CN114712317A - Ticagrelor pharmaceutical composition, and preparation method and application thereof - Google Patents
Ticagrelor pharmaceutical composition, and preparation method and application thereof Download PDFInfo
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- CN114712317A CN114712317A CN202110004266.3A CN202110004266A CN114712317A CN 114712317 A CN114712317 A CN 114712317A CN 202110004266 A CN202110004266 A CN 202110004266A CN 114712317 A CN114712317 A CN 114712317A
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- pharmaceutical composition
- ticagrelor
- disintegrating
- excipient
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- AVOLMBLBETYQHX-UHFFFAOYSA-N etacrynic acid Chemical compound CCC(=C)C(=O)C1=CC=C(OCC(O)=O)C(Cl)=C1Cl AVOLMBLBETYQHX-UHFFFAOYSA-N 0.000 description 1
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- SMANXXCATUTDDT-QPJJXVBHSA-N flunarizine Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)N1CCN(C\C=C\C=2C=CC=CC=2)CC1 SMANXXCATUTDDT-QPJJXVBHSA-N 0.000 description 1
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- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229960002003 hydrochlorothiazide Drugs 0.000 description 1
- 229940050526 hydroxyethylstarch Drugs 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 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 1
- 229960004569 indapamide Drugs 0.000 description 1
- NDDAHWYSQHTHNT-UHFFFAOYSA-N indapamide Chemical compound CC1CC2=CC=CC=C2N1NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 NDDAHWYSQHTHNT-UHFFFAOYSA-N 0.000 description 1
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- 201000005851 intracranial arteriosclerosis Diseases 0.000 description 1
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- 229960002479 isosorbide Drugs 0.000 description 1
- 229960000829 kaolin Drugs 0.000 description 1
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- 235000019359 magnesium stearate Nutrition 0.000 description 1
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- 229960002817 metolazone Drugs 0.000 description 1
- AQCHWTWZEMGIFD-UHFFFAOYSA-N metolazone Chemical compound CC1NC2=CC(Cl)=C(S(N)(=O)=O)C=C2C(=O)N1C1=CC=CC=C1C AQCHWTWZEMGIFD-UHFFFAOYSA-N 0.000 description 1
- 229910000150 monocalcium phosphate Inorganic materials 0.000 description 1
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- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- IHLAQQPQKRMGSS-UHFFFAOYSA-N oxiracetam Chemical compound NC(=O)CN1CC(O)CC1=O IHLAQQPQKRMGSS-UHFFFAOYSA-N 0.000 description 1
- 229960001227 oxiracetam Drugs 0.000 description 1
- SHZKQBHERIJWAO-AATRIKPKSA-N ozagrel Chemical compound C1=CC(/C=C/C(=O)O)=CC=C1CN1C=NC=C1 SHZKQBHERIJWAO-AATRIKPKSA-N 0.000 description 1
- 229950003837 ozagrel Drugs 0.000 description 1
- 229960003207 papaverine hydrochloride Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 1
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- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- NCTHNHPAQAVBEB-WGCWOXMQSA-M sodium ferulate Chemical compound [Na+].COC1=CC(\C=C\C([O-])=O)=CC=C1O NCTHNHPAQAVBEB-WGCWOXMQSA-M 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- OKODKVMXHLUQSW-JITBQSAISA-M sodium;(e)-4-hydroxy-4-oxobut-2-enoate;octadecanoic acid Chemical compound [Na+].OC(=O)\C=C\C([O-])=O.CCCCCCCCCCCCCCCCCC(O)=O OKODKVMXHLUQSW-JITBQSAISA-M 0.000 description 1
- YWAFNFGRBBBSPD-OCMLZEEQSA-M sodium;[[(2r,3s,4r,5r)-5-(4-amino-2-oxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-oxidophosphoryl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound [Na+].O[C@@H]1[C@H](O)[C@@H](COP([O-])(=O)OP([O-])(=O)OCC[N+](C)(C)C)O[C@H]1N1C(=O)N=C(N)C=C1 YWAFNFGRBBBSPD-OCMLZEEQSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 229960000216 tenecteplase Drugs 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- 229960000103 thrombolytic agent Drugs 0.000 description 1
- 229960005461 torasemide Drugs 0.000 description 1
- 229960001288 triamterene Drugs 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
Abstract
The invention provides a ticagrelor pharmaceutical composition and a preparation method thereof, wherein the pharmaceutical composition comprises 10-20% of ticagrelor, a disintegrant and other pharmaceutically acceptable carriers according to weight percentage, and through the combination of a specific disintegration excipient and other disintegrants, the invention remarkably shortens the disintegration time of the pharmaceutical composition and improves the dissolution speed while reducing the component types in the ticagrelor pharmaceutical composition, and is especially suitable for patients with dysphagia, thereby improving the patient compliance and bioavailability of the ticagrelor pharmaceutical composition.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a ticagrelor pharmaceutical composition, and a preparation method and application thereof.
Background
Ticagrelor is a novel strong P2Y12 receptor antagonist, is clinically used as an anti-platelet aggregation antithrombotic agent, and is widely used for treating Acute Coronary Syndrome (ACS).
Ticagrelor is white or off-white crystalline powder, is almost insoluble in water, and the bioavailability of ticagrelor is directly influenced by the dissolution speed. As an oral solid preparation, disintegration is the rate-limiting step in its dissolution, which in turn affects bioavailability. CN107530288A and its division disclose a ticagrelor orally disintegrating tablet, which adopts mannitol, microcrystalline cellulose, crospovidone, xylitol and anhydrous calcium hydrogen phosphate as composite auxiliary materials to be added into a tablet composition, and further granulation is carried out to realize rapid disintegration. However, ticagrelor has poor flowability, and the rapid disintegration of the drug is still difficult to realize after granulation, and the inventors found that most of the obtained samples disintegrated within 30s, even more than 1 min.
Therefore, how to develop a ticagrelor pharmaceutical composition which is quick in disintegration, simple in preparation process and better in taste after being taken becomes a technical problem which needs to be solved urgently in the field.
Disclosure of Invention
The invention aims to provide a ticagrelor pharmaceutical composition which comprises 10-20 wt% of ticagrelor, a disintegrating agent and other pharmaceutically acceptable carriers, wherein the ratio of the disintegrating agent is more than or equal to 60%.
In a preferred technical scheme of the invention, the ticagrelor in the pharmaceutical composition is 14-16% by weight.
In the preferred technical scheme of the invention, the ratio of the disintegrating agent is more than or equal to 65 percent.
In a preferred embodiment of the present invention, the disintegrant is selected from the group consisting of a combination of a disintegrating excipient and another disintegrant.
In the preferable technical scheme of the invention, the ratio of the disintegration excipient is more than or equal to 50%, preferably more than or equal to 55%, and more preferably more than or equal to 60%.
In the preferred technical scheme of the invention, the disintegration excipient consists of hydrophilic auxiliary materials and hydrophobic auxiliary materials, wherein the weight percentage of the hydrophilic auxiliary materials is more than or equal to 80 percent based on the disintegration excipient.
In a preferred technical scheme of the invention, the hydrophilic auxiliary material is selected from any one of mannitol, microcrystalline cellulose, xylitol and lactose or a combination thereof.
In a preferred technical scheme of the invention, the hydrophilic auxiliary material is selected from a composition of mannitol and microcrystalline cellulose.
In a preferred technical scheme of the invention, the hydrophobic auxiliary material is selected from any one of or a combination of anhydrous calcium hydrogen phosphate, crospovidone, calcium carbonate, calcium dihydrogen phosphate and kaolin.
In a preferred technical scheme of the invention, the hydrophobic auxiliary material is selected from anhydrous calcium hydrophosphate and a crospovidone composition.
In the preferred technical scheme of the invention, the disintegration excipient comprises, by weight, 60% -80% of mannitol, 15% -20% of microcrystalline cellulose, 5% -10% of crospovidone and 1% -5% of anhydrous calcium hydrogen phosphate.
In the preferred technical scheme of the invention, the disintegration excipient comprises 65-75% of mannitol, 15-20% of microcrystalline cellulose, 7-9% of crospovidone and 3-5% of anhydrous calcium hydrogen phosphate according to weight percentage.
In a preferred technical scheme of the invention, the disintegrating excipient is prepared by mixing and spray drying.
In a preferred technical scheme of the invention, in the pharmaceutical composition, the weight percentage of the other disintegrating agents is 1-10%, preferably 3-5%.
In a preferred embodiment of the present invention, the other disintegrant is selected from any one or a combination of crospovidone, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, and partially pregelatinized starch.
In a preferred embodiment of the present invention, the other pharmaceutically acceptable carrier is selected from any one of a binder, a diluent, a lubricant, a glidant, or a combination thereof.
In the preferred technical scheme of the invention, the adhesive accounts for 1-3 wt%, the diluent accounts for 10-25 wt%, the lubricant accounts for 1-3 wt%, and the flow aid accounts for 0.1-1 wt%.
In a preferred technical scheme of the invention, the binder is selected from any one of or a combination of hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, polyvinyl alcohol, arabic gum and dextrin.
In a preferred embodiment of the present invention, the diluent is selected from any one of mannitol, microcrystalline cellulose, calcium carbonate, sodium carbonate, lactose, monocalcium phosphate, sodium phosphate, and kaolin, or a combination thereof.
In a preferred embodiment of the present invention, the lubricant is selected from any one of sodium fumarate stearate, stearic acid, magnesium stearate, calcium stearate, sucrose fatty acid ester, or a combination thereof.
In a preferred technical scheme of the invention, the glidant is selected from any one of colloidal silicon dioxide and talcum powder or a combination thereof.
In a preferred technical scheme of the invention, the pharmaceutical composition is in a preparation form selected from any one of tablets, capsules and granules.
In a preferred technical scheme of the invention, the pharmaceutical composition is in the form of an orally disintegrating tablet.
In the preferable technical scheme of the invention, in the process of preparing the pharmaceutical composition into the orally disintegrating tablet, the addition mode of the disintegration excipient is an external addition method.
In the preferable technical scheme of the invention, in the process of preparing the pharmaceutical composition into the orally disintegrating tablet, the other disintegrating agents and the glidants are added in two parts, wherein the amount of the prescription is not less than 10 percent by adopting an internal addition method, and the rest is added by adopting an external addition method.
In a preferred technical scheme of the invention, the dynamic disintegration time of the orally disintegrating tablet is less than 20 s.
In the preferable technical scheme of the invention, the static disintegration time of the orally disintegrating tablet is less than 30s, and the static disintegration time of the pharmaceutical composition is preferably less than or equal to 20 s.
The invention also aims to provide a preparation method of the ticagrelor pharmaceutical composition, which comprises the following steps:
(a) weighing and uniformly mixing the ticagrelor, the filler and the adhesive in the formula amount;
(b) adding the mixture prepared in the step (a) into a wetting agent to prepare granules, drying and straightening;
(c) adding the disintegrant, the lubricant and the glidant into the granules prepared in the step (b), uniformly mixing, and tabletting.
In a preferred technical scheme of the invention, before the step (a), the ticagrelor and the pharmaceutically acceptable carrier are crushed and sieved to obtain the ticagrelor-containing pharmaceutical composition.
In the preferred technical scheme of the invention, the shearing speed in the granulation process in the step (b) is 500-2000r/min, preferably 600-1500r/min, and the stirring speed is 100-500r/min, preferably 200-400 r/min.
In the preferable technical scheme of the invention, the drying in the step (b) is to dry the wet granules to ensure that the moisture content in the granules is less than or equal to 3 percent, preferably less than or equal to 2 percent.
In the preferable technical scheme of the invention, in the granulating process in the step (b), the screen is 2-4X 2-4mm, and the rotating speed is 100-500 rpm.
In a preferred embodiment of the present invention, the disintegrant includes a disintegration excipient and other disintegrants.
In the preferred technical scheme of the invention, the other disintegrating agent and the glidant are added in two parts; wherein not less than 10% of the prescribed amount of the other disintegrant is added in step (a) (internal addition method) and the remaining prescribed amount of the other disintegrant is added in step (c) (external addition method).
In a preferred embodiment of the invention, at least 15% of the prescribed amount of other disintegrant is added in step (a).
In a preferred technical scheme of the invention, the glidant with the amount not less than 30% of the prescription amount is added in the step (a), and the glidant with the rest of the prescription amount is added in the step (a).
In a preferred embodiment of the present invention, the other disintegrant is selected from crospovidone, and the glidant is selected from colloidal silicon dioxide.
The invention also aims to provide a preparation method of the ticagrelor pharmaceutical composition, which comprises the following steps:
(a) weighing ticagrelor, a filler, an adhesive, other disintegrants of which the prescription amount is not less than 10% and a glidant of which the prescription amount is not less than 30% and uniformly mixing;
(b) adding a wetting agent into the mixture prepared in the step (a) to prepare granules, drying and finishing the granules;
(c) adding disintegrating excipient, lubricant, other disintegrating agent and glidant in the rest prescription amount into the granules prepared in the step (b), uniformly mixing, and tabletting.
Another object of the present invention is to provide a pharmaceutical composition of ticagrelor for use in the preparation of a medicament for the treatment of any one of coronary artery disease, cerebrovascular disease or peripheral vascular disease or a complication thereof.
In a preferred embodiment of the present invention, the coronary artery disease is selected from any one of coronary atherosclerosis, coronary heart disease, coronary arteritis, and coronary aneurysm, or a complication thereof.
In a preferred embodiment of the present invention, the cerebrovascular disease is any one or a complication selected from the group consisting of cerebral atherosclerosis, thrombosis, stenosis, occlusion, cerebral arteritis, cerebral artery injury, cerebral aneurysm, intracranial vascular malformation, and cerebral arteriovenous fistula.
In a preferred embodiment of the present invention, the peripheral vascular disease is any one selected from the group consisting of arteriosclerotic occlusion, arteriovenous thrombosis, and aneurysm, or a complication thereof.
Another object of the present invention is to provide a pharmaceutical composition of ticagrelor for use in combination with other drugs selected from any one of anti-coronary artery disease drugs, anti-cerebrovascular disease drugs, anti-peripheral vascular disease drugs or a combination thereof.
In a preferred technical scheme of the invention, the anti-coronary artery disease drug is any one or combination of papaverine hydrochloride, cyclandelate, nicotinic acid, calcium channel blocker, betadine, sodium bicarbonate, kalanchoe tablets and victoria.
In a preferred technical scheme of the invention, the anti-cerebrovascular disease drug is any one or combination of a venous thrombolytic drug, an antiplatelet drug, an anticoagulant drug, a defibrination drug, a dilatation drug, a vasodilation drug, a diuretic drug, a dehydration drug and a microcirculation improving drug.
In a preferred embodiment of the present invention, the intravenous thrombolytic agent is any one selected from urokinase and tenecteplase, or a combination thereof.
In a preferred technical scheme of the invention, the antiplatelet drug is selected from any one of aspirin, clopidogrel aspirin, dipyridamole, ozagrel, sodium ferulate and troxerutin or a combination thereof.
In a preferred embodiment of the present invention, the anticoagulant is selected from any one of heparin, warfarin, argatroban, and thrombin inhibitors, or a combination thereof.
In a preferred technical scheme of the invention, the defibrination reducing agent is selected from any one of defibrination, batroxobin and lumbrokinase or a combination thereof.
In a preferred embodiment of the present invention, the volume-expanding drug is selected from one or a combination of hydroxyethyl starch, low-molecular dextran, and human serum albumin.
In a preferred technical scheme of the invention, the vasodilator is selected from any one of cinepazide, flunarizine, buflomedil, nicergoline, ulirelidin, vinpocetine and fasudil or a combination thereof.
In a preferred technical scheme of the invention, the diuretic is selected from any one of bumetanide, ethacrynic acid, chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide, metolazone, amiloride, eplerenone, spironolactone, triamterene, furosemide and torasemide or a combination thereof.
In a preferred embodiment of the present invention, the dehydration drug is selected from any one or a combination of mannitol, glycerol fructose, sorbitol, isosorbide, urea, glycerol, and hypertonic glucose.
In a preferred technical scheme of the invention, the microcirculation improving drug is selected from any one of butylphthalide, edaravone, oxiracetam, monosialyl glucoside (GM1), alprostadil, troxerutin, calf serum, vinpocetine, citicoline sodium, nimodipine and nicardipine or a combination thereof.
Unless otherwise indicated, when the present invention relates to percentages between liquids, said percentages are volume/volume percentages; the invention relates to the percentage between liquid and solid, said percentage being volume/weight percentage; the invention relates to the percentages between solid and liquid, said percentages being weight/volume percentages; the balance being weight/weight percent.
Compared with the prior art, the invention has the following beneficial technical effects:
1. the invention obviously shortens the disintegration time of the pharmaceutical composition and improves the dissolution speed while reducing the component types in the pharmaceutical composition of ticagrelor, and is particularly suitable for patients with dysphagia, thereby improving the patient compliance and bioavailability of the pharmaceutical composition of ticagrelor.
2. The preparation method is simple, is simple and convenient to operate, and is suitable for large-scale industrial production.
Detailed Description
The following description of the embodiments of the present invention is not intended to limit the present invention, and those skilled in the art may make various changes and modifications without departing from the spirit of the present invention, which is defined in the appended claims.
Comparative example 1
Prescription composition
TABLE 1
Preparation method
(1) Pretreatment: weighing 3000 parts of ticagrelor, mannitol, colloidal silicon dioxide, hydroxypropyl cellulose and crospovidone CL-F (internal addition) according to the prescription amount, putting the weighed materials into a self-sealing bag, manually mixing for 5min, and sieving by a 24-mesh sieve for later use.
(2) And (3) granulating: placing the pretreated internal raw and auxiliary materials in a wet mixing granulator, setting the shearing speed to be 800r/min and the stirring speed to be 250r/min, starting the machine for mixing for 10min, and stopping the machine; weighing a proper amount of purified water, slowly adding the purified water with the prescription amount to prepare a soft material under a starting state (the shearing speed is 800r/min, and the stirring speed is 250r/min), continuously stirring and shearing for 30s after the addition is finished (54s), stopping the machine, adjusting the stirring speed to 360r/min, adjusting the shearing speed to 1200r/min, keeping the stirring speed unchanged, continuously preparing the soft material for 150s, and discharging; the soft material is granulated by a vertical granulator with a 3X 3mm screen, and the rotation speed is 200-400 rpm.
(3) And (3) drying the particles: setting the air inlet temperature at 50-60 deg.C and the air quantity at 70-120m3And h (ensuring the good fluidization state of the material), putting the wet particles into the multifunctional fluidized bed, starting air supply and heating, and drying the particles. Recording time, air inlet temperature, material temperature, air outlet temperature and air quantity in the drying process, stopping heating and air supply when the material temperature reaches about 35 ℃, sampling and measuring the moisture of the particles, and controlling the moisture of the particles to be less than or equal to 2.0 percent (95 ℃ and 5min by a rapid moisture measuring instrument).
(4) Straightening: the vertical granulator is provided with a 1.2mm screen, and the rotation speed is 200 plus 400 rpm.
(5) Total mixing: weighing the additional auxiliary materials according to the particle yield, sieving the additional auxiliary materials by a vertical granulator with a 2.0mm sieve, and then placing the additional auxiliary materials and the dry particles in a 5L hopper mixer at the rotating speed of 15rpm for mixing for 20 min.
(6) Tabletting: adopting a phi 14mm round chamfer flat punching sheet, controlling the weight of the sheet to be 600mg +/-2 percent, and controlling the hardness to be 5.5-7.5 kg.
Example 1
Prescription composition
TABLE 2
Preparation method
(1) Weighing 3000 parts of ticagrelor, mannitol, colloidal silicon dioxide, hydroxypropyl cellulose and crospovidone CL-F (internal addition) according to the prescription amount, putting the weighed materials into a self-sealing bag, manually mixing for 5min, and sieving by a 24-mesh sieve for later use.
(2) And (3) granulating: placing the pretreated internal raw and auxiliary materials in a wet mixing granulator, setting the shearing speed to be 800r/min and the stirring speed to be 250r/min, starting the granulator for mixing for 10min, and stopping the granulator; weighing a proper amount of purified water, slowly adding the purified water with the prescription amount to prepare a soft material under a starting state (the shearing speed is 800r/min, and the stirring speed is 250r/min), continuously stirring and shearing for 30s after the addition is finished (54s), stopping the machine, adjusting the shearing speed to 1200r/min, adjusting the stirring speed to 360r/min, continuously preparing the soft material for 150s, and discharging; the soft material is granulated by a vertical granulator with a 3X 3mm screen, and the rotation speed is 200-400 rpm.
(3) And (3) drying the particles: setting the air inlet temperature at 50-60 deg.C and the air quantity at 70-120m3And h (ensuring that the material has a good fluidization state), putting the wet particles into the multifunctional fluidized bed, starting air supply and heating, and drying the particles. Recording time, air inlet temperature, material temperature, air outlet temperature and air quantity in the drying process, stopping heating and air supply when the material temperature reaches about 35 ℃, sampling and measuring the moisture of the particles, and controlling the moisture of the particles to be less than or equal to 2.0 percent (95 ℃ and 5min by a rapid moisture measuring instrument).
(4) Straightening: the vertical granulator is provided with a 1.2mm screen, and the rotation speed is 200 plus 400 rpm.
(5) Total mixing: weighing the additional auxiliary materials according to the particle yield, sieving the additional auxiliary materials by a vertical granulator with a 2.0mm sieve, and then placing the additional auxiliary materials and the dry particles in a 5L hopper mixer at the rotating speed of 15rpm for mixing for 20 min.
(6) Tabletting: adopting a phi 14mm round chamfer flat punching sheet, controlling the weight of the sheet to be 600mg +/-2 percent and the hardness to be 5.5-7.5 kg.
Test example 1Investigation of tablet Properties
The tablet weights of the tablets prepared in comparative example 1 and example 1 were measured by weighing method.
And (4) detecting the hardness and friability of the plain tablets prepared in the embodiment by adopting a hardness detector and a friability detector.
The dynamic disintegration time limit of the tablets obtained in comparative example 1 and example 1 was measured with reference to the method in "chinese pharmacopoeia 2015 edition (fourth part)" 0921 ". And, according to the characteristic of orally disintegrating tablet to determine its static disintegration time, the method is as follows: test articles (comparative example 1 and example 1) were taken as a tablet and placed in a 20ml beaker containing 2ml of purified water, and the time taken for the water to diffuse from the edge of the tablet to the center of the tablet was recorded. The results are shown in the following table.
TABLE 3 examination of the tablet Properties
| Investigation item | Comparative example 1(n ═ 6) | Example 1(n ═ 6) |
| Friability of plain tablets | 0.13％ | 0.02％ |
| Phenomenon(s) | Slight edge gouge | Hardly knock edge |
| Hardness of plain sheet | 5-7kg | 5-7kg |
| Plain sheet appearance | One side of the sheet is smooth and clean | The surface of the sheet is smooth and clean |
| Dynamic disintegration time limit | 20-25s | 13-17s |
| Static disintegration (2ml water) | 30-35s | 12-18s |
Test example 2Dissolution determination
Different mediums (shown in the following table) are used as dissolution mediums, and according to general rules of the four departments of the 'Chinese pharmacopoeia' 2015 edition, the dissolution rates of the tablets prepared in the comparative example and the example 1 are measured by a paddle method, wherein the rotating speed is 900r/min, and the temperature is (37.0 +/-0.5) DEG C. The results are shown in the following table.
TABLE 40.1 dissolution Profile in hydrochloric acid + 0.1% Tween Medium
TABLE 5 dissolution curves in pH4.5 acetate + 0.1% Tween medium
TABLE 60.1% Twain pH6.8 phosphate dissolution Profile in phosphate media
TABLE 70.1 dissolution Curve in Tween aqueous Medium
Test example 3Consideration of influence factor
The stability of the tablets of comparative example 1 and example 1 was examined for 10 days at 0 days, light, high humidity RH 75%, high temperature 60 ℃ by HPLC, under the following conditions: and (4) operating in dark. Taking a proper amount of sample fine powder, precisely weighing, adding water-acetonitrile (65:35) to perform ultrasonic dissolution to prepare a solution containing about 1mg in each 1ml, shaking up, and filtering to obtain a test sample solution; a suitable amount of the sample solution is precisely measured, and diluted quantitatively with water-acetonitrile (65:35) to obtain a solution containing about 2. mu.g of the sample solution per 1ml as a control solution. Precisely weighing a proper amount of the reference substance of the ticagrelor, adding water-acetonitrile (65:35) to perform ultrasonic dissolution and quantitative dilution to prepare a solution containing 0.25 mu g of the reference substance in each 1ml, and shaking up to be used as a quantitative limiting solution. Performing high performance liquid chromatography (Chinese pharmacopoeia 2020 edition) with octadecylsilane chemically bonded silica as filler (Agilent Zorbax SB-C18, 150mm × 4.6mm, 1.8 um); taking 10ml of phosphate buffer solution (1.0 mol/L sodium dihydrogen phosphate buffer solution (pH value is adjusted to 3.0 by phosphoric acid), adding water to 900ml, shaking up ] -acetonitrile (90:10) as a mobile phase A; taking 10ml of phosphate buffer solution (1.0 mol/L sodium dihydrogen phosphate buffer solution (pH value is adjusted to 3.0 by phosphoric acid), adding water to 300ml, shaking up ] -acetonitrile (30:70) as a mobile phase B, and carrying out gradient elution according to the following table; flow rate 1.0ml per minute; the column temperature was 55 ℃; the detection wavelength was 242 nm. The tailing factor of the ticagrelor peak should not be more than 1.5, and the number of theoretical plates should not be less than 13500 in terms of ticagrelor peak. Precisely measuring the quantitative limiting solution, the sample solution and the reference solution by 5 μ l each, injecting into a liquid chromatograph, and recording chromatogram. If an impurity peak exists in the chromatogram of the test solution, the area of the impurity 1 peak multiplied by a correction factor of 0.5 is not more than the area (0.2%) of the main peak of the control solution; the peak area of the impurity 2 is not more than the main peak area (0.2%) of the control solution, the peak area of the impurity 3 is not more than 0.5 times (0.1%) of the main peak area of the control solution, and the peak areas of other single impurities are not more than the main peak area (0.2%) of the control solution; the total impurities should not be greater than 0.5%. Any peak in the chromatogram of the test solution that is smaller than the area of the main peak of the quantitation limit solution is negligible.
TABLE 8 mobile phase gradient elution Table
The example 1 sample exhibited better light stability and the results are shown in the following table.
TABLE 9 examination of influence factors
Wherein, the structural formula of the impurity 1 is as follows:
impurity 2 is of the formula:
impurity 3 (a set of enantiomers) is of the formula:
test example 4
The sample of example 1 was measured by the method of examining the uniformity of 0941 content in four parts of the 2015 version, which is the "Chinese pharmacopoeia" (A: theoretical content minus absolute value of average content and S: standard deviation of relative content).
Table 10 content uniformity determination for example 1
The above description of the specific embodiments of the present invention is not intended to limit the present invention, and those skilled in the art may make various changes and modifications according to the present invention without departing from the spirit of the present invention, which is defined in the appended claims.
Claims (10)
1. The ticagrelor pharmaceutical composition is characterized by comprising 10-20% of ticagrelor, a disintegrant and other pharmaceutically acceptable carriers according to weight percentage, wherein the ratio of the disintegrant is more than or equal to 60%.
2. The pharmaceutical composition of claim 1, wherein ticagrelor in said pharmaceutical composition is between 14% and 16%.
3. The pharmaceutical composition of claim 2, wherein the disintegrant is selected from the group consisting of disintegrating excipients and other disintegrants; preferably, the ratio of the disintegrating excipient is more than or equal to 50%, preferably more than or equal to 55%, and more preferably more than or equal to 60%.
4. The pharmaceutical composition of claim 3, wherein the disintegration excipient consists of hydrophilic excipients and hydrophobic excipients, wherein the weight percentage of the hydrophilic excipients is more than or equal to 80% of the disintegration excipient; preferably, the hydrophilic adjuvant is selected from any one of mannitol, microcrystalline cellulose, xylitol, lactose or a combination thereof; preferably, the hydrophilic excipient is selected from the group consisting of mannitol and microcrystalline cellulose.
5. The pharmaceutical composition of claim 4, wherein the disintegrating excipient comprises, by weight, 60% to 80% of mannitol, 15% to 20% of microcrystalline cellulose, 5% to 10% of crospovidone, and 1% to 5% of anhydrous calcium hydrogen phosphate; preferably, the disintegrating excipient comprises 65-75% of mannitol, 15-20% of microcrystalline cellulose, 7-9% of crospovidone and 3-5% of anhydrous calcium hydrophosphate.
6. The pharmaceutical composition of claim 5, wherein the disintegrating excipient is prepared by mixing, spray drying; preferably, in the process of preparing the pharmaceutical composition into orally disintegrating tablets, the addition mode of the disintegration excipient is an external addition method; preferably, in the process of preparing the orally disintegrating tablet from the pharmaceutical composition, the other disintegrating agents and the glidants are added in two parts, wherein the amount of the prescription is not less than 10 percent by adopting an internal addition method, and the rest is added by adopting an external addition method.
7. A process for the preparation of a pharmaceutical composition of ticagrelor according to any of claims 1 to 6, comprising the steps of:
(a) weighing and uniformly mixing the ticagrelor, the filler and the adhesive in the formula amount;
(b) adding a wetting agent into the mixture prepared in the step (a) to prepare granules, drying and finishing the granules;
(c) adding the disintegrating agent, the lubricant and the glidant into the granules prepared in the step (b), uniformly mixing, and tabletting;
preferably, the other disintegrating agent and the glidant are added in two parts; wherein not less than 10% of the prescribed amount of the other disintegrant is added in step (a) (internal addition method) and the remaining prescribed amount of the other disintegrant is added in step (c) (external addition method);
preferably, the glidant in an amount not less than 30% of the prescription is added in step (a) and the remaining prescription of the glidant is added in step (a).
8. A process for the preparation of a pharmaceutical composition of ticagrelor according to any of claims 1 to 6, comprising the steps of:
(a) weighing ticagrelor, a filler, an adhesive, other disintegrants of which the prescription amount is not less than 10% and a glidant of which the prescription amount is not less than 30% and uniformly mixing;
(b) adding a wetting agent into the mixture prepared in the step (a) to prepare granules, drying and finishing the granules;
(c) adding disintegrating excipient, lubricant, other disintegrating agent and glidant in the rest prescription amount into the granules prepared in the step (b), uniformly mixing, and tabletting.
9. Use of a ticagrelor pharmaceutical composition according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment of any one of coronary artery disease, cerebrovascular disease or peripheral vascular disease, or a complication thereof.
10. A combination of the ticagrelor pharmaceutical composition of any of claims 1-6 and a further agent selected from any one of an anti-coronary artery disease agent, an anti-cerebrovascular disease agent, an anti-peripheral vascular disease agent, or a combination thereof.
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