids, magnesium stearate, glycerol behenate, precipitated silica.
  • the active ingredient is preferably mixed with calcium oxide from approximately 1.0 to approximately 10% by weight and/or magnesium stearate from approximately 0.5 to approximately 5% by weight and/or precipitated silica from approximately 0.5 to approximately 2.0% by weight calculated with respect to the active ingredient.
  • the granulate obtained in b) is preferably mixed with magnesium hydroxide from approximately 1.0 to 10.0% by weight and/or microcrystalline cellulose from approximately 1.0 to approximately 20.0% by weight and/or hydrogenated fatty acids from approximately 1.0 to approximately 10% by weight and/or malic acid from approximately 1 to approximately 10% by weight and/or glutamic acid from approximately 1 to approximately 10% by weight and/or glucono-delta-lactone from approximately 1 to approximately 10% by weight, magnesium stearate from approximately 0.5 to approximately 5% by weight and/or glycerol behenate from approximately 1.0 to approximately 5.0% calculated with respect to the active ingredient.
  • magnesium hydroxide from approximately 1.0 to 10.0% by weight and/or microcrystalline cellulose from approximately 1.0 to approximately 20.0% by weight and/or hydrogenated fatty acids from approximately 1.0 to approximately 10% by weight and/or malic acid from approximately 1 to approximately 10% by weight and/or glutamic acid from approximately 1 to approximately 10% by weight and/or glucono-delta-lactone from approximately 1 to approximately 10% by
  • At least one further active ingredient preferably selected from melatonin, 1-theanine and/or 1-tryptophan and/or 5-hydroxytryptophan and/or their mixtures may be added to the mixture for the treatment of depressive states.
  • coating with hydrogenated fatty acids may be performed using conventional processes known in the art, with if appropriate the addition of surfactants which are miscible in the oily liquid.
  • the coating mentioned in stage e) may be performed using hydrogenated fatty acids, preferably molten hydrogenated vegetable fatty acids, in a quantity of between approximately 0.4 and approximately 1.5% by weight with respect to the weight of the composition.
  • stage h) in the process according to this invention makes it possible to reduce the hygroscopic nature of the tablet obtained in stage g) by approximately twelve times, bringing about appreciable advantages in any subsequent stage of aqueous phase film-forming.
  • Aqueous phase film-forming (stage i) may be carried out using a substance or varnish preferably selected from gum Lac (ShellacTM) and/or its salts, methacrylic acid, cellulose acetophthalates, titanium dioxide, talc, triethyl citrate, PVP K30, curcumin, lutein, hydroxypropylcellulose, hydroxypropylmethylcellulose and/or mixtures thereof.
  • gum Lac ShineTM
  • methacrylic acid methacrylic acid
  • cellulose acetophthalates titanium dioxide
  • talc triethyl citrate
  • PVP K30 triethyl citrate
  • curcumin curcumin
  • lutein lutein
  • hydroxypropylcellulose hydroxypropylmethylcellulose and/or mixtures thereof.
  • the said film-forming may be carried out using substances preferably selected from gum Lac (ShellacTM) and/or its salts.
  • a further object of this invention is the use of SAMe or its salts in association with calcium and magnesium for the preparation of pharmaceutical, dietetic and/or nutritional/pharmaceutical compositions for the treatment of depressive states.
  • Yet a further object of this invention is a method for stabilising SAMe and/or NADH, preferably the (S,S) enantiomer, or its salts, which comprises the use of calcium oxide and/or calcium hydroxide in the percentages indicated above.
  • SAMe ion/tablet Composition based on SAMe sulphate p-toluene sulphonate A. SAMe sulphate p-toluene sulphonate 800.00 mg B Calcium oxide 70.00 mg C. Magnesium hydroxide 80.00 mg D. Saccharose 100.00 mg E. Calcium carbonate 80.00 mg F. Magnesium stearate 20.00 mg G. Malic acid 40.00 mg E. Hydrogenated fatty acid 50.00 mg Total weight of core 1240.00 mg F. Hydrogenated vegetable fatty acids 4.00 mg G. Shellac ® 30.00 mg H. PVP K 30 6.0 mg I. Titanium dioxide 5.00 mg L. Talc 10.00 mg M. Triethyl citrate 5.00 mg N. Curcumin 0.050 mg Total weight of tablet 1300.50 mg
  • the working environment was conditioned to a temperature of 20° C. and a relative humidity value of approximately 20% RH.
  • A, B, C, D, E and G and 50% of F were then transferred to the mixer in the quantities indicated above, leaving them with stirring for approximately 30 minutes.
  • the resulting mixture was transferred to dry containers, always controlling moisture content and temperature.
  • Precompression of the mixture was effected using a rotary machine equipped with round punches of 25.0 mm.
  • the hardness of the tablets produced had to be regulated to subsequently produce a granulate having good flow characteristics.
  • the tablets produced during the first processing stage were granulated on a 1000-1500 ⁇ m mesh, again in a humidity-controlled environment.
  • stage 1 . 3 The granulate obtained in stage 1 . 3 was transferred into the mixer, adding magnesium stearate and leaving it with stirring for approximately 30 minutes. At the end of this operation the resulting mixture was transferred into dry containers.
  • Final compression of the granulate was carried out using a rotary machine equipped with oblong punches of 21.0 ⁇ 9.8 mm adjusting the weight to 1240 mg/tablet and the compression force to at least 25 KP.
  • the tablets produced had a hardness of between 25 and 35 Kp.
  • Friability ⁇ 1.0%; disaggregation time: ⁇ 15 minutes (measured using the method described in U.S.P. 24 th ed.)
  • the tablets resulting from the preceding processing stages were coated in a bowl with a mixture of hydrogenated fatty acids (4.0 mg/tablet).
  • Hydrogenated fatty acid melting at 70° C. was placed in a glass container of 2.0 litres and the temperature of the mixture was raised to approximately 75° C. obtaining a homogeneous fused mass.
  • ShellacTM and PVP were dissolved in a container of suitable size until a solution of 20% w/v was obtained, and triethyl citrate was added slowly with constant stirring.
  • talc, titanium dioxide and curcumin were dispersed in 4.0 l of deionised water.
  • the resulting suspension was poured into the ShellacTM solution, washing the container with approximately 1.0 l of deionised water, subsequently diluting with a further 4.0 l of deionised water.
  • the temperature of the cores was held at 54° C. for approximately 40 minutes, and this was then reduced in regular steps down to a value of 45° C. in the final stage.
  • SAMe ion/tablet Compositions based on SAMe sulphate p-toluene sulphonate A. SAMe sulphate p-toluene sulphonate 800.00 mg B. L-melatonin 2.00 mg C Calcium oxide 70.00 mg D. Magnesium hydroxide 100.00 mg E. Calcium sulphate hemihydrate 100.00 mg F. Calcium carbonate 160.00 mg G. Magnesium stearate 20.00 mg H. Malic acid 40.00 mg I. Hydrogenated fatty acid 40.00 mg Total weight of core 1332.00 mg L. Hydrogenated vegetable fatty acids 4.00 mg M. Shellac ® 30.00 mg N. PVP K 30 6.0 mg O. Titanium dioxide 5.00 mg P. Talc 10.00 mg Q. Triethyl citrate 5.00 mg R. Curcumin 0.050 mg Total weight of tablet 1302.50 mg
  • the quantities relate to the preparation of a standard industrial lot of 250.00 kg of tablets.
  • the tablets were prepared in the manner described in Example 1 using the components and quantities indicated above.
  • SAMe ion/tablet Composition based on SAMe sulphate p-toluene sulphonate A. SAMe sulphate p-toluene sulphonate 800.00 mg B. L-theanine 200.00 mg C Calcium oxide 70.00 mg D. Magnesium hydroxide 100.00 mg E. Xylitol 50.00 mg F. Calcium carbonate 100.00 mg G. Microcrystalline cellulose 60.00 mg H. Magnesium stearate 20.00 mg I. Malic acid 40.00 mg L. Hydrogenated fatty acid 40.00 mg Total weight of core 1480.00 mg M. Hydrogenated vegetable fatty acids 4.00 mg N. Shellac ® 30.00 mg O. PVP K 30 6.0 mg P. Titanium dioxide 5.00 mg Q. Talc 10.00 mg R. Triethyl citrate 5.00 mg S. Hydroxypropylmethylcellulose 10.00 mg T. Curcumin 0.050 mg Total weight of tablet 1550.05 mg
  • the quantities relate to the preparation of a standard industrial lot of 250.00 kg of tablets.
  • the tablets were prepared in the manner described in Example 1 using the components and quantities indicated above.
  • SAMe ion/tablet Composition based on SAMe sulphate p-toluene sulphonate A. SAMe sulphate p-toluene sulphonate 800.00 mg B Calcium oxide 70.00 mg C. Magnesium hydroxide 100.00 mg D. Calcium carbonate 150.00 mg E. Magnesium stearate 20.00 mg F. Malic acid 40.00 mg G. Hydrogenated fatty acid 40.00 mg Total weight of core 1220.00 mg H. Hydrogenated vegetable fatty acids 8.00 mg I. Hydroxypropylmethylcellulose 30.00 mg L. PVP K 30 6.0 mg M Titanium dioxide 5.00 mg N. Talc 10.00 mg O. Triethyl citrate 5.00 mg P. Curcumin 0.050 mg Total weight of tablet 1284.05 mg
  • the quantities relate to the preparation of a standard industrial lot of 250.00 kg of tablets.
  • the tablets were prepared in the manner described in Example 1 using the components and quantities indicated above.
  • the quantities relate to the preparation of a standard industrial lot of 250.00 kg of tablets.
  • the tablets were prepared in the manner described in Example 1 using the components and quantities indicated above.
  • SAMe ion/tablet Composition based on SAMe sulphate p-toluene sulphonate A. SAMe sulphate p-toluene sulphonate 800.00 mg B. Folic acid 3.00 mg C. Melatonin 2.00 mg C Calcium oxide 70.00 mg D. Magnesium hydroxide 100.00 mg E. Calcium carbonate 100.00 mg F. Calcium sulphate 100.00 mg G. Magnesium stearate 20.00 mg H. Malic acid 40.00 mg I. Hydrogenated fatty acid 40.00 mg Total weight of core 1275.00 mg
  • the quantities relate to the preparation of a standard industrial lot of 250.00 kg of tablets.
  • the tablets were prepared in the manner described in Example 1 using the components and quantities indicated above.
  • the quantities relate to the preparation of a standard industrial lot of 20.00 kg of tablets
  • the tablets were prepared in stoppered glass bottles and enclosed in such a way as to reproduce the conditions of final packaging (generally aluminium/aluminium blister).
  • the samples so prepared were stored for six months in a stove thermostatted to a temperature of 40 ⁇ 2° C. and 75% RH.
  • the tablets were packed in stoppered glass bottles and enclosed in such a way as to reproduce the conditions of final packaging (generally aluminium/aluminium blister).
  • the samples were selected in the same way and in the same quantities as described for the stress test and kept in an environment thermostatted to a temperature of 25 ⁇ 2° C. and a humidity of 60% RH.
  • SAMe ion/tablet Composition based on SAMe sulphate p-toluene sulphonate A. SAMe sulphate p-toluene sulphonate 800.00 mg B Calcium oxide absent 00.00 mg C. Magnesium hydroxide 150.00 mg D. Saccharose 100.00 mg E. Calcium carbonate 80.00 mg F. Magnesium stearate 20.00 mg G. Malic acid 40.00 mg E. Hydrogenated fatty acid 50.00 mg Total weight of core 1240.00 mg F. Hydrogenated vegetable fatty acids 4.00 mg G. Shellac ® 30.00 mg H. PVP K 30 6.0 mg I. Titanium dioxide 5.00 mg L. Talc 10.00 mg M. Triethyl citrate 5.00 mg N. Curcumin 0.050 mg Total weight of tablet 1300.50 mg
  • SAMe ion/tablet Compositions based on SAMe sulphate p-toluene sulphonate A. SAMe sulphate p-toluene sulphonate 800.00 mg B. L-melatonin 2.00 mg C Calcium oxide absent 00.00 mg D. Magnesium hydroxide 170.00 mg E. Calcium sulphate hemihydrate 100.00 mg F. Calcium carbonate 160.00 mg G. Magnesium stearate 20.00 mg H. Malic acid 40.00 mg I. Hydrogenated fatty acid 40.00 mg Total weight of core 1332.00 mg L. Hydrogenated vegetable fatty acids 4.00 mg M. Shellac ® 30.00 mg N. PVP K 30 6.0 mg O. Titanium dioxide 5.00 mg P. Talc 10.00 mg Q. Triethyl citrate 5.00 mg R. Curcumin 0.050 mg Total weight of tablet 1302.50 mg
  • the quantities relate to the preparation of a standard industrial lot of 250.00 kg of tablets.
  • the tablets were prepared in the manner described in Example 1 using the components and quantities indicated above.
  • SAMe ion/tablet Composition based on SAMe sulphate p-toluene sulphonate A. SAMe sulphate p-toluene sulphonate 800.00 mg B. L-theanine 200.00 mg C Calcium oxide absent 00.00 mg D. Magnesium hydroxide 170.00 mg E. Xylitol 50.00 mg F. Calcium carbonate 100.00 mg G. Microcrystalline cellulose 60.00 mg H. Magnesium stearate 20.00 mg I. Malic acid 40.00 mg L. Hydrogenated fatty acid 40.00 mg Total weight of core 1480.00 mg M. Hydrogenated vegetable fatty acids 4.00 mg N. Shellac ® 30.00 mg O. PVP K 30 6.0 mg P. Titanium dioxide 5.00 mg Q. Talc 10.00 mg R. Triethyl citrate 5.00 mg S. Hydroxypropylmethylcellulose 10.00 mg T. Curcumin 0.050 mg Total weight of tablet 1550.05 mg
  • the quantities relate to the preparation of a standard industrial lot of 250.00 kg of tablets.
  • the tablets were prepared in the manner described in Example 1 using the components and quantities indicated above.
  • the tablets were prepared in stoppered glass bottles and enclosed in such a way as to reproduce the conditions of final packaging (generally aluminium/aluminium blister).
  • the samples so prepared were stored for six months in a stove thermostatted to a temperature of 40 ⁇ 2° C. and 75% RH.
  • Example 1A Nine samples from three different lots were used for the 400 mg tablets (Examples 1A, 2A, 3A,), and each sample from each lot was sampled after 0, 1, 3 and 6 months.
  • the tablets were packed in stoppered glass bottles and enclosed in such a way as to reproduce the conditions of final packaging (generally aluminium/aluminium blister).
  • the samples were selected in the same way and in the same quantities as described for the stress test and kept in an environment thermostatted to a temperature of 25 ⁇ 2° C. and a humidity of 60% RH.
  • Example 1A Nine samples originating from three different lots were used for the 400 mg tablets (Examples 1A, 2A, 3A,), and each sample from each lot was sampled after 0, 3, 6, 12 months.

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US12/240,002 2006-03-31 2008-09-29 Solid oral compositions based on s-adenosyl methionine and/or nadh and process for obtaining them Abandoned US20090110729A1 (en)

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IT000629A ITMI20060629A1 (it) 2006-03-31 2006-03-31 Composizioni solide orali a base di s-adenosilmetionina e processo per il loro ottenimento
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US20110027360A1 (en) * 2009-07-28 2011-02-03 Methylation Sciences International Srl Pharmacokinetics of s-adenosylmethionine formulations
US20110059903A1 (en) * 2009-08-06 2011-03-10 Ironwood Pharmaceuticals, Inc. Formulations Comprising Linaclotide
EA015508B1 (ru) * 2011-03-03 2011-08-30 Екофарм Патент Менеджмент Аг Фармацевтическая композиция, стимулирующая биосинтез s-аденозилметионина, и пероральное лекарственное средство
WO2012012902A1 (en) * 2010-07-28 2012-02-02 Msi Methylation Sciences Inc. S-adenosylmethionine formulations with enhanced bioavailability
US8802628B2 (en) 2008-08-15 2014-08-12 Ironwood Pharmaceuticals, Inc. Stable solid formulation of a GC-C receptor agonist polypeptide suitable for oral administration
US8933030B2 (en) 2010-02-17 2015-01-13 Ironwwod Pharmaceuticals, Inc. Treatments for gastrointestinal disorders
US9708371B2 (en) 2011-08-17 2017-07-18 Ironwood Pharmaceuticals, Inc. Treatments for gastrointestinal disorders
US10675325B2 (en) 2010-08-11 2020-06-09 Ironwood Pharmaceuticals, Inc. Stable formulations of linaclotide

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EP2189154A1 (en) 2008-11-25 2010-05-26 Gnosis S.p.A. Effervescent tablets and mouth-soluble granulates of S-adenosyl methionine and process for the preparation thereof
IT1393331B1 (it) * 2009-02-09 2012-04-20 Graal S R L Composizioni orosolubili e/o effervescenti contenenti almeno un sale di s-adenosilmetionina (same)
TR201103625A1 (tr) * 2011-04-14 2012-12-21 Sanovel İlaç Sanayi̇ Ve Ti̇caret Anoni̇m Şi̇rketi̇ Sefuroksim içeren tablet formülasyonu üretim prosesi.
ITMI20131906A1 (it) * 2013-11-18 2015-05-19 Gnosis Spa Composizioni solide orali a lento rilascio
ES2775734T3 (es) * 2015-08-31 2020-07-28 Nutramax Lab Inc Composiciones que comprenden magnolia, felodendron, teanina y/o proteína de suero
IT202000006127A1 (it) * 2020-03-23 2021-09-23 Fmc S R L Formulazione farmaceutica, dietetica e/o alimentare a base ademetionina e processo di realizzazione di detta formulazione
CN115708820B (zh) * 2023-01-09 2023-06-02 广东科泰鼎润药业科技有限公司 L-茶氨酸缓释制剂、双释放制剂、应用和药物

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US3954726A (en) * 1973-06-27 1976-05-04 Bioresearch Limited Double salts of S-adenosil-L-methionine
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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090088404A1 (en) * 2007-01-31 2009-04-02 Methylation Sciences International Srl Extended Release Pharmaceutical Formulations of S-Adenosylmethionine
US8802628B2 (en) 2008-08-15 2014-08-12 Ironwood Pharmaceuticals, Inc. Stable solid formulation of a GC-C receptor agonist polypeptide suitable for oral administration
US8865203B2 (en) 2009-07-28 2014-10-21 Methylation Sciences International Srl Pharmacokinetics of S-adenosylmethionine formulations
WO2011012989A1 (en) * 2009-07-28 2011-02-03 Msi Methylation Sciences Inc. S-adenosylmethionine formulations with enhanced bioavailability
US9931356B2 (en) 2009-07-28 2018-04-03 Methylation Sciences International Srl Pharmacokinetics of S-adenosylmethionine formulations
US20110027360A1 (en) * 2009-07-28 2011-02-03 Methylation Sciences International Srl Pharmacokinetics of s-adenosylmethionine formulations
US20110027342A1 (en) * 2009-07-28 2011-02-03 Msi Methylation Sciences, Inc. S-adenosylmethionine formulations with enhanced bioavailability
US8329208B2 (en) 2009-07-28 2012-12-11 Methylation Sciences International Srl Pharmacokinetics of S-adenosylmethionine formulations
US8580296B2 (en) 2009-07-28 2013-11-12 Methylation Sciences International Srl Pharmacokinetics of S-adenosylmethionine formulations
AU2010277301B2 (en) * 2009-07-28 2014-01-23 Msi Methylation Sciences Inc. S-adenosylmethionine formulations with enhanced bioavailability
US8748573B2 (en) * 2009-08-06 2014-06-10 Ironwood Pharmaceuticals, Inc. Formulations comprising linaclotide
US20110059903A1 (en) * 2009-08-06 2011-03-10 Ironwood Pharmaceuticals, Inc. Formulations Comprising Linaclotide
US8933030B2 (en) 2010-02-17 2015-01-13 Ironwwod Pharmaceuticals, Inc. Treatments for gastrointestinal disorders
WO2012012902A1 (en) * 2010-07-28 2012-02-02 Msi Methylation Sciences Inc. S-adenosylmethionine formulations with enhanced bioavailability
US10675325B2 (en) 2010-08-11 2020-06-09 Ironwood Pharmaceuticals, Inc. Stable formulations of linaclotide
US10702576B2 (en) 2010-08-11 2020-07-07 Ironwood Pharmaceuticals, Inc. Stable formulations of linaclotide
EA015508B1 (ru) * 2011-03-03 2011-08-30 Екофарм Патент Менеджмент Аг Фармацевтическая композиция, стимулирующая биосинтез s-аденозилметионина, и пероральное лекарственное средство
US9708371B2 (en) 2011-08-17 2017-07-18 Ironwood Pharmaceuticals, Inc. Treatments for gastrointestinal disorders

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HUE047955T2 (hu) 2020-05-28
DK2007479T3 (da) 2020-02-24
EP2007479A2 (en) 2008-12-31
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AU2006341243B2 (en) 2012-02-23
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US10471088B2 (en) 2019-11-12
BRPI0621556B8 (pt) 2021-05-25
MEP22708A (en) 2010-06-10
ME00115B (me) 2010-10-10
WO2007113885A8 (en) 2008-11-13
ZA200808118B (en) 2009-12-30
CN101415464B (zh) 2013-10-30
IL194254A0 (en) 2009-09-22
ITMI20060629A1 (it) 2007-10-01
CN101415464A (zh) 2009-04-22
PL2007479T3 (pl) 2020-09-21
IL194254A (en) 2015-07-30
HRP20200315T1 (hr) 2020-06-12
JP5562632B2 (ja) 2014-07-30
ES2774913T3 (es) 2020-07-23
RS20080441A (en) 2009-07-15
CA2645767A1 (en) 2007-10-11
BRPI0621556B1 (pt) 2020-09-29
CA2645767C (en) 2015-03-17
AU2006341243A1 (en) 2007-10-11
US20150306126A1 (en) 2015-10-29
WO2007113885A2 (en) 2007-10-11
SI2007479T1 (sl) 2020-04-30
EA017895B1 (ru) 2013-04-30

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