CN114788819B - Aidosaban tablet and preparation method thereof - Google Patents
Aidosaban tablet and preparation method thereof Download PDFInfo
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- CN114788819B CN114788819B CN202110103621.2A CN202110103621A CN114788819B CN 114788819 B CN114788819 B CN 114788819B CN 202110103621 A CN202110103621 A CN 202110103621A CN 114788819 B CN114788819 B CN 114788819B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000002156 mixing Methods 0.000 claims abstract description 33
- 239000008187 granular material Substances 0.000 claims abstract description 24
- 239000000314 lubricant Substances 0.000 claims abstract description 15
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 34
- 239000002245 particle Substances 0.000 claims description 19
- 235000019359 magnesium stearate Nutrition 0.000 claims description 17
- 239000011248 coating agent Substances 0.000 claims description 15
- 238000000576 coating method Methods 0.000 claims description 15
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical class CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims description 14
- 238000010438 heat treatment Methods 0.000 claims description 13
- 239000000243 solution Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 11
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 11
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 8
- 239000011230 binding agent Substances 0.000 claims description 7
- -1 polyethylene Polymers 0.000 claims description 7
- 239000000853 adhesive Substances 0.000 claims description 6
- 230000001070 adhesive effect Effects 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- 239000004698 Polyethylene Substances 0.000 claims description 5
- 229920000573 polyethylene Polymers 0.000 claims description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 5
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- 229920000881 Modified starch Polymers 0.000 claims description 4
- 239000000945 filler Substances 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical group C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 3
- 229960000913 crospovidone Drugs 0.000 claims description 3
- 238000005469 granulation Methods 0.000 claims description 3
- 230000003179 granulation Effects 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 3
- 238000007873 sieving Methods 0.000 claims description 2
- 239000007884 disintegrant Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000004080 punching Methods 0.000 abstract description 4
- 238000005550 wet granulation Methods 0.000 abstract description 2
- 239000003826 tablet Substances 0.000 description 19
- 239000000203 mixture Substances 0.000 description 15
- 239000000463 material Substances 0.000 description 9
- 238000004090 dissolution Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 230000001050 lubricating effect Effects 0.000 description 3
- 229960004029 silicic acid Drugs 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 238000007599 discharging Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- HGVDHZBSSITLCT-JLJPHGGASA-N Edoxaban Chemical compound N([C@H]1CC[C@@H](C[C@H]1NC(=O)C=1SC=2CN(C)CCC=2N=1)C(=O)N(C)C)C(=O)C(=O)NC1=CC=C(Cl)C=N1 HGVDHZBSSITLCT-JLJPHGGASA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- 108010014173 Factor X Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- YIKSCQDJHCMVMK-UHFFFAOYSA-N Oxamide Chemical compound NC(=O)C(N)=O YIKSCQDJHCMVMK-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- LRCFXGAMWKDGLA-UHFFFAOYSA-N dioxosilane;hydrate Chemical compound O.O=[Si]=O LRCFXGAMWKDGLA-UHFFFAOYSA-N 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000007580 dry-mixing Methods 0.000 description 1
- 229960000622 edoxaban Drugs 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000009477 fluid bed granulation Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000011361 granulated particle Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000012432 intermediate storage Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- NIXKBAZVOQAHGC-UHFFFAOYSA-N phenylmethanesulfonic acid Chemical class OS(=O)(=O)CC1=CC=CC=C1 NIXKBAZVOQAHGC-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- 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
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Abstract
The invention discloses an ideoxaban tablet and a preparation method thereof. The preparation method of the tablet improves the mixing mode of the original granules, the wet granulation granules containing the raw medicines and the lubricant are added into a fluidized bed together for mixing and are heated, the obtained granules are not sticky and punched when being pressed in a higher humidity range, the sticky and punching problem in the tabletting is solved, and the production is facilitated.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and in particular relates to an ideoxaban tablet and a preparation method thereof.
Background
Ai Duosha Ban Youchen Adesaban (Edoxaban), chemical name N- (5-chloropyridin-2-yl) -N' - [ (1S, 2R, 4S) -4- (N, N-dimethylformamide) -2- (5-methyl-4, 5,6, 7-tetrahydro [1,3] thiazolo [5,4-c ] pyridine-2-carboxamide) cyclohexyl ] oxamide, the active ingredient of the commercial drug is Ai Duosha class p-toluenesulfonate monohydrate, structural formula:
tosylate Ai Duosha class is a small molecule factor X (FXa) inhibitor developed by japan first co-pharmaceutical co-product. Ai Duosha class 2011 under the trade nameThe United states Food and Drug Administration (FDA) was approved for the market in Japan and then for the Ai Duosha shift in 2015 for toluenesulfonic acid.
In the existing process of preparing the Ai Duosha class of toluenesulfonic acid tablets, sticking and punching phenomena easily occur in the tabletting process, and the smooth implementation of mass production is not facilitated.
Disclosure of Invention
Aiming at the technical problems existing at present, the invention provides a toluene sulfonic acid Ai Duosha tablet and a preparation method thereof, and the method can solve the sticking problem during tabletting to obtain the toluene sulfonic acid Ai Duosha tablet with good stability, dissolution and compressibility.
An object of the present invention is to provide a method for preparing a tablet of toluene sulfonic acid Ai Duosha class, comprising the steps of: 1) Preparing an aqueous binder solution; 2) Wet granulation: mixing Ai Duosha class of toluene sulfonic acid with filler and disintegrating agent, adding adhesive aqueous solution, granulating; 3) And (3) hot mixing: mixing the granules obtained by granulating the step 2) with a lubricant under heating; 4) Tabletting.
In some embodiments, the hot mixing of step 3) is performed by heating and mixing in a fluidized bed to a temperature of 55-65deg.C, and stopping heating.
In some typical embodiments, the heated mixing in the fluidized bed is preferably set at an inlet air temperature of 65-95 ℃, preferably 75-95 ℃, further preferably 85-95 ℃; and the fan frequency is set to 20-25Hz. In some typical embodiments, the particles are removed after the heated mixing in the fluidized bed is preferably stopped and the temperature of the exhaust air is reduced to 30-50 c, preferably 35-40 c.
In some embodiments, the concentration of the aqueous binder solution in step 1) is 7% (w/w).
In some embodiments, the step 2) may be granulated with a fluid bed one-step granulator or a high efficiency mixer granulator, preferably fluid bed granulation.
In some embodiments, the thermal mixing of step 3) comprises the steps of: heating and drying the granules prepared in the step 2) until the water content of the granules is less than or equal to 2%, and mixing with a lubricant; preferably in a three-dimensional mixer; and said step 4) is tabletted at ambient humidity < 10% RH.
In some embodiments, the method of making further comprises a coating step that employs a gastric soluble coating powder.
In some more specific embodiments, the steps of the invention are:
1) Preparing an aqueous binder solution: after the hydroxypropyl cellulose is dissolved in water, mixing the dissolved solution to obtain an adhesive aqueous solution;
2) Granulating: mixing Ai Duosha class of toluenesulfonic acid, a filler and a disintegrating agent with a polyethylene bag, sieving with a 40-mesh sieve, and adding the adhesive solution in the step 1) to complete granulation;
3) And (3) hot mixing: adding the granules obtained by granulating and a lubricant into a fluidized bed, setting the air inlet temperature to be 85-95 ℃, the fan frequency to be 25-30Hz, drying until the temperature of the granules reaches 55-65 ℃, stopping heating, and taking out the granules when the air exhaust temperature reaches 35-40 ℃;
4) Tabletting: compressing the mixed particles into tablets to obtain Ai Duosha Ban Su tablets of toluene sulfonic acid;
5) Coating: adding the gastric-soluble coating powder premix into water to uniformly disperse the gastric-soluble coating powder premix, and preparing coating liquid; the toluene sulfonic acid Ai Duosha Ban Su tablets were coated with the coating solution.
The binder is selected from carboxymethyl ethyl cellulose, light anhydrous silicic acid, hydroxypropyl cellulose or corn starch, preferably hydroxypropyl cellulose.
The filler is selected from one or more of lactose, microcrystalline cellulose, mannitol, pregelatinized starch, preferably mannitol and pregelatinized starch.
The disintegrating agent is selected from carboxymethylcellulose calcium, carboxymethylcellulose sodium, hydrated silica, croscarmellose sodium, crospovidone or light anhydrous silicic acid, preferably crospovidone.
The lubricant is selected from one or more of magnesium stearate, talcum powder and sodium stearyl fumarate, preferably magnesium stearate.
The weight percentage of the lubricant is 0.4-1%, preferably 0.4-0.8% of the plain tablet.
The Ai Duosha tablet of methanesulfonic acid prepared by the preparation method adopts the following formula: the components comprise, by weight, 20.2 parts of toluene sulfonic acid Ai Duosha parts, 30-60 parts of mannitol, 15-30 parts of pregelatinized starch, 4-6 parts of a disintegrating agent, 2.5-3.5 parts of an adhesive and 0.4-0.8 part of a lubricant.
The beneficial effects of the invention are as follows:
according to the preparation process of the tosylate Ai Duosha tablet, wet granulated particles containing raw medicines and a lubricant are added into a fluidized bed for mixing, heating is performed, proper air inlet temperature and proper air quantity are controlled, so that the particles reach proper boiling height, good drying effect of the particles is achieved, the lubricant can exert better lubricating effect, the lubricating effect of the lubricant in the total mixing process is improved, the tabletting is not sticky and punched any more under a higher humidity range, and the sticky and punching problem in the tabletting is solved.
The following terms and phrases used herein are intended to contain the following meanings:
the term "RH" is the relative humidity in the present invention;
the term "rpm" is a unit of rotation speed in the present invention and refers to revolutions per minute;
the term "Hz" is in the present invention device power, referring to hertz;
the term "w/w" is in the invention the ratio of the mass of solute to the mass of solution;
the term "moisture content (%) of the particles" is a value measured by a drying loss method. For example, the moisture content (%) of the particles can be calculated by heating to evaporate water from the collected particles and measuring the ratio of the amount of water evaporated by the heating to 1g of the collected particles. For example, when the collected particles are m (g) and are converted to n (g) by heating, water is m-n (g), the water content (%) of the particles can be calculated from (m-n)/m×100;
the term "dry end point material temperature" in the present invention refers to the end point equilibrium temperature that the total mix particles eventually reach at a certain hot mix temperature.
The apparatus used in the present invention can be obtained by a normal commercial means, and the raw materials used are commercially available.
Drawings
FIG. 1 shows a Ai Duosha class of tosylate coated tablets prepared in example 4 and a reference formulationIs a dissolution profile of (2)
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be described in detail below. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, based on the examples herein, which are within the scope of the invention as defined by the claims, will be within the scope of the invention as defined by the claims.
The expression "0.4% equivalent of magnesium stearate" in the examples below means that the weight percentage of magnesium stearate is 0.4% of the tablet
Example 1
The ingredients shown in formula A of Table 1, except for the hydroxypropyl cellulose and magnesium stearate, were mixed in a polyethylene bag, sieved through a 40 mesh sieve, added to a fluidized bed for premixing, and granulated by adding an aqueous solution of the hydroxypropyl cellulose at a concentration of 7% (w/w) via a spray gun. After the granulation is completed, the granules are divided into three parts for treatment:
1. 1/3 of the granules are taken and added into a baking oven for drying at 85 ℃ until the water content of the granules is less than or equal to 2%, and the magnesium stearate with the prescription quantity of 1/3 is added and mixed for 15 minutes by a three-dimensional mixer;
2. taking 1/3 of the magnesium stearate in the amount of 1/3 of the prescription, keeping the magnesium stearate in the fluidized bed, mixing the magnesium stearate and the equipment at room temperature for 15 minutes without heating, and discharging the materials;
3. adding the rest 1/3 of unmixed particles into a fluidized bed, sucking magnesium stearate with the prescription amount of 1/3, heating and mixing, setting the air inlet temperature to be 85 ℃, mixing for 15 minutes, cooling and discharging materials;
table 1 different mixing modes investigation table
As can be seen from the data in table 1, for the same prescription composition particles, the three-dimensional mixing and the common fluidized bed mixing tabletting all have the sticking and punching phenomenon, and the fluidized bed hot mixing has the obvious anti-sticking advantage, so that the lubricating effect of the magnesium stearate can be effectively improved.
Example 2
For the granules obtained in the different mixing modes of example 1, we examined the tabletting tolerance of the granules to different environmental humidity, and the examination results are shown in table 2.
Table 2 examination of environmental humidity of compressed tablet
From Table 2, it was found that the granules prepared by the fluidized bed hot mixing process had a higher tolerance to the humidity of the tabletting environment and a better tabletting effect than the granules prepared by the three-dimensional mixer.
Example 3
The ingredients shown in Table 1, except for the hydroxypropyl cellulose and magnesium stearate, were mixed in a polyethylene bag, sieved through a 40 mesh sieve, added to a fluidized bed, and the mixture was granulated by using an aqueous solution of hydroxypropyl cellulose at a concentration of 7% (w/w). The pellets thus prepared were added to a fluidized bed together with magnesium stearate for dry mixing, and the effect of different fluidized bed parameters on the total mix was examined, the results of which are shown in table 3.
TABLE 3 screening of fluidized bed thermal mixing parameters
| Air inlet temperature | Fan frequency | Material temperature | Mixing time | Tabletting phenomenon |
| 65℃ | 25～30HZ | 45～50℃ | 10min | The punch is whitened and sticky |
| 75℃ | 25～30HZ | 50～55℃ | 10min | The punch is whitened and sticky |
| 85℃ | 20～25HZ | 55～60℃ | 10min | Smooth and non-sticking punch |
| 95℃ | 20～25HZ | 60～65℃ | 10min | Smooth and non-sticking punch |
Table 3 shows that the hot mixing parameters of the fluidized bed are screened, when the air inlet temperature is 85-95 ℃, the fan frequency is 20-25HZ, the material temperature is 55-65 ℃ and the mixture is mixed for 10 minutes, the prepared particles have good tabletting effect and are not sticky.
Example 4
To examine the effect of the moisture content (%) of the granules during the storage period on the tabletting phenomenon, the ingredients shown in the formula 4-1 of Table 4, except for the hydroxypropyl cellulose and magnesium stearate, were mixed with a polyethylene bag, sieved with a 40 mesh sieve, added to a fluidized bed for premixing, and granulated with an aqueous solution of the hydroxypropyl cellulose having a concentration of 7% (w/w) by a spray gun. After the sizing is completed, the particles are dried, and the particles are equally divided into two parts: prescription 1 and prescription 2.
Table 4 prescription
Prescription 1: directly taking out, adding 0.4% equivalent of magnesium stearate, and mixing by a three-dimensional mixer. The moisture content of the pellets in the total mix was determined to be 1.98%.
Prescription 2: and (3) keeping the mixture in a fluidized bed, sucking 0.4% equivalent of magnesium stearate, heating and mixing the mixture, setting the air inlet temperature to 85 ℃, and drying the end material at 55 ℃, so as to obtain a total mixed material, wherein the water content of particles in the material is measured to be 1.78%.
The total mix of formulations 1, 2 was divided into three portions, and 4-1-2, 4-1-3, 4-2-2 and 4-2-3 were placed under 92.5% RH humidity to absorb moisture, and placed according to the placement time of Table 5 to form a total mix of different humidity with 4-1-1 and 4-2-1 without high humidity treatment, and the results are shown in Table 5.
Tabletting is carried out on the obtained total mixed materials with different particle water contents, the ambient humidity is about 40-60% RH, and the tabletting investigation results are shown in Table 5.
Coated tablet prepared by using tosylate Ai Duosha Ban Su tablet prepared according to prescription 2 and gastric-soluble coating powder through coating machine and reference preparationDissolution characteristics were checked by paddle method at 50rpm using pH6.0 citric acid/disodium hydrogen phosphate buffer as medium, volume 900 mL. The dissolution rate was calculated as the average percent dissolution of 6 tablets. FIG. 1 shows a coated tablet of toluene sulfonic acid Ai Duosha class and a reference formulation +.>Is a dissolution profile of (a).
Table 5 comparison of the moisture content of different granulates
As can be seen from Table 5 and FIG. 1, the hot mix granules of the fluidized bed have good moisture tolerance, the moisture content of the granules after drying increases, the granule properties remain good, and the dissolution of the tablets tends to be consistent. Providing a favorable space for intermediate storage in actual production.
Claims (4)
1. A preparation method of a tosylate Ai Duosha class tablet comprises the following steps:
1) Preparing an aqueous binder solution: after the hydroxypropyl cellulose is dissolved in water, mixing the dissolved solution to obtain an adhesive aqueous solution;
2) Granulating: mixing Ai Duosha class of toluenesulfonic acid, a filler and a disintegrating agent with a polyethylene bag, sieving with a 40-mesh sieve, and adding the adhesive solution in the step 1) to complete granulation;
3) And (3) hot mixing: adding the granules obtained by granulating and a lubricant into a fluidized bed, setting the air inlet temperature to be 85-95 ℃, the air inlet quantity to be 20-25HZ, drying until the temperature of the granules reaches 55-65 ℃, stopping heating, and taking out the granules when the air exhaust temperature reaches 35-40 ℃;
4) Tabletting: compressing the mixed particles into tablets to obtain Ai Duosha Ban Su tablets of toluene sulfonic acid;
5) Coating: adding the gastric-soluble coating powder premix into water to uniformly disperse the gastric-soluble coating powder premix, and preparing coating liquid; coating the toluene sulfonic acid Ai Duosha Ban Su tablets by using the coating liquid; wherein the components of the tablet are, by weight, 20.2 parts of toluene sulfonic acid Ai Duosha class, 30-60 parts of mannitol, 15-30 parts of pregelatinized starch, 4-6 parts of disintegrating agent, 2.5-3.5 parts of binder and 0.4-0.8 part of lubricant, and the lubricant is magnesium stearate, and the binder is selected from hydroxypropyl cellulose.
2. The method of claim 1, wherein the disintegrant is selected from crospovidone.
3. The preparation method as claimed in claim 1, wherein the weight percentage of the lubricant is 0.4-1% of the plain tablet.
4. The preparation method as claimed in claim 1, wherein the proportion of the lubricant in the tablet is 0.4-0.8% by weight.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108743556A (en) * | 2018-02-02 | 2018-11-06 | 重庆植恩药业有限公司 | A kind of Yi Dushaban tablets and preparation method thereof |
| WO2020239986A1 (en) * | 2019-05-29 | 2020-12-03 | Alfred E. Tiefenbacher (Gmbh & Co. Kg) | Pharmaceutical tablet composition comprising edoxaban |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108743556A (en) * | 2018-02-02 | 2018-11-06 | 重庆植恩药业有限公司 | A kind of Yi Dushaban tablets and preparation method thereof |
| WO2020239986A1 (en) * | 2019-05-29 | 2020-12-03 | Alfred E. Tiefenbacher (Gmbh & Co. Kg) | Pharmaceutical tablet composition comprising edoxaban |
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