CN112402384A - Preparation method of rivaroxaban tablet, rivaroxaban tablet and rivaroxaban oral medicine - Google Patents
Preparation method of rivaroxaban tablet, rivaroxaban tablet and rivaroxaban oral medicine Download PDFInfo
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- CN112402384A CN112402384A CN202011364586.1A CN202011364586A CN112402384A CN 112402384 A CN112402384 A CN 112402384A CN 202011364586 A CN202011364586 A CN 202011364586A CN 112402384 A CN112402384 A CN 112402384A
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- rivaroxaban
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- alginic acid
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- KGFYHTZWPPHNLQ-AWEZNQCLSA-N rivaroxaban Chemical compound S1C(Cl)=CC=C1C(=O)NC[C@@H]1OC(=O)N(C=2C=CC(=CC=2)N2C(COCC2)=O)C1 KGFYHTZWPPHNLQ-AWEZNQCLSA-N 0.000 title claims abstract description 149
- 229960001148 rivaroxaban Drugs 0.000 title claims abstract description 149
- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- 239000003814 drug Substances 0.000 title abstract description 52
- 238000007908 dry granulation Methods 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 30
- 239000000783 alginic acid Substances 0.000 claims abstract description 29
- 235000010443 alginic acid Nutrition 0.000 claims abstract description 29
- 229920000615 alginic acid Polymers 0.000 claims abstract description 29
- 229960001126 alginic acid Drugs 0.000 claims abstract description 29
- 150000004781 alginic acids Chemical class 0.000 claims abstract description 29
- 238000002156 mixing Methods 0.000 claims abstract description 13
- 239000007888 film coating Substances 0.000 claims description 24
- 238000009501 film coating Methods 0.000 claims description 24
- 239000008187 granular material Substances 0.000 claims description 21
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 16
- 239000003085 diluting agent Substances 0.000 claims description 12
- 239000000314 lubricant Substances 0.000 claims description 12
- 239000011230 binding agent Substances 0.000 claims description 8
- 235000019359 magnesium stearate Nutrition 0.000 claims description 8
- 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 claims description 7
- 239000000853 adhesive Substances 0.000 claims description 7
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- 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 claims description 5
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- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 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 3
- 239000004375 Dextrin Substances 0.000 claims description 3
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- 229930195725 Mannitol Natural products 0.000 claims description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 229920002472 Starch Polymers 0.000 claims description 3
- 235000021355 Stearic acid Nutrition 0.000 claims description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 3
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- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 3
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- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 3
- 229960003943 hypromellose Drugs 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 3
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- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 3
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- 239000008107 starch Substances 0.000 claims description 3
- 235000019698 starch Nutrition 0.000 claims description 3
- 239000008117 stearic acid Substances 0.000 claims description 3
- 229910002012 Aerosil® Inorganic materials 0.000 claims description 2
- 239000000454 talc Substances 0.000 claims description 2
- 235000012222 talc Nutrition 0.000 claims description 2
- 229910052623 talc Inorganic materials 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 abstract description 30
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- 230000000052 comparative effect Effects 0.000 description 15
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- 229940126701 oral medication Drugs 0.000 description 9
- 239000000463 material Substances 0.000 description 6
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- 229920002785 Croscarmellose sodium Polymers 0.000 description 4
- 229960001681 croscarmellose sodium Drugs 0.000 description 4
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000005550 wet granulation Methods 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 206010051055 Deep vein thrombosis Diseases 0.000 description 2
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- 206010047249 Venous thrombosis Diseases 0.000 description 2
- 239000012752 auxiliary agent Substances 0.000 description 2
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- 238000012986 modification Methods 0.000 description 2
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- 238000013112 stability test Methods 0.000 description 2
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- 210000001519 tissue Anatomy 0.000 description 2
- APZPPBDYNUYFSL-CQSZACIVSA-N 3-[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl]thiophene-2-carboxamide Chemical compound O=C1O[C@H](CN1C1=CC=C(C=C1)N1C(COCC1)=O)C1=C(SC=C1)C(=O)N APZPPBDYNUYFSL-CQSZACIVSA-N 0.000 description 1
- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 108010074860 Factor Xa Proteins 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 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
- 238000007907 direct compression Methods 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 210000004394 hip joint Anatomy 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 210000000629 knee joint Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000013307 optical fiber Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
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- 229910002027 silica gel Inorganic materials 0.000 description 1
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- 208000011580 syndromic disease Diseases 0.000 description 1
Classifications
-
- 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
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
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- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
Abstract
The invention relates to the technical field of medicines, and particularly relates to a preparation method of rivaroxaban tablets, rivaroxaban tablets and rivaroxaban oral medicines. The preparation method of the rivaroxaban tablets comprises the steps of mixing rivaroxaban and alginic acid, performing dry granulation, and tabletting. Alginic acid is added into rivaroxaban, and meanwhile, a dry granulation process is adopted for granulation and then tabletting, so that the obtained rivaroxaban tablets have the advantages of high dissolution speed and good uniformity.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a preparation method of rivaroxaban tablets, rivaroxaban tablets and rivaroxaban oral medicines.
Background
Rivaroxaban (Rivaroxaban), chemically known as 5-chloro-nitrogen- ((5S) -2-oxo-3- [ -4- (3-oxo-4-morpholinyl) phenyl ] -1, 3-oxazolidin-5-yl-2-thiophene-carboxamide, is a low molecular weight oral anticoagulant with high selectivity for direct inhibition of factor Xa.
It can be used for preventing Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) of patients after hip joint and knee joint replacement, and can also be used for preventing cerebral apoplexy and non-central nervous system embolism of patients with non-valvular atrial fibrillation, and reducing risk of coronary artery syndrome recurrence.
According to the drug evaluation report of EMA to bexastal by the european medicines agency, the BCS of rivaroxaban is classified as a class II (low solubility, high permeability) drug, i.e. the solubility of its drug substance and the dissolution of the formulation will be the limiting factors for the absorption of the drug in vivo.
Therefore, how to improve the dissolution rate of rivaroxaban tablets is the main research focus at present.
Disclosure of Invention
Therefore, the technical problem to be solved by the invention is to overcome the defect of low dissolution rate of rivaroxaban tablets in the prior art, so that a preparation method of rivaroxaban tablets, rivaroxaban tablets and rivaroxaban oral drugs are provided.
In order to solve the technical problems, the technical scheme provided by the invention is as follows:
a preparation method of rivaroxaban tablets comprises the steps of mixing rivaroxaban and alginic acid, performing dry granulation, and tabletting.
Optionally, the addition ratio of rivaroxaban to alginic acid is 1: (3-4).
Optionally, the method further comprises the step of adding at least one of a binder, a lubricant and a diluent to rivaroxaban before dry granulation.
Optionally, the binder includes at least one of hypromellose, povidone, hydroxypropyl cellulose, and sodium carboxymethyl cellulose.
Optionally, the lubricant comprises at least one of magnesium stearate, stearic acid, talc, aerosil and hydrogenated vegetable oil.
Optionally, the diluent comprises at least one of lactose, starch, microcrystalline cellulose, dextrin, and mannitol.
Optionally, the dry granulation comprises mixing the raw materials, compacting under 30-50bar into blocks, and pulverizing into granules.
The invention also provides rivaroxaban tablets prepared by the preparation method according to any one of the schemes.
Optionally, the rivaroxaban tablets comprise, by weight:
rivaroxaban 11%, alginic acid 34-45%, adhesive 3%, lubricant 6% and diluent 28-40%.
The invention also provides a rivaroxaban oral medicine, which comprises: rivaroxaban tablets according to any one of the above protocols, and a film coating over the rivaroxaban tablets.
The technical scheme of the invention has the following advantages:
1. in the preparation method of the rivaroxaban tablets, alginic acid is used as an expanding agent which swells but does not dissolve in water, by adding alginic acid into rivaroxaban, on one hand, alginic acid can provide a good microenvironment for insoluble drugs in the dissolution process, so that the insoluble drugs can be fully moistened, thereby being beneficial to the dissolution of the preparation, on the other hand, the alginic acid can improve the tissue structure of the granules, so that the gaps among the granules are more uniform, thereby being beneficial to the uniformity of the preparation, meanwhile, compared with the wet granulation and the solid dispersion preparation process, the dry granulation has higher stability and simpler, more convenient and faster process, and by adding alginic acid into rivaroxaban, meanwhile, a dry granulation process is adopted for granulation and then tabletting, so that the obtained rivaroxaban tablets have the advantages of high dissolution speed and good uniformity.
2. According to the preparation method of the rivaroxaban tablets, due to the fact that too little addition amount of alginic acid causes insoluble drugs to be incapable of being wetted completely, rivaroxaban dissolution is low, and due to the fact that too much addition amount of alginic acid causes gelation to be easily formed after swelling, rivaroxaban dissolution is slow, and by limiting the dosage of rivaroxaban and alginic acid, rivaroxaban in the obtained rivaroxaban tablets has the advantages of being high in dissolution speed, high in dissolution rate and good in uniformity.
3. According to the preparation method of the rivaroxaban tablets, at least one of the binder, the lubricant and the diluent is added before dry granulation is carried out, the binder can increase the binding power between a main drug and an auxiliary material, so that the main drug and the auxiliary material are agglomerated into granules, the strength and the density of the granules can be ensured, smooth proceeding of subsequent processes is facilitated, the lubricant can reduce the friction between the granules and a die wall, and therefore the difficulty in tabletting caused by overlarge friction is prevented, the diluent can fill the weight or the volume of the tablets, the convenience is brought for tabletting, and the addition of various auxiliaries can facilitate smooth proceeding of the dry granulation process.
4. According to the preparation method of the rivaroxaban tablets, the oil pressure can affect the binding force between the powders, so that the strength of dry-method granules is affected, the oil pressure is too high, the granule strength is high, the dissolution rate is slow, the oil pressure is too low, the granule binding force is insufficient, and insoluble drugs cannot be completely dissolved.
5. According to the rivaroxaban tablet provided by the invention, the raw materials and the preparation method are limited, so that rivaroxaban in the obtained rivaroxaban tablet has the advantages of high dissolution speed and good uniformity.
6. The rivaroxaban oral medicine provided by the invention has the advantages of high dissolution speed and good uniformity, so that rivaroxaban in the rivaroxaban oral medicine is more easily dissolved and absorbed by a patient, and the development of the rivaroxaban oral medicine is facilitated.
Detailed Description
The technical solutions of the present invention will be described clearly and completely below, and it should be apparent that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
In addition, the technical features involved in the different embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
The invention relates to a preparation method of rivaroxaban tablets, which comprises the steps of mixing rivaroxaban and alginic acid, then carrying out dry granulation and tabletting.
The preparation method comprises the steps of preparing rivaroxaban tablets, preparing a solution of a poorly soluble drug, adding alginic acid into the rivaroxaban tablets, wherein the alginic acid is used as an expanding agent, and is swelled but not dissolved in water, on one hand, the alginic acid can provide a good microenvironment for the poorly soluble drug in the dissolution process, so that the poorly soluble drug can be fully wetted, and the dissolution of the preparation is facilitated, on the other hand, the alginic acid can improve the tissue structure of the particles, so that gaps among the particles are more uniform, and the uniformity of the preparation is facilitated, and meanwhile, compared with a wet granulation and solid dispersion preparation process, the dry granulation process has higher stability and is more stable and faster in process.
Dry granulation refers to a method of mixing the powders of the drug and the excipients uniformly, compacting into large tablets, plates or hard strips, and then crushing into the required granules.
Optionally, the rivaroxaban dissolution rate is low due to the fact that the slightly soluble drug cannot be completely wetted due to too small addition amount of alginic acid, and the rivaroxaban dissolution rate is slow due to the fact that gelation is easily formed after swelling due to too large addition amount of alginic acid, so that the addition mass ratio of rivaroxaban to alginic acid is set as 1: (3-4), rivaroxaban in the obtained rivaroxaban tablets has the advantages of high dissolution speed, high dissolution rate and good uniformity.
Optionally, the method further comprises the step of adding at least one of a binder, a lubricant and a diluent to rivaroxaban before dry granulation.
Specifically, the adhesive can increase the adhesive force between the main drug and the auxiliary material, so that the main drug and the auxiliary material are agglomerated into granules, the strength and the density of the granules can be ensured, the subsequent process can be smoothly carried out, the lubricant can reduce the friction force between the granules and the wall of the punching die, so that the difficult tabletting caused by the overlarge friction force is prevented, the diluent can fill the weight or the volume of the tablet, so that the tabletting is conveniently carried out, and the addition of various auxiliary agents can facilitate the smooth implementation of the dry granulation process. The addition of the above-mentioned adjuvants is mainly to ensure the smooth proceeding of the dry granulation process, and has little influence on the dissolution rate of rivaroxaban, so that other functional adjuvants besides the above-mentioned adjuvants can also be added to ensure the smooth proceeding of the dry granulation process. The specific addition content of the auxiliary agent can also be adjusted and designed according to the actual processing condition.
Specifically, the binder comprises at least one of hypromellose, povidone, hydroxypropyl cellulose, and sodium carboxymethyl cellulose. The lubricant comprises at least one of magnesium stearate, stearic acid, talcum powder, superfine silica gel powder and hydrogenated vegetable oil. The diluent comprises at least one of lactose, starch, microcrystalline cellulose, dextrin and mannitol.
Optionally, the dry granulation comprises mixing the raw materials, compacting under 30-50bar into blocks, and pulverizing into granules. Preferably, the > 24 mesh particles should be not less than 25%.
The dry granulation process is characterized in that the dry granules have different strengths and can influence the dissolution speed of the preparation to a certain extent, so that the dissolution speed of the preparation can be ensured by limiting the process parameters of the dry granulation step. Specifically, the oil pressure can affect the binding force between the powders, thereby affecting the strength of the dry-process granules, and the oil pressure is too large, the granule strength is large, the dissolution rate is slow, the oil pressure is too small, the binding force of the granules is not enough, and the indissolvable drug cannot be completely dissolved. The grain with the grain size larger than 24 meshes is not less than 25 percent, so that the subsequent tabletting process is facilitated.
Specifically, in the embodiment related to the invention, the dry granulation is carried out by using a traditional Chinese medicine Longli LS4120 type dry granulator, the oil pressure is 30-50bar, preferably 40bar, the rotating speed of a pulverizer is 90-150rpm, preferably 120rpm, the rotating speed of a granulator is 150-200rpm, preferably 175rpm, and the material pushing speed is 40-100rpm, preferably 70 rpm.
The invention also provides rivaroxaban tablets prepared by the preparation method according to any one of the schemes.
Optionally, the rivaroxaban tablets comprise, by weight:
rivaroxaban 11%, alginic acid 34-45%, adhesive 3%, lubricant 6% and diluent 28-40%. .
Under the proportion, the rivaroxaban is high in dissolution speed and good in uniformity, and is suitable for a dry granulation process.
The invention also provides a rivaroxaban oral medicine, which comprises: rivaroxaban tablets according to any one of the above protocols, and a film coating over the rivaroxaban tablets.
Example 1
The embodiment relates to a rivaroxaban oral medicine, which comprises a rivaroxaban tablet and a film coating coated outside the rivaroxaban tablet, wherein in the embodiment, the film coating is opadry, and specific components and contents of the rivaroxaban oral medicine are shown in table 1.
The rivaroxaban oral of this example was prepared as follows:
s1, premixing rivaroxaban, lactose, alginic acid, hydroxypropyl methylcellulose and 50% of magnesium stearate according to the prescription amount for 3min, and performing dry granulation in a Longli LS4120 type dry granulation machine which is a Chinese medicine, wherein the process parameters are as follows: oil pressure: 40bar, the rotating speed of a crusher is 120rpm, the rotating speed of a granulator is 175rpm, and the pushing speed is 70rpm, wherein the content of particles larger than 24 meshes is more than or equal to 25 percent;
s2, adding the croscarmellose sodium and the rest magnesium stearate into the dry granules obtained in the step S1, and finally mixing at the rotating speed of a mixer of 12rpm for 5 min;
s3, tabletting the mixture obtained in the step S2 according to 86.0mg of standard tablet weight, and obtaining rivaroxaban tablets by a tabletting machine at the rotating speed of 20-30 rpm;
s4, further performing film coating on the rivaroxaban tablets obtained in the step S3, wherein the coating temperature is 40 ℃.
Example 2
The embodiment relates to a rivaroxaban oral medicine, which comprises a rivaroxaban tablet and a film coating coated outside the rivaroxaban tablet, wherein in the embodiment, the film coating is opadry, and specific components and contents of the rivaroxaban oral medicine are shown in table 1.
The preparation method of rivaroxaban oral of this example was consistent with example 1.
Example 3
The embodiment relates to a rivaroxaban oral medicine, which comprises a rivaroxaban tablet and a film coating coated outside the rivaroxaban tablet, wherein in the embodiment, the film coating is opadry, and specific components and contents of the rivaroxaban oral medicine are shown in table 1.
The preparation method of rivaroxaban oral according to this example only differs from example 1 in that in this example the oil pressure used for dry granulation was 30 bar.
Example 4
The embodiment relates to a rivaroxaban oral medicine, which comprises a rivaroxaban tablet and a film coating coated outside the rivaroxaban tablet, wherein in the embodiment, the film coating is opadry, and specific components and contents of the rivaroxaban oral medicine are shown in table 1.
The preparation method of rivaroxaban oral according to this example only differs from example 1 in that in this example the oil pressure used for dry granulation was 50 bar.
Example 5
The embodiment relates to a rivaroxaban oral medicine, which comprises a rivaroxaban tablet and a film coating coated outside the rivaroxaban tablet, wherein in the embodiment, the film coating is opadry, and specific components and contents of the rivaroxaban oral medicine are shown in table 1.
The preparation method of rivaroxaban oral according to this example only differs from example 1 in that in this example the oil pressure used for dry granulation was 20 bar.
Example 6
The embodiment relates to a rivaroxaban oral medicine, which comprises a rivaroxaban tablet and a film coating coated outside the rivaroxaban tablet, wherein in the embodiment, the film coating is opadry, and specific components and contents of the rivaroxaban oral medicine are shown in table 1.
The preparation method of rivaroxaban oral according to this example only differs from example 1 in that in this example the oil pressure used for dry granulation was 60 bar.
Examples 7 to 11
Examples 7 to 11 relate to a rivaroxaban oral drug, which comprises a rivaroxaban tablet and a film coating coated on the rivaroxaban tablet, wherein in examples 7 to 11, the film coating is opadry, and the specific components and contents of the rivaroxaban oral drug are shown in table 1.
The rivaroxaban oral drugs of examples 7-11 were prepared in accordance with example 1.
Comparative example 1
Comparative example 1 this comparative example 1 relates to a rivaroxaban oral, and the only difference between this comparative example 1 and example 1 is that in this comparative example microcrystalline cellulose is used instead of alginic acid, and the specific components and contents of the rivaroxaban oral are shown in table 1.
The preparation method of rivaroxaban oral of this example was consistent with example 1.
Comparative example 2
The comparative example relates to a rivaroxaban oral medicine, which comprises a rivaroxaban tablet and a film coating coated outside the rivaroxaban tablet, wherein in the embodiment, the film coating is opadry, and the specific components and contents of the rivaroxaban oral medicine are shown in table 1.
The rivaroxaban tablets of the comparative example are prepared by wet granulation, and the preparation method of the rivaroxaban oral medicament is as follows:
s1, preparing a hydroxypropyl methylcellulose water solution with the mass fraction of 6.0% as an adhesive;
s2, mixing the adhesive obtained in the step S1 with rivaroxaban, lactose and alginic acid in an SKH100 type mixer for wet granulation, stirring at 400rpm, cutting at 1200rpm for 4min, and sieving with a 24-mesh sieve;
s3, adding the croscarmellose sodium and the magnesium stearate into the material obtained in the step S2, and finally mixing for 5min at the rotating speed of a mixer of 12 rpm;
s4, tabletting the mixture obtained in the step S3 according to the standard tablet weight to obtain the rivaroxaban tablet.
S5, further performing film coating on the rivaroxaban tablets obtained in the step S4, wherein the coating temperature is 40 ℃.
Comparative example 3
The comparative example relates to a rivaroxaban oral medicine, which comprises a rivaroxaban tablet and a film coating coated outside the rivaroxaban tablet, wherein in the embodiment, the film coating is opadry, and the specific components and contents of the rivaroxaban oral medicine are shown in table 1.
The rivaroxaban tablets of the comparative example are prepared by a powder direct compression method, and the preparation method of the rivaroxaban oral medicine is as follows:
s1, pre-mixing rivaroxaban, alginic acid, hydroxypropyl methylcellulose, 50% of the prescription amount of croscarmellose sodium and 50% of the prescription amount of magnesium stearate for 3min, and rotating the speed of a mixer at 12 rpm.
S2, adding the residual croscarmellose sodium and the residual magnesium stearate into the dry granules obtained in the step S1, and finally mixing at the rotating speed of a mixer of 12rpm for 5 min;
s3, tabletting the mixture obtained in the step S2 according to 86.0mg of standard tablet weight, and obtaining rivaroxaban tablets by a tabletting machine at the rotating speed of 20-30 rpm;
s4, further performing film coating on the rivaroxaban tablets obtained in the step S3, wherein the coating temperature is 40 ℃.
TABLE 1 prescription of rivaroxaban tablets for each example and comparative example
Test example 1
The dissolution of rivaroxaban oral drug is detected by online detection with an optical fiber dissolution instrument by using a pH4.5 (acetate buffer solution + 0.1% SLS) medium.
Wherein, the dissolution rate is rivaroxaban dissolution amount/rivaroxaban dosage, and the content uniformity (A +2.4S) is determined as follows: taking 10 test samples, respectively measuring the relative content X of each drug with the labeled amount as 100 according to the method specified in each drug item in Chinese pharmacopoeia, and calculating the average value X, the standard deviation S and the absolute value A of the difference between the labeled amount and the average value X. The determination of the dissolution rate and the content uniformity is a general method recorded in Chinese pharmacopoeia. The results are shown in Table 2.
TABLE 2 test results of rivaroxaban oral drugs of each example and comparative example
Test example 2
Taking the rivaroxaban oral drugs of examples 1-4 as an example, according to the method recorded in the Chinese pharmacopoeia, the rivaroxaban oral drugs and the bairemol provided in the above examples 1-4 and comparative examples 1-3 were subjected to an accelerated stability test at 40 ℃ and 75% RH, and the content of related substances, main drugs and impurities was measured, and the results of the measurement are shown in Table 3.
TABLE 3 rivaroxaban oral drug stability test results for each example and comparative example
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.
Claims (10)
1. The preparation method of the rivaroxaban tablets is characterized by comprising the steps of mixing rivaroxaban and alginic acid, performing dry granulation, and tabletting.
2. The preparation method of claim 1, wherein the ratio of the added rivaroxaban to the added alginic acid is 1: (3-4).
3. The method of claim 1 or 2, further comprising the step of adding at least one of a binder, a lubricant, and a diluent to rivaroxaban prior to dry granulation.
4. The method according to claim 3, wherein the binder comprises at least one of hypromellose, povidone, hydroxypropyl cellulose, and sodium carboxymethyl cellulose.
5. The method of claim 3, wherein the lubricant comprises at least one of magnesium stearate, stearic acid, talc, aerosil, hydrogenated vegetable oil.
6. The method of claim 3, wherein the diluent comprises at least one of lactose, starch, microcrystalline cellulose, dextrin, and mannitol.
7. The process according to any one of claims 1 to 6, wherein the dry granulation comprises the steps of mixing the raw materials, compacting at 30 to 50bar into a mass and then comminuting into granules.
8. Rivaroxaban tablets, characterized in that they are prepared according to the preparation process as claimed in any one of claims 1 to 7.
9. The rivaroxaban tablet according to claim 8, wherein the rivaroxaban tablet comprises, in weight percent:
rivaroxaban 11%, alginic acid 34-45%, adhesive 3%, lubricant 6% and diluent 28-40%.
10. A rivaroxaban oral, comprising: the rivaroxaban tablet of any one of claims 8-9, and a film coating over the rivaroxaban tablet.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GR1010231B (en) * | 2021-03-24 | 2022-05-10 | Φαρματεν Α.Β.Ε.Ε., | Pharmaceutical composition comprising rivaroxaban and method of preparation thereof |
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| CN104971355A (en) * | 2014-04-02 | 2015-10-14 | 上海现代药物制剂工程研究中心有限公司 | Rivaroxaban-containing composition and preparation method thereof |
| CN105796528A (en) * | 2016-05-31 | 2016-07-27 | 海南通用三洋药业有限公司 | Amoxicillin and dicloxacillin sodium compound medicine composition |
| CN110420188A (en) * | 2019-08-06 | 2019-11-08 | 浙江爱诺生物药业股份有限公司 | A method of improving Entecavir tablet uniformity of dosage units |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104971355A (en) * | 2014-04-02 | 2015-10-14 | 上海现代药物制剂工程研究中心有限公司 | Rivaroxaban-containing composition and preparation method thereof |
| CN105796528A (en) * | 2016-05-31 | 2016-07-27 | 海南通用三洋药业有限公司 | Amoxicillin and dicloxacillin sodium compound medicine composition |
| CN110420188A (en) * | 2019-08-06 | 2019-11-08 | 浙江爱诺生物药业股份有限公司 | A method of improving Entecavir tablet uniformity of dosage units |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GR1010231B (en) * | 2021-03-24 | 2022-05-10 | Φαρματεν Α.Β.Ε.Ε., | Pharmaceutical composition comprising rivaroxaban and method of preparation thereof |
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