S-adenosine-L-methionine p-toluenesulfonic acid sulfate composition, coating preparation and preparation method thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to an S-adenosine-L-methionine p-toluenesulfonic acid sulfate composition, a coating preparation and a preparation method of the coating preparation. The invention provides an S-adenosine-L-methionine p-toluenesulfonic acid sulfate composition. The S-adenosine-L-methionine p-toluenesulfonic acid sulfate composition is prepared from the following components in percentage by mass: 40 to 90 percent of S-adenosine-L-methionine p-toluenesulfonic acid sulfate, 1 to 40 percent of anhydrous calcium hydrogen phosphate and 1 to 30 percent of pharmaceutically acceptable auxiliary materials. According to the S-adenosine-L-methionine p-toluenesulfonic acid sulfate composition, the anhydrous calcium hydrogen phosphate and the S-adenosine-L-methionine p-toluenesulfonic acid sulfate are compounded, and meanwhile, the mass ratio of the S-adenosine-L-methionine p-toluenesulfonic acid sulfate to the anhydrous calcium hydrogen phosphate is optimized, so that the obtained S-adenosine-L-methionine p-toluenesulfonic acid sulfate composition does not easily absorb moisture and is good in stability.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to a composition of S-adenosyl-L-methionine tosylate sulfate and a coated preparation thereof, and a preparation method thereof. Background Art

[0002] S-adenosyl-L-methionine tosylate sulfate (hereinafter referred to as SAMe-T) is a metabolite formed by the combination of the sulfur-containing amino acid methionine and adenosine triphosphate, the main energy substance in the human body. In the human body, SAMe-T is an important physiologically active substance that participates in more than 40 biochemical reactions and is an active precursor of sulfur-containing compounds such as glutathione, cysteine, taurine, and coenzyme A. SAMe-T can be used to treat diseases such as depression, arthritis, and liver function disorders, and is also a high-grade health care drug for preventing cancer, cardiovascular diseases, and anti-aging, with the characteristics of rapid onset, small side effects, safety and reliability. Its important physiological effects have attracted wide attention. In addition, SAMe-T can also be used as an antioxidant and a raw material for the enzymatic synthesis of biotin, spermidine, and spermine, etc., and it is also used to produce beauty cosmetics for removing dandruff, relieving itching, reducing wrinkles, and anti-aging.

[0003] SAMe-T can be obtained by chemical synthesis, in vitro enzymatic synthesis, or extraction by microbial fermentation. The most critical problem in the production and application of SAMe-T is its poor stability and easy inactivation reaction. Since SAMe-T is a chemically unstable substance, it will decompose rapidly even at room temperature, which is a major obstacle to the use of drugs and supplements. This has greatly limited its clinical application. Summary of the Invention

[0004] The purpose of the present invention is to provide a composition of S-adenosyl-L-methionine tosylate sulfate and a coated preparation thereof, and a preparation method thereof. The composition of S-adenosyl-L-methionine tosylate sulfate and the coated preparation provided by the present invention are not easy to absorb moisture and have good stability.

[0005] To achieve the above purpose, the present invention provides the following technical solutions: The present invention provides a composition of S-adenosyl-L-methionine tosylate sulfate, comprising the following components in mass percentage: 40-90% of S-adenosyl-L-methionine tosylate sulfate, 1-40% of anhydrous calcium hydrogen phosphate, and 1-30% of pharmaceutically acceptable excipients.

[0006] Preferably, the pharmaceutically acceptable excipients include one or more of excipients, binders, lubricants, and glidants.

[0007] Preferably, the excipient includes one or more of microcrystalline cellulose, anhydrous lactose, mannitol, starch, pregelatinized starch, and sucrose; The binder includes one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, and polyvinylpyrrolidone; The lubricant includes one or more of magnesium stearate, stearic acid, and sodium stearyl fumarate; The glidant includes colloidal silica and / or talc powder.

[0008] Preferably, the pharmaceutically acceptable excipients include the following components in mass percentage: Excipient 1 - 10%, binder 1 - 5%, lubricant 0.1 - 3%, and glidant 0.1 - 2%.

[0009] The present invention provides a method for preparing the S-adenosyl-L-methionine p-toluenesulfonate sulfate composition according to the above technical solution, including the following steps: Mix S-adenosyl-L-methionine p-toluenesulfonate sulfate, anhydrous calcium hydrogen phosphate, and pharmaceutically acceptable excipients to obtain a mixed material; Perform dry granulation on the mixed material to obtain dry granules of the S-adenosyl-L-methionine p-toluenesulfonate sulfate composition.

[0010] Preferably, the conditions for dry granulation include: the feeding speed is 20 - 80 r / min; the pressure roller speed is 5 - 16 r / min; the final granulation speed is 20 - 140 r / min; the hydraulic pressure is 0 - 15 MPa and not 0; the pressure roller spacing is 0 - 5 mm and not 0.

[0011] The present invention provides an S-adenosyl-L-methionine p-toluenesulfonate sulfate coating preparation, including the S-adenosyl-L-methionine p-toluenesulfonate sulfate composition according to the above technical solution or the S-adenosyl-L-methionine p-toluenesulfonate sulfate composition prepared by the preparation method according to the above technical solution; and a coating material.

[0012] Preferably, the coating material includes one or more of methacrylic acid - ethyl acrylate copolymer, polyvinyl alcohol, talc powder, titanium dioxide, glycerol monocaprylate / dicaprylate, and sodium lauryl sulfate.

[0013] Preferably, it includes coated granules or coated tablets.

[0014] The present invention provides a method for preparing the S-adenosyl-L-methionine p-toluenesulfonate sulfate coating preparation according to the above technical solution, including the following steps: Mix the coating material and a diluent to obtain a coating solution; When the S-adenosyl-L-methionine p-toluenesulfonate coated preparation is a coated granule, the dry granules of the S-adenosyl-L-methionine p-toluenesulfonate composition are coated with a coating solution to obtain the S-adenosyl-L-methionine p-toluenesulfonate coated granule; When the S-adenosyl-L-methionine p-toluenesulfonate coated preparation is a coated tablet, the dry granules of the S-adenosyl-L-methionine p-toluenesulfonate composition are tabletted to obtain a plain tablet; the plain tablet is coated with a coating solution to obtain the S-adenosyl-L-methionine p-toluenesulfonate coated tablet.

[0015] The present invention provides an S-adenosyl-L-methionine p-toluenesulfonate composition, comprising the following components in mass percentage: 40-90% of S-adenosyl-L-methionine p-toluenesulfonate, 1-40% of anhydrous calcium hydrogen phosphate, and 1-30% of pharmaceutically acceptable excipients. The present invention uses anhydrous calcium hydrogen phosphate and S-adenosyl-L-methionine p-toluenesulfonate in combination, and at the same time optimizes the mass ratio of S-adenosyl-L-methionine p-toluenesulfonate and anhydrous calcium hydrogen phosphate, so that the obtained S-adenosyl-L-methionine p-toluenesulfonate composition is not easy to absorb moisture and has good stability.

[0016] The present invention provides a preparation method of the S-adenosyl-L-methionine p-toluenesulfonate composition described in the above technical solution, comprising the following steps: mixing S-adenosyl-L-methionine p-toluenesulfonate, anhydrous calcium hydrogen phosphate and pharmaceutically acceptable excipients to obtain a mixed material; subjecting the mixed material to dry granulation to obtain dry granules of the S-adenosyl-L-methionine p-toluenesulfonate composition. The present invention uses the method of dry granulation to prepare dry granules, which is beneficial to reducing the moisture content in the dry granules. At the same time, the preparation method of the dry granules of the S-adenosyl-L-methionine p-toluenesulfonate composition provided by the present invention has simple processes, high production efficiency, increased production capacity, is beneficial to reducing costs, and is suitable for industrial application. Detailed implementation manners

[0017] The present invention provides an S-adenosyl-L-methionine p-toluenesulfonate composition, comprising the following components in mass percentage: 40-90% of S-adenosyl-L-methionine p-toluenesulfonate, 1-40% of anhydrous calcium hydrogen phosphate, and 1-30% of pharmaceutically acceptable excipients.

[0018] In the present invention, unless otherwise specified, all preparation raw materials / components are commercially available products well-known to those skilled in the art.

[0019] In terms of mass percentage, the S-adenosyl-L-methionine p-toluenesulfonate sulfate composition provided by the present invention comprises 40-90% of S-adenosyl-L-methionine p-toluenesulfonate sulfate, preferably 50-85%, more preferably 60-85%, and may be 80% or 82% in the examples.

[0020] In terms of mass percentage, the S-adenosyl-L-methionine p-toluenesulfonate sulfate composition provided by the present invention comprises 1-40% of anhydrous calcium hydrogen phosphate, preferably 5-35%, more preferably 6-25%, and may be 12% or 7.75% in the examples.

[0021] In terms of mass percentage, the S-adenosyl-L-methionine p-toluenesulfonate sulfate composition provided by the present invention comprises 1-30% of pharmaceutically acceptable excipients, preferably 2-30%, more preferably 2.2-20%, further preferably 6-14%, and may be 8% or 10.25% in the examples. In the present invention, the pharmaceutically acceptable excipients include one or more of excipients, binders, lubricants, and glidants.

[0022] In the present invention, the excipients preferably include one or more of microcrystalline cellulose, anhydrous lactose, mannitol, starch, pregelatinized starch, and sucrose. The binders preferably include one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, and polyvinylpyrrolidone. The lubricants preferably include one or more of magnesium stearate, stearic acid, and sodium stearyl fumarate. The glidants preferably include colloidal silicon dioxide and / or talc powder.

[0023] In terms of mass percentage, the S-adenosyl-L-methionine p-toluenesulfonate sulfate composition provided by the present invention preferably comprises 1-10% of excipients, more preferably 4.5-7.75%, and may be 4.5% or 7.75% in the examples.

[0024] In terms of mass percentage, the S-adenosyl-L-methionine p-toluenesulfonate sulfate composition provided by the present invention preferably comprises 1-5% of binders, more preferably 2-3% of binders, and may be 3% or 2% in the examples.

[0025] In terms of mass percentage, the S-adenosyl-L-methionine p-toluenesulfonate sulfate composition provided by the present invention preferably comprises 0.1-3% of lubricants, more preferably 0.1-2%, and may be 0.2% in the examples.

[0026] In terms of mass percentage, the S-adenosyl-L-methionine p-toluenesulfonate sulfate composition provided by the present invention preferably comprises 0.1-2% of glidants, more preferably 0.1-1%, and may be 0.3% in the examples.

[0027] In the present invention, the S-adenosyl-L-methionine p-toluenesulfonate composition is preferably dry granules of the S-adenosyl-L-methionine p-toluenesulfonate composition. The dry granules of the S-adenosyl-L-methionine p-toluenesulfonate composition are preferably granules between 20-mesh and 40-mesh sieves.

[0028] The present invention provides a method for preparing the S-adenosyl-L-methionine p-toluenesulfonate composition according to the above technical solution, comprising the following steps: Mix S-adenosyl-L-methionine p-toluenesulfonate, anhydrous calcium hydrogen phosphate and a pharmaceutically acceptable excipient to obtain a mixed material; Perform dry granulation on the mixed material to obtain dry granules of the S-adenosyl-L-methionine p-toluenesulfonate composition.

[0029] In the present invention, S-adenosyl-L-methionine p-toluenesulfonate, anhydrous calcium hydrogen phosphate and a pharmaceutically acceptable excipient are mixed to obtain a mixed material. In the present invention, before the mixing, the S-adenosyl-L-methionine p-toluenesulfonate, anhydrous calcium hydrogen phosphate and a pharmaceutically acceptable excipient are preferably sieved. The sieving preferably uses a 24-mesh sieve, and the sieving preferably selects the undersize. The mixing is preferably carried out in a hopper mixer.

[0030] After obtaining the mixed material, the present invention performs dry granulation on the mixed material to obtain dry granules of the S-adenosyl-L-methionine p-toluenesulfonate composition. In the present invention, the dry granulation is preferably carried out in a dry granulator. The conditions for dry granulation preferably include: the feeding rotation speed is preferably 20-80 r / min, more preferably 20-50 r / min; the pressure roller rotation speed is preferably 5-16 r / min, more preferably 10-15 r / min; the final sizing rotation speed is preferably 20-140 r / min, more preferably 100-140 r / min; the hydraulic pressure is preferably 0-15 MPa and not 0, more preferably 6-12 MPa, and can be 9 MPa in the examples; the pressure roller spacing is preferably 0-5 mm and not 0, more preferably 1-3 mm.

[0031] In the present invention, after dry granulation, an initial particle product is obtained. The present invention preferably sieves the initial particle product. The sieving preferably uses 20-mesh and 40-mesh sieves. The present invention preferably obtains the undersize of the 20-mesh sieve and the oversize of the 40-mesh sieve to obtain the dry granules of the S-adenosyl-L-methionine p-toluenesulfonate composition.

[0032] The present invention provides a coated preparation of S-adenosyl-L-methionine p-toluenesulfonate sulfate, which comprises the S-adenosyl-L-methionine p-toluenesulfonate sulfate composition described in the above technical solution or the S-adenosyl-L-methionine p-toluenesulfonate sulfate composition prepared by the preparation method described in the above technical solution; and a coating material.

[0033] The coated preparation of S-adenosyl-L-methionine p-toluenesulfonate sulfate provided by the present invention comprises an S-adenosyl-L-methionine p-toluenesulfonate sulfate composition. The S-adenosyl-L-methionine p-toluenesulfonate sulfate composition is preferably dry granules of the S-adenosyl-L-methionine p-toluenesulfonate sulfate composition. The dry granules of the S-adenosyl-L-methionine p-toluenesulfonate sulfate composition are preferably granules between 20-mesh and 40-mesh sieves.

[0034] The coated preparation of S-adenosyl-L-methionine p-toluenesulfonate sulfate provided by the present invention comprises a coating material. In the present invention, the coating material preferably comprises one or more of methyl methacrylate-ethyl acrylate copolymer, polyvinyl alcohol, talcum powder, titanium dioxide, glycerol monocaprylate / dicaprylate and sodium lauryl sulfate.

[0035] In the present invention, the coated preparation of S-adenosyl-L-methionine p-toluenesulfonate sulfate preferably comprises a coated granule or a coated tablet. By using the coated preparation in the present invention, the S-adenosyl-L-methionine p-toluenesulfonate sulfate can be wrapped by the coating material, effectively blocking the moisture in the air and being beneficial to the long-term preservation of the dry granules.

[0036] In the present invention, when the coated preparation of S-adenosyl-L-methionine p-toluenesulfonate sulfate is a coated granule, the coating material preferably comprises methyl methacrylate-ethyl acrylate copolymer, polyvinyl alcohol, talcum powder, titanium dioxide, glycerol monocaprylate / dicaprylate and sodium lauryl sulfate.

[0037] In the present invention, the coating material in the coated granule of S-adenosyl-L-methionine p-toluenesulfonate sulfate preferably comprises components with the following mass percentages: 11-16% of methyl methacrylate-ethyl acrylate copolymer, 1-4% of polyvinyl alcohol, 1-2.5% of talcum powder, 0.1-0.5% of titanium dioxide, 0.1-0.7% of glycerol monocaprylate / dicaprylate and 0.05-0.1% of sodium lauryl sulfate. The balance of the coated granule of S-adenosyl-L-methionine p-toluenesulfonate sulfate is the S-adenosyl-L-methionine p-toluenesulfonate sulfate composition.

[0038] In the present invention, when the coated preparation of S-adenosyl-L-methionine p-toluenesulfonate sulfate is a coated tablet, the coating material preferably comprises polyvinyl alcohol, talcum powder, titanium dioxide, glycerol monocaprylate / dicaprylate and sodium lauryl sulfate.

[0039] In the present invention, the coating material of the S-adenosyl-L-methionine tosylate sulfate coated tablets preferably comprises components with the following mass percentages: polyvinyl alcohol 1-4%, talcum powder 1-2.5%, titanium dioxide 0.1-0.5%, glycerol monocaprylate / dicaprylate / caprate 0.1-0.7%, and sodium lauryl sulfate 0.05-0.1%. The balance of the S-adenosyl-L-methionine tosylate sulfate coated tablets is the S-adenosyl-L-methionine tosylate sulfate composition.

[0040] In the present invention, in the S-adenosyl-L-methionine tosylate sulfate coated preparation, the mass percentage of the coating material is preferably 5-24%, more preferably 10-24%, further preferably 15-24%, and in the examples, it can be 5%, 7.8%, 16%, 18.8%, 21% or 23.8%. The balance of the S-adenosyl-L-methionine tosylate sulfate coated preparation is the S-adenosyl-L-methionine tosylate sulfate composition.

[0041] The present invention provides a method for preparing the S-adenosyl-L-methionine tosylate sulfate coated preparation according to the above technical solution, comprising the following steps: Mix the coating material and the diluent to obtain a coating solution; When the S-adenosyl-L-methionine tosylate sulfate coated preparation is a coated granule, coat the dry granules of the S-adenosyl-L-methionine tosylate sulfate composition with the coating solution to obtain S-adenosyl-L-methionine tosylate sulfate coated granules; When the S-adenosyl-L-methionine tosylate sulfate coated preparation is a coated tablet, compress the dry granules of the S-adenosyl-L-methionine tosylate sulfate composition into a plain tablet; coat the plain tablet with the coating solution to obtain S-adenosyl-L-methionine tosylate sulfate coated tablets.

[0042] In the present invention, the coating material and the diluent are mixed to obtain a coating solution. The diluent is preferably an aqueous ethanol solution, and the aqueous ethanol solution is preferably obtained by mixing an aqueous ethanol solution with an ethanol volume content of 95 wt% and purified water. The mass percentage of the coating material in the coating solution is preferably 8-10%.

[0043] The present invention preferably mixes the coating material, an aqueous ethanol solution with an ethanol content of 95% (v:v), and purified water to obtain the coating solution. In the examples, the mass ratio of the aqueous ethanol solution with an ethanol content of 95% (v:v) to purified water can be 90:10.

[0044] The present invention preferably uses an aqueous ethanol solution as a diluent for the coating solution, which can reduce the water absorption of dry granules during the coating process.

[0045] After obtaining the coating solution, when the S-adenosyl-L-methionine tosylate coating preparation is a coated granule, the present invention coats the dry granules of the S-adenosyl-L-methionine tosylate composition with the coating solution (hereinafter referred to as the first coating) to obtain S-adenosyl-L-methionine tosylate coated granules. In the present invention, the first coating is preferably a fluidized bed spray drying method. The fluidized bed spray drying method is preferably a continuous production. The first coating is preferably carried out in a fluidized bed. The first coating preferably includes: placing the dry granules of the S-adenosyl-L-methionine tosylate composition in a fluidized bed, spraying the coating solution at the bottom of the fluidized bed, and coating and spray drying the dry granules of the S-adenosyl-L-methionine tosylate composition placed in the fluidized bed. The conditions of the first coating preferably include: the inlet air temperature is preferably 50-65 °C, the outlet air temperature is preferably 40-45 °C, the air volume is preferably 10-15 Hz, the atomization pressure is preferably 1.5-2 bar, and the peristaltic pump speed is preferably 5-8 rpm.

[0046] The present invention uses dry granules of the S-adenosyl-L-methionine tosylate composition, and the particle sizes of the granules are basically the same. The uniform particle size is beneficial to uniformly coating the dry granules with the coating solution during the first coating process.

[0047] After obtaining the coating solution, when the S-adenosyl-L-methionine tosylate coating preparation is a coated tablet, the present invention compresses the dry granules of the S-adenosyl-L-methionine tosylate composition to obtain a plain tablet; the plain tablet is coated with the coating solution (hereinafter referred to as the second coating) to obtain an S-adenosyl-L-methionine tosylate coated tablet. In the present invention, the compression is carried out using a tablet press, and the weight of the plain tablet is preferably 1000 mg / tablet. The hardness of the plain tablet is preferably 25-30 Kp. The second coating is preferably carried out in a coating pan. The second coating is preferably spray coating. The conditions of the second coating preferably include: the inlet air temperature is preferably 45-50 °C, the outlet air temperature is preferably 35-40 °C, the inlet air volume is preferably 140-150 m 3 / h, the atomization pressure is preferably 1.3-1.5 bar, the slurry spraying speed is preferably 5-10 rpm, and the main machine speed is preferably 5-10 rpm.

[0048] The coating preparation method provided by the present invention for S-adenosyl-L-methionine p-toluenesulfonate sulfate reduces the moisture content of the coating preparation, simplifies the production process, and improves the stability of the active ingredient. The production process is simple, and dry granulation is adopted. The first coating uses the fluidized bed spray drying method, which is a continuous production process, improving production efficiency, increasing production capacity, and facilitating cost reduction.

[0049] To further illustrate the present invention, the technical solutions provided by the present invention will be described in detail below in conjunction with embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0050] Example 1 This example provides an S-adenosyl-L-methionine p-toluenesulfonate sulfate composition. The formula of the dry granules is shown in Table 1, and the formula of the particle coating powder of the coated granules is shown in Table 2. The mass percentages of the substances in Table 2 are the mass percentages of each material in the coating powder in the coated granule agent.

[0051] Table 1 Formula of the S-adenosyl-L-methionine p-toluenesulfonate sulfate dry granules provided in Example 1

[0052] Table 2 Formula of the particle coating powder of the coated granules provided in Example 1

[0053] This example provides a method for preparing S-adenosyl-L-methionine p-toluenesulfonate sulfate coated granules, which includes the following steps: (1) Weigh the dry granule raw materials (SAMe-T, anhydrous calcium hydrogen phosphate, microcrystalline cellulose, magnesium stearate, colloidal silica) according to the formula amount of the S-adenosyl-L-methionine p-toluenesulfonate sulfate composition in Table 1. After passing the dry granule raw materials through a 24-mesh sieve, put them into a hopper mixer and mix evenly. After mixing evenly, add them to a dry granulator, adjust the pressure roller spacing, hydraulic pressure, pressure roller speed, and feeding speed, and turn on the instrument to prepare granules. The parameter settings are: feeding speed 20.0 r / min, pressure roller speed 15.0 r / min, final granulation speed 140.0 r / min, hydraulic pressure 9.0 MPa, and pressure roller spacing 1.0 mm.

[0054] Finally, pass the granules obtained by granulation through a 20-mesh sieve and a 40-mesh sieve, and take the granules between the 20-mesh sieve and the 40-mesh sieve to obtain the dry granule product.

[0055] Dry granule coating: Add coating powder into 95% (v:v) ethanol and purified water (the mass ratio of 95% (v:v) ethanol to purified water is 90:10) to prepare a coating powder solution with a mass percentage of 8 wt% coating powder; Place the dry granule product in a fluidized bed, and perform bottom spray coating and fluidized bed drying on the dry granules (after the fluidized bed coating is completed, close the bottom spray coating gun head, maintain the temperature, and perform drying in the fluidized bed). The condition parameters for bottom spray coating in the fluidized bed are set as follows: inlet air temperature 65.0 °C, exhaust air temperature 45.0 °C, air volume 15.0 Hz, atomization pressure 2.0 bar, peristaltic pump speed 8.0 rpm. When performing fluidized bed drying, close the atomization pressure and peristaltic pump parameters, and keep the others unchanged.

[0056] Example 2 This example provides an S-adenosyl-L-methionine p-toluenesulfonate sulfate composition. The formula of the dry granules is shown in Table 3, and the formula of the granule coating powder for the coated granules is shown in Table 4.

[0057] Table 3 Formula of S-adenosyl-L-methionine p-toluenesulfonate sulfate dry granules provided in Example 2

[0058] Table 4 Formula of granule coating powder for coated granules provided in Example 2

[0059] This example provides a method for preparing S-adenosyl-L-methionine p-toluenesulfonate sulfate coated granules, which includes the following steps: (1) Weigh the dry granule raw materials (SAMe-T, anhydrous calcium hydrogen phosphate, anhydrous lactose, hypromellose, magnesium stearate, colloidal silicon dioxide) according to the formula amount of the S-adenosyl-L-methionine p-toluenesulfonate sulfate composition in Table 3. After passing the dry granule raw materials through a 24-mesh sieve, put them into a hopper mixer and mix evenly; After mixing evenly, add them into a dry granulator, adjust the pressure roller spacing, hydraulic pressure, pressure roller speed, and feeding speed, and turn on the instrument to prepare granules; The parameter settings are: feeding speed 20.0 r / min, pressure roller speed 15.0 r / min, final sizing speed 140.0 r / min, hydraulic pressure 9.0 MPa, pressure roller spacing 1.0 mm.

[0060] Finally, pass the granules obtained from granulation through a 20-mesh sieve and a 40-mesh sieve, and take the granules between the 20-mesh sieve and the 40-mesh sieve to obtain the dry granule product.

[0061] Dry granule coating: Add coating powder into 95% (v:v) ethanol and purified water (the mass ratio of 95% (v:v) ethanol to purified water is 90:10) to prepare a coating powder solution with a mass percentage of 8 wt% coating powder; Place the dry granule product in a fluidized bed, and perform bottom spray coating on the dry granules in the fluidized bed and fluidized bed drying (after the fluidized bed coating is completed, close the bottom spray coating gun head, maintain the temperature, and perform drying in the fluidized bed). The condition parameters for bottom spray coating in the fluidized bed are set as follows: inlet air temperature 65.0 °C, exhaust air temperature 45.0 °C, air volume 15.0 Hz, atomization pressure 2.0 bar, peristaltic pump speed 8.0 rpm. When performing fluidized bed drying, turn off the two parameters of atomization pressure and peristaltic pump, and keep the others unchanged.

[0062] The difference between Example 1 and Example 2 is that no binder is added in Example 1. Example 1 and Example 2 investigate the influence of the binder on the preparation characteristics. It is found through experimental data that the preparation characteristics of the formulation with the added binder are better than those without the added binder.

[0063] Example 3 This example provides a composition of S-adenosyl-L-methionine p-toluenesulfonate sulfate. The formula of the dry granules is shown in Table 5, and the formula of the granule coating powder of the coated granules is shown in Table 6.

[0064] Table 5 Formula of S-adenosyl-L-methionine p-toluenesulfonate sulfate dry granules provided in Example 3

[0065] Table 6 Formula of the granule coating powder of the coated granules provided in Example 3

[0066] This example provides a preparation method for S-adenosyl-L-methionine p-toluenesulfonate sulfate coated granules. The preparation method of the coated granules is the same as that in Example 2.

[0067] Example 4 This example provides a composition of S-adenosyl-L-methionine p-toluenesulfonate sulfate. The formula of the dry granules is shown in Table 7, and the formula of the tablet coating powder of the coated tablets is shown in Table 8.

[0068] Table 7 Formula of S-adenosyl-L-methionine p-toluenesulfonate sulfate dry granules provided in Example 4

[0069] Table 8 Formula of the tablet coating powder of the coated tablets provided in Example 4

[0070] This example provides a method for preparing S-adenosyl-L-methionine p-toluenesulfonate sulfate coated tablets, which includes the following steps: In this example, the method for preparing the dry granule product is the same as that in Example 3.

[0071] After obtaining the dry granule product, tableting is carried out: using a tableting machine for tableting, adjusting the tablet weight to 1000 mg / tablet, and the tablet hardness to be between 25 and 30 N.

[0072] Tablet coating: Add the coating powder into 95% (v:v) ethanol and purified water (the mass ratio of 95% (v:v) ethanol to purified water is 90:10) to prepare a coating powder solution with a mass percentage content of 8 wt% of the coating powder; place the obtained tablets in a coating pan for coating. When coating in the coating pan, the condition parameters for spray coating are set as follows: inlet air temperature 50.0 °C, exhaust air temperature 40.0 °C, inlet air volume 150.0 m 3 / h, atomization pressure 1.5 bar, spraying speed 10.0 rpm, main machine speed: 10.0 rpm.

[0073] Example 5 It is basically the same as the method for preparing the S-adenosyl-L-methionine p-toluenesulfonate sulfate composition and coated granules provided in Example 2, except that: the microcrystalline cellulose in Example 2 is replaced with anhydrous lactose. The performance of the obtained coated granule product is similar to that of Example 2.

[0074] Comparative Example 1 Refer to Example 1 disclosed on page 18 of the specification of Chinese Patent CN101415464A to prepare tablets of 400 mg SAMe ions / tablet.

[0075] Test Example 1 Take appropriate amounts of the granules or tablets prepared in Examples 1 to 5 and Comparative Example 1, and determine the moisture content by the Karl Fischer method. The test results are shown in Table 9, and the moisture content at point 0 in Table 9 is the moisture content at the initial moment when the product production is completed.

[0076] Table 9 Moisture content results at point 0 of the granules or tablets prepared in Examples 1 to 5 and Comparative Example 1

[0077] Test Example 2 Take appropriate amounts of the granules or tablets prepared in Examples 1 to 5 and Comparative Example 1 (granules ≥ 3.0 g, tablets ≥ 3 tablets), and determine the cumulative moisture absorption weight gain at 25 °C and 60% RH. The test results are shown in Table 10.

[0078] Table 10 Moisture absorption weight gain results of the granules or tablets prepared in Examples 1 to 5 and Comparative Example 1

[0079] Test Example 3 Take the granules prepared in Examples 1 to 3 and Example 5 (equal in mass to 1 tablet in Example 4), 1 tablet of the tablets prepared in Example 4, and 1 tablet of the tablets prepared in Comparative Example 1. After double-aluminum packaging, conduct stability sampling, place them in a stability chamber at 40°C and 75% RH, and determine the related substances after 1 month and 3 months. The results are shown in Tables 11 and 12.

[0080] Table 11 Results of related substances after being placed in a stability chamber at 40°C and 75% RH for 1 month

[0081] Table 12 Results of related substances after being placed in a stability chamber at 40°C and 75% RH for 3 months

[0082] The above results show that the SAMe-T granules prepared by the method of the present invention reduce the moisture content of SAMe-T, are stable during long-term storage, have lower requirements for environmental humidity and temperature, are easy to produce, and improve production efficiency.

[0083] As can be seen from the above examples, the present invention provides an S-adenosyl-L-methionine p-toluenesulfonate sulfate composition, which comprises the following components in mass percentage: 40-90% of S-adenosyl-L-methionine p-toluenesulfonate sulfate, 1-40% of anhydrous calcium hydrogen phosphate, and the balance being pharmaceutically acceptable excipients. The present invention uses anhydrous calcium hydrogen phosphate to compound with S-adenosyl-L-methionine p-toluenesulfonate sulfate, and at the same time optimizes the mass ratio of S-adenosyl-L-methionine p-toluenesulfonate sulfate and anhydrous calcium hydrogen phosphate, so that the obtained S-adenosyl-L-methionine p-toluenesulfonate sulfate composition is not easy to absorb moisture and has good stability.

[0084] Although the above embodiments have described the present invention in detail, they are only a part of the embodiments of the present invention, rather than all embodiments. Other embodiments can also be obtained according to these embodiments without creative efforts, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A S-adenosyl-L-methionine p-toluenesulfonic acid sulfate composition, characterized in that: Includes the following components in percentage by mass: S-adenosyl-L-methionine p-toluenesulfonic acid sulfate 40-90%, anhydrous calcium hydrogen phosphate 1-40%, and pharmaceutically acceptable excipients 1-30%.

2. The S-adenosyl-L-methionine p-toluenesulfonic acid sulfate composition according to claim 1, characterized in that: The pharmaceutically acceptable excipients include one or more of excipients, binders, lubricants and glidants.

3. The S-adenosyl-L-methionine p-toluenesulfonic acid sulfate composition according to claim 2, characterized in that: The excipients include one or more of microcrystalline cellulose, anhydrous lactose, mannitol, starch, pregelatinized starch and sucrose; The binder comprises one or more of hydroxypropyl cellulose, hypromellose, ethyl cellulose and povidone; The lubricant includes one or more of magnesium stearate, stearic acid and sodium stearyl fumarate; The glidant includes colloidal silicon dioxide and / or talc.

4. The S-adenosyl-L-methionine p-toluenesulfonic acid sulfate composition according to any one of claims 1 to 3, characterized in that: The pharmaceutically acceptable excipients include the following components in percentage by weight: Excipients 1~10%, binders 1~5%, lubricants 0.1~3% and glidants 0.1~2%.

5. The method for preparing the S-adenosyl-L-methionine p-toluenesulfonic acid sulfate composition according to any one of claims 1 to 4, characterized in that: The following steps are involved: Mixing S-adenosyl-L-methionine p-toluenesulfonic acid sulfate, anhydrous calcium hydrogen phosphate and a pharmaceutically acceptable auxiliary material to obtain a mixed material; The mixed material is subjected to dry granulation to obtain dry granules of S-adenosyl-L-methionine p-toluenesulfonic acid sulfate composition.

6. The preparation method according to claim 5, characterized in that: The conditions of the dry granulation include: a feeding speed of 20-80 r / min; a pressing wheel speed of 5-16 r / min; a final granulation speed of 20-140 r / min; a hydraulic pressure of 0-15 MPa, and not 0; and a pressing wheel spacing of 0-5 mm, and not 0.

7. A S-adenosyl-L-methionine p-toluenesulfonic acid sulfate coating preparation, characterized in that: The invention comprises the S-adenosine-L-methionine p-toluenesulfonate sulfate composition according to any one of claims 1 to 4 or the S-adenosine-L-methionine p-toluenesulfonate sulfate composition prepared by the preparation method according to claim 5 or 6; and a coating material.

8. The S-adenosyl-L-methionine p-toluenesulfonic acid sulfate coating preparation according to claim 7, characterized in that: The coating material comprises one or more of methacrylic acid-ethyl acrylate copolymer, polyvinyl alcohol, talc, titanium dioxide, mono- and di-caprylic acid capric acid glyceride and sodium lauryl sulfate.

9. The S-adenosyl-L-methionine p-toluenesulfonic acid sulfate coating preparation according to claim 7 or 8, characterized in that: Including coated granules or coated tablets.

10. The method for preparing the S-adenosyl-L-methionine p-toluenesulfonic acid sulfate coating preparation according to any one of claims 7 to 9, characterized in that: The following steps are involved: mixing the coating material and the diluent to obtain a coating solution; When the S-adenosine-L-methionine p-toluenesulfonic acid sulfate coated preparation is a coated granule, the dry granules of the S-adenosine-L-methionine p-toluenesulfonic acid sulfate composition are coated with a coating solution to obtain S-adenosine-L-methionine p-toluenesulfonic acid sulfate coated granules; When the S-adenosine-L-methionine p-toluenesulfonic acid sulfate coated preparation is a coated tablet, the dry particles of the S-adenosine-L-methionine p-toluenesulfonic acid sulfate composition are tableted to obtain plain tablets; the plain tablets are coated with a coating solution to obtain S-adenosine-L-methionine p-toluenesulfonic acid sulfate coated tablets.

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