CN101716148A - Tirofiban hydrochloride freeze-dried powder injection preparation and preparation method thereof - Google Patents
Tirofiban hydrochloride freeze-dried powder injection preparation and preparation method thereof Download PDFInfo
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- CN101716148A CN101716148A CN200910231233A CN200910231233A CN101716148A CN 101716148 A CN101716148 A CN 101716148A CN 200910231233 A CN200910231233 A CN 200910231233A CN 200910231233 A CN200910231233 A CN 200910231233A CN 101716148 A CN101716148 A CN 101716148A
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- China
- Prior art keywords
- freeze
- tirofiban hydrochloride
- dried powder
- preparation
- tirofiban
- Prior art date
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Links
- 229960004929 tirofiban hydrochloride Drugs 0.000 title claims abstract description 70
- HWAAPJPFZPHHBC-FGJQBABTSA-N tirofiban hydrochloride Chemical compound O.Cl.C1=CC(C[C@H](NS(=O)(=O)CCCC)C(O)=O)=CC=C1OCCCCC1CCNCC1 HWAAPJPFZPHHBC-FGJQBABTSA-N 0.000 title claims abstract description 70
- 238000002360 preparation method Methods 0.000 title claims abstract description 47
- 238000002347 injection Methods 0.000 title claims abstract description 38
- 239000007924 injection Substances 0.000 title claims abstract description 38
- 239000000843 powder Substances 0.000 title claims abstract description 37
- 239000007788 liquid Substances 0.000 claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 10
- 239000007962 solid dispersion Substances 0.000 claims description 39
- 239000000047 product Substances 0.000 claims description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 19
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 16
- 229960003425 tirofiban Drugs 0.000 claims description 16
- COKMIXFXJJXBQG-NRFANRHFSA-N tirofiban Chemical compound C1=CC(C[C@H](NS(=O)(=O)CCCC)C(O)=O)=CC=C1OCCCCC1CCNCC1 COKMIXFXJJXBQG-NRFANRHFSA-N 0.000 claims description 16
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 12
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 10
- 239000008215 water for injection Substances 0.000 claims description 10
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 claims description 9
- 238000004108 freeze drying Methods 0.000 claims description 9
- 238000005303 weighing Methods 0.000 claims description 9
- 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 8
- 229930195725 Mannitol Natural products 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 239000000594 mannitol Substances 0.000 claims description 8
- 235000010355 mannitol Nutrition 0.000 claims description 8
- 239000012982 microporous membrane Substances 0.000 claims description 8
- 238000010792 warming Methods 0.000 claims description 8
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 claims description 7
- 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 6
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 6
- 229920003081 Povidone K 30 Polymers 0.000 claims description 6
- 229960000502 poloxamer Drugs 0.000 claims description 6
- 229920001983 poloxamer Polymers 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000008103 glucose Substances 0.000 claims description 5
- 239000008101 lactose Substances 0.000 claims description 5
- 229920002307 Dextran Polymers 0.000 claims description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 4
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 4
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 229960003511 macrogol Drugs 0.000 claims description 4
- 239000001632 sodium acetate Substances 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- 239000001509 sodium citrate Substances 0.000 claims description 3
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 3
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 239000004380 Cholic acid Substances 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 239000004202 carbamide Substances 0.000 claims description 2
- 235000013877 carbamide Nutrition 0.000 claims description 2
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 claims description 2
- 229960002471 cholic acid Drugs 0.000 claims description 2
- 235000019416 cholic acid Nutrition 0.000 claims description 2
- 229960004106 citric acid Drugs 0.000 claims description 2
- 238000004140 cleaning Methods 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 238000005262 decarbonization Methods 0.000 claims description 2
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 claims description 2
- 229960003964 deoxycholic acid Drugs 0.000 claims description 2
- 238000011049 filling Methods 0.000 claims description 2
- 238000007710 freezing Methods 0.000 claims description 2
- 230000008014 freezing Effects 0.000 claims description 2
- 229940093430 polyethylene glycol 1500 Drugs 0.000 claims description 2
- 238000005057 refrigeration Methods 0.000 claims description 2
- 239000011265 semifinished product Substances 0.000 claims description 2
- 238000000859 sublimation Methods 0.000 claims description 2
- 230000008022 sublimation Effects 0.000 claims description 2
- 229940045136 urea Drugs 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims 2
- 239000002904 solvent Substances 0.000 claims 2
- 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 claims 1
- 239000013618 particulate matter Substances 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 3
- 239000012905 visible particle Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 10
- 238000000034 method Methods 0.000 description 9
- 238000012360 testing method Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000012856 packing Methods 0.000 description 7
- 238000002390 rotary evaporation Methods 0.000 description 7
- 239000004411 aluminium Substances 0.000 description 6
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 6
- 229910052782 aluminium Inorganic materials 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 230000009191 jumping Effects 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 239000001384 succinic acid Substances 0.000 description 6
- 229960004756 ethanol Drugs 0.000 description 5
- 229940119744 dextran 40 Drugs 0.000 description 4
- 238000001647 drug administration Methods 0.000 description 4
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 230000002950 deficient Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- TZBAVQKIEKDGFH-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound [Cl-].C1=CC=C2SC(C(=O)NCC[NH+](CC)CC)=CC2=C1 TZBAVQKIEKDGFH-UHFFFAOYSA-N 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 230000001133 acceleration Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000012876 carrier material Substances 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000003978 infusion fluid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 2
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 1
- 108010035030 Platelet Membrane Glycoprotein IIb Proteins 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000000250 revascularization Effects 0.000 description 1
- 231100000817 safety factor Toxicity 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 150000003608 titanium Chemical class 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a tirofiban hydrochloride freeze-dried powder injection preparation and a preparation method thereof. The tirofiban hydrochloride freeze-dried powder injection preparation produced by a freeze-dried technology of the invention greatly enhances solubility of tirofiban hydrochloride; and since the pH of redissolved liquid medicine is within the range of 2.0-8.0 and visible particles and particulate matter satisfy the requirement of the pharmacopeia, the safety of medicine is greatly improved. The tirofiban hydrochloride freeze-dried powder injection preparation has simple preparation, controllable quality, stable physical and chemical properties and safe and effective use.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of tirofiban hydrochloride freeze-dried powder preparation and preparation method thereof.
Background technology
Tirofiban (English name Tirofibon) is a kind of platelet glycoprotein GP IIb/IIIa receptor antagonist of non-titanium class; effect with anti-platelet aggregation, its chemistry is by name: N-(normal-butyl sulfonyl)-O-[4-(4-piperidyl) butyl]-L-tyrosine hydrochloride monohydrate.Tirofiban hydrochloride is used for the treatment of acute coronary syndrome (unstable angina pectoris or non-q wave myocardial infarction) patient, is applicable to that also coronary ischemia syndrome patient carries out atherectomy in arteria coronaria angioplasty or the arteria coronaria.Tirofiban hydrochloride can reduce death, myocardial infarction, the incidence rate of the compound terminal point incident of intractable myocardial ischemia/myocardial revascularization.
The tirofiban hydrochloride dosage form of listing mostly is liquid preparation both at home and abroad at present, this product injection at first went on the market in the U.S. in May, 1998, the listing dosage form is for being the concentrated solution for injection and the infusion solutions of isoosmotic adjusting agent with sodium chloride, specification has: 50ml: 12.5mg, 250ml: 12.5mg, 500ml: 25mg, put down in writing the detailed prescription of this medicine in the offering circular, CN96197877.5 has authorized this pharmaceutical composition on July 21st, 2004, wherein is added with citric acid and sodium citrate as pH regulator agent and stabilizing agent.Chinese food Drug Administration ratifies the listing of tirofiban hydrochloride sodium chloride injection in August, 2004, specification is 100ml: 5mg, CN200410061014.0 discloses a kind of injection that suppresses platelet aggregation and preparation method thereof, consist of tirofiban hydrochloride, sodium chloride, water, above-mentioned transfusion exists all that volume weight is big, transportation inconvenience, damaged, shortcoming that the visible foreign matters qualification rate is low easily.
CN100367961C discloses tirofiban hydrochloride freeze-dried powder preparation and preparation method thereof, and lactose is an excipient, and pH transfers to 2～3, and there is following problem in the sample by this prepared:
Though 1. visible foreign matters is that mannitol, dextran are good than excipient, does not fundamentally solve the problem of visible foreign matters, still have minority product visible foreign matters defective after experimental results show that redissolution, bring certain hidden danger for patient's medication.
2. medicinal liquid pH transfers to 2～3.Solubility experiment proves, in this scope, tirofiban hydrochloride dissolubility maximum is higher or lower than this scope, dissolubility all can diminish, but low pH scope like this, drug administration by injection has certain hidden danger to human body, and is well-known, the pH value of intravenously administrable injection is more near the pH7.4 of blood of human body, safe more to human body, there is safety factors scarcely in this patent medicinal liquid pH far below blood pH.
3. used excipient is a lactose, but lactose does not have the injection specification at present, and as the injection excipient, consumption is big, and its safety is not confirmed, and has potential safety hazard.
Summary of the invention
The lyophilization powder injection formulation that the purpose of this invention is to provide a kind of tirofiban hydrochloride has that simple, quality controllable, physics of preparation and chemical property are stable, effective advantage safe in utilization.
Another object of the present invention is to provide a kind of preparation method of lyophilization powder injection formulation of tirofiban hydrochloride.
The invention provides a kind of tirofiban hydrochloride injection freeze-dried powder and preparation technology thereof, overcome the defective that exists in the prior art.Tirofiban hydrochloride is slightly soluble in water, meets the pharmacopeia regulation so will guarantee visible foreign matters, particulate matter after lyophilizing is redissolved, and the most key is to improve the dissolubility of tirofiban hydrochloride in water.Freeze-dried powder dissolubility of the present invention is good, and the back visible foreign matters that redissolves is up to specification, and pH is stable in 2.0～8.0 scopes, is a kind of safe and effective, the simple hydrochloride for injection tirofiban of preparation technology preparation.
The present invention adopts solid dispersion technology, tirofiban hydrochloride is become the tirofiban hydrochloride solid dispersion with the solid dispersion preparing carriers, surrounded by the soluble carrier material around making medicine, improved the wettability of medicine, improve the dissolubility of tirofiban hydrochloride greatly.
The pH scope of medicinal liquid of the present invention is all stable 2.0～8.0, preferred 5.0～7.5, because the pH value of intravenously administrable injection is safe more to human body more near the pH value 7.4 of blood of human body, therefore the most preferred pH scope of the present invention is 6.5～7.5, and the safety to human body behind the drug administration by injection improves greatly.
The used freeze-dried excipient of the present invention is can be for the adjuvant of drug administration by injection, and with the lactose that does not obtain the safety confirmation, safety is more secure.
Hydrochloride for injection tirofiban freeze-dried powder provided by the invention is compared with its infusion solution, the storage, the transportation more convenient, cost is lower.
The present invention adopts solid dispersion technology, because the freeze-dried powder packaging material is the good cillin bottle of moisture resistance, moisture does not almost have influence to the stability of dispersion, by the selection to carrier material, utilizes rational preparation technology, and preparation solid dispersion stability better.
Hydrochloride for injection tirofiban freeze-dried powder provided by the invention is made up of tirofiban hydrochloride, solid dispersion carrier, excipient etc., and concrete weight proportion is as follows:
1 part of tirofiban hydrochloride (in tirofiban)
0.5～5 part in solid dispersion carrier
0.5～10 part of excipient
Wherein above-mentioned described hydrochloride for injection tirofiban freeze-dried powder, described excipient is one or more in mannitol, dextran, glucose, sodium chloride and the glucose.
Above-mentioned described hydrochloride for injection tirofiban freeze-dried powder is in polyethylene glycol 1500, Macrogol 2000, Macrogol 4000,30 POVIDONE K 30 BP/USP 15,30 POVIDONE K 30 BP/USP 30,30 POVIDONE K 30 BP/USP 90, carbamide, poloxamer, citric acid, succinic acid, cholic acid, the deoxycholic acid one or more in described solid dispersion carrier wherein.
Above-mentioned described tirofiban hydrochloride injection freeze-dried powder also comprises the pH regulator agent, and wherein said PH regulator is one or more in sodium hydroxide, potassium hydroxide, sodium citrate, sodium carbonate, sodium bicarbonate, the sodium acetate.Join solution the pH scope be decided to be 2.0～8.0, preferred 5.0～7.5, most preferably be pH6.5～7.5.
The preparation technology of above-mentioned described hydrochloride for injection tirofiban freeze-dried powder, it comprises the steps:
1. take by weighing tirofiban hydrochloride, the solid dispersion carrier of recipe quantity, join in an amount of ethanol, 30～75 ℃ of following stirring and dissolving;
2. 40～80 ℃, rotary evaporation, preparation solid dispersion.
3. detect tirofiban hydrochloride content in the solid dispersion, take by weighing a certain amount of solid dispersion, be dissolved in the water for injection, add freeze-dried excipient, stir and make dissolving, add active carbon, medicinal liquid is carried out decarbonization filtering, stir, regulate pH to 2.0～8.0, medicinal liquid detects semi-finished product through the degerming of 0.22um filtering with microporous membrane.
According to medicinal liquid content, press the principal agent specification with a certain amount of liquid medicine filling in the cillin bottle of cleaning, the false add plug is put into the freeze dryer lyophilizing, rolls lid, the packing promptly.
The preparation method of above-mentioned described hydrochloride for injection tirofiban freeze-dried powder is characterized in that described freezing dry process comprises the steps:
1. pre-freeze: sample is placed on the freeze dryer shelf, open freeze dried refrigeration system and sample is freezed, cool the temperature to-60～-35 ℃ with 0.5～3 ℃/min rate of cooling.Kept this temperature 3～9 hours.
2. sublimation drying: treat product freeze fully real after, the open cold condenser is reduced to below-40 ℃ its temperature, the beginning evacuation, the sample temperature that progressively raises under the vacuum state makes the basic lyophilizing of moisture in the sample to-10～-5 ℃.
3. parsing-desiccation: keep vacuum state, sample is warming up to 25～40 ℃, and keeps a period of time under this temperature, lyophilizing finishes, total head plug outlet.
Technique effect of the present invention is:
1. tirofiban hydrochloride freeze-dried powder preparation provided by the invention, physics and chemical property are stable, and be quality controllable, especially solved the defective phenomenon of tirofiban hydrochloride redissolution back visible foreign matters, the pH scope is 2.0～8.0, has improved the safety of tirofiban hydrochloride freeze-dried powder medication;
2. technology of the present invention is simple, is beneficial to operation, is fit to industrialized great production.
The specific embodiment
Specify the present invention and beneficial effect thereof by the following examples, embodiment only is used for the purpose of illustration, should not be construed as limiting the scope of the invention, those of ordinary skills are also contained within the present invention conspicuous change and the modification that the present invention did.
Embodiment 1
1 part of tirofiban hydrochloride (in tirofiban)
0.5 part of Macrogol 4000
10 parts in mannitol
Sodium hydroxide solution (0.05mol/l) is transferred pH to 2.0
Preparation technology:
(1) takes by weighing tirofiban hydrochloride, the Macrogol 4000 of recipe quantity, be dissolved in 30 ℃ of ethanol 40 ℃ of rotary evaporations, the preparation solid dispersion, solid dispersion is added water for injection, stir and make dissolving, add mannitol again, stirring makes dissolving, regulate pH to 2.0 with sodium hydroxide solution, then with the filtering with microporous membrane degerming of medicinal liquid through 0.22 μ m, the qualified after testing back fill of filtrate is in cillin bottle, the false add plug is put into freeze drying box then.
(2) open freeze dryer product is carried out pre-freeze, with 2 ℃/min products temperature is reduced to-35 ℃ approximately, kept this temperature 9 hours, treat product freeze fully real after, the open cold condenser is reduced to below-40 ℃ temperature, the beginning evacuation carries out lyophilizing, and progressively elevated temperature makes the basic lyophilizing of moisture in the sample to-5 ℃ then, continue to be warming up to about 40 ℃, keep the about 8h of this temperature, lyophilizing finishes, the outlet of jumping a queue entirely.
(3) the outer aluminium lid that rolls, check, packing, promptly.
Embodiment 2
1 part of tirofiban hydrochloride (in tirofiban)
5 parts of polyvidone k30
0.5 part of Dextran 40
Potassium hydroxide solution (0.05mol/l) is transferred pH to 7.0
Preparation technology:
(1) takes by weighing tirofiban hydrochloride, the polyvidone k30 of recipe quantity, be dissolved in 75 ℃ of ethanol 80 ℃ of rotary evaporations, the preparation solid dispersion, solid dispersion is added water for injection, stir and make dissolving, add Dextran 40 again, stirring makes dissolving, regulate pH to 7.0 with potassium hydroxide solution, then with the filtering with microporous membrane degerming of medicinal liquid through 0.22 μ m, the qualified after testing back fill of filtrate is in cillin bottle, the false add plug is put into freeze drying box then.
(2) open freeze dryer product is carried out pre-freeze, with 0.5 ℃/min products temperature is reduced to approximately below-60 ℃, keep this temperature about 3 hours, treat product freeze fully real after, the beginning evacuation carries out lyophilizing, then progressively elevated temperature to-10 ℃, make the basic lyophilizing of moisture in the sample, continue to be warming up to about 40 ℃, keep the about 8h of this temperature, lyophilizing finishes, the outlet of jumping a queue entirely.
(3) the outer aluminium lid that rolls, check, packing, promptly.
Embodiment 3
1 part of tirofiban hydrochloride (in tirofiban)
1 part of succinic acid
1 part in sodium chloride
Sodium hydroxide solution (0.05mol/l) is transferred pH to 8.0
Preparation technology:
(1) takes by weighing tirofiban hydrochloride, the succinic acid of recipe quantity, be dissolved in 40 ℃ of 75% ethanol 55 ℃ of rotary evaporations, the preparation solid dispersion, solid dispersion is added water for injection, stir and make dissolving, add sodium chloride again, stirring makes dissolving, regulate pH to 8.0 with sodium hydroxide solution, then with the filtering with microporous membrane degerming of medicinal liquid through 0.22 μ m, the qualified after testing back fill of filtrate is in cillin bottle, the false add plug is put into freeze drying box then.
(2) open freeze dryer product is carried out pre-freeze, with 3 ℃/min products temperature is reduced to-50 ℃ approximately, keep this temperature about 4 hours, treat product freeze fully real after, the beginning evacuation carries out lyophilizing, then progressively elevated temperature to-6 ℃, make the basic lyophilizing of moisture in the sample, continue to be warming up to about 35 ℃, keep the about 7h of this temperature, lyophilizing finishes, the outlet of jumping a queue entirely.
(3) the outer aluminium lid that rolls, check, packing, promptly.
Embodiment 4
1 part of tirofiban hydrochloride (in tirofiban)
2 parts of citric acid
1 part of succinic acid
1 part of glucose
Sodium hydroxide solution (0.05mol/l) is transferred pH to 5.0
Preparation technology:
(1) takes by weighing tirofiban hydrochloride, succinic acid, the citric acid of recipe quantity, be dissolved in 45 ℃ of dehydrated alcohol 65 ℃ of rotary evaporations, the preparation solid dispersion, solid dispersion is added water for injection, stir and make dissolving, add glucose again, stirring makes dissolving, regulate pH to 5.0 with sodium hydroxide solution, then with the filtering with microporous membrane degerming of medicinal liquid through 0.22 μ m, the qualified after testing back fill of filtrate is in cillin bottle, the false add plug is put into freeze drying box then.
(2) open freeze dryer product is carried out pre-freeze, with 1.5 ℃/min products temperature is reduced to-40 ℃ approximately, keep this temperature about 4 hours, treat product freeze fully real after, the beginning evacuation carries out lyophilizing, then progressively elevated temperature to-7 ℃, make the basic lyophilizing of moisture in the sample, continue to be warming up to about 40 ℃, keep the about 6h of this temperature, lyophilizing finishes, the outlet of jumping a queue entirely.
(3) the outer aluminium lid that rolls, check, packing, promptly.
Embodiment 5
1 part of tirofiban hydrochloride (in tirofiban)
1 part of poloxamer
1 part of succinic acid
2 parts in mannitol
5% sodium carbonate liquor is transferred pH to 6.5
Preparation technology:
(1) takes by weighing tirofiban hydrochloride, succinic acid, the poloxamer of recipe quantity, be dissolved in 35 ℃ of 90% ethanol 45 ℃ of rotary evaporations, the preparation solid dispersion, solid dispersion is added water for injection, stir and make dissolving, add mannitol again, stirring makes dissolving, regulate pH to 6.5 with 5% sodium carbonate liquor, then with the filtering with microporous membrane degerming of medicinal liquid through 0.22 μ m, the qualified after testing back fill of filtrate is in cillin bottle, the false add plug is put into freeze drying box then.
(2) open freeze dryer product is carried out pre-freeze, with 2 ℃/min products temperature is reduced to-50 ℃ approximately, keep this temperature about 4 hours, treat product freeze fully real after, the beginning evacuation carries out lyophilizing, then progressively elevated temperature to-6 ℃, make the basic lyophilizing of moisture in the sample, continue to be warming up to about 25 ℃, keep the about 9h of this temperature, lyophilizing finishes, the outlet of jumping a queue entirely.
(3) the outer aluminium lid that rolls, check, packing, promptly.
Embodiment 6
1 part of tirofiban hydrochloride (in tirofiban)
1 part of poloxamer
0.5 part of succinic acid
40 3 parts of dextrans
6% sodium acetate solution is transferred pH to 7.5
Preparation technology:
(1) takes by weighing tirofiban hydrochloride, poloxamer, the succinic acid of recipe quantity, be dissolved in 40 ℃ of dehydrated alcohol 50 ℃ of rotary evaporations, the preparation solid dispersion, solid dispersion is added water for injection, stir and make dissolving, add Dextran 40 again, stirring makes dissolving, regulate pH to 7.5 with 6% sodium acetate solution, then with the filtering with microporous membrane degerming of medicinal liquid through 0.22 μ m, the qualified after testing back fill of filtrate is in cillin bottle, the false add plug is put into freeze drying box then.
(2) open freeze dryer product is carried out pre-freeze, with 0.5 ℃/min products temperature is reduced to-40 ℃ approximately, keep this temperature about 4 hours, treat product freeze fully real after, the beginning evacuation carries out lyophilizing, then progressively elevated temperature to-6 ℃, make the basic lyophilizing of moisture in the sample, continue to be warming up to about 35 ℃, keep the about 8h of this temperature, lyophilizing finishes, the outlet of jumping a queue entirely.
(3) the outer aluminium lid that rolls, check, packing, promptly.
Checking embodiment 1
1, tirofiban hydrochloride solid dispersion and tirofiban hydrochloride material dissolution degree (all in tirofiban hydrochloride) are relatively.
| Sample | Dissolubility in the water |
| The tirofiban hydrochloride solid dispersion | ??12.4mg/ml |
| Tirofiban hydrochloride | ??5.1mg/ml |
2, dried frozen aquatic products A, dried frozen aquatic products B, commercially available liquid drugs injection sample stability data relatively (acceleration environment: 40 ℃, 75%RH)
A: the freeze-dried powder that utilizes the solid dispersions technique preparation
B: adopt the freeze-dried powder of common process, common process: tirofiban hydrochloride and Macrogol 4000, mannitol are dissolved in the water for injection, and sodium hydroxide is transferred pH, common process lyophilizing.
From last table, find out, be prepared into solid dispersion after, the tirofiban hydrochloride dissolubility improves greatly, the lyophilizing sample redissolves back visible foreign matters, particulate matter and all meets 2005 editions pharmacopeia requirements.Investigated in 6 months through accelerated test, the every index of product is all up to specification, shows constant product quality.
Checking embodiment 2
1, tirofiban hydrochloride solid dispersion and tirofiban hydrochloride material dissolution degree (all in tirofiban hydrochloride) are relatively.
| Sample | Dissolubility in the water |
| The tirofiban hydrochloride solid dispersion | ??25.2mg/ml |
| Tirofiban hydrochloride | ??5.1mg/ml |
2, the stability data of dried frozen aquatic products A, dried frozen aquatic products B (acceleration environment: 40 ℃, 75%RH)
A: the freeze-dried powder that utilizes the solid dispersions technique preparation.
B: adopt the freeze-dried powder of common process, common process: tirofiban hydrochloride and polyvidone k30, Dextran 40 are dissolved in the water for injection, and potassium hydroxide is transferred pH, common process freeze in.
From last table, find out, be prepared into solid dispersion after, the tirofiban hydrochloride dissolubility improves greatly, the lyophilizing sample redissolves back visible foreign matters, particulate matter and all meets 2005 editions pharmacopeia requirements.Investigated in 6 months through accelerated test, the every index of product is all up to specification, shows constant product quality.
Claims (12)
1. tirofiban hydrochloride injection freeze-dried powder, it is characterized in that forming and weight proportion as follows:
1 part of tirofiban hydrochloride (in tirofiban)
0.5～5 part in solid dispersion carrier
0.5～10 part of excipient
2. according to the described tirofiban hydrochloride injection of claim 1 freeze-dried powder, it is characterized in that described solid dispersion carrier be polyethylene glycol 1500, Macrogol 2000, Macrogol 4000,30 POVIDONE K 30 BP/USP 15,30 POVIDONE K 30 BP/USP 30,30 POVIDONE K 30 BP/USP 90, carbamide, poloxamer, citric acid, succinic acid, cholic acid, deoxycholic acid, in one or more.
3. according to the described tirofiban hydrochloride injection of claim 1 freeze-dried powder, it is characterized in that described excipient is one or more of mannitol, dextran, glucose, lactose and sodium chloride.
4. according to the described tirofiban hydrochloride injection of claim 1 freeze-dried powder, it is characterized in that its composition also contains the PH regulator.
5. according to the described tirofiban hydrochloride injection of claim 4 freeze-dried powder, described PH regulator is one or more in sodium hydroxide, potassium hydroxide, sodium citrate, sodium carbonate, sodium bicarbonate, the sodium acetate.
6. according to the described tirofiban hydrochloride injection of claim 1-5 freeze-dried powder, it is characterized in that lyophilizing pH scope preceding and redissolution back medicinal liquid is 2.0～8.0.
7. according to the described tirofiban hydrochloride injection of claim 6 freeze-dried powder, it is characterized in that lyophilizing pH scope preceding and redissolution back medicinal liquid is 5.0～7.5.
8. according to the described tirofiban hydrochloride injection of claim 7 freeze-dried powder, it is characterized in that lyophilizing pH scope preceding and redissolution back medicinal liquid is 6.5～7.5.
9. according to the preparation method of the described tirofiban hydrochloride injection of claim 1-5 freeze-dried powder, comprise following steps:
(1) preparation solid dispersion;
(2) prepared solid dispersion is dissolved in the water for injection, adds freeze-dried excipient, stir and make dissolving, add active carbon, medicinal liquid is carried out decarbonization filtering, stir, regulate pH to 2.0～8.0, medicinal liquid detects semi-finished product through the filtering with microporous membrane degerming;
(3) according to medicinal liquid content, press the principal agent specification with a certain amount of liquid medicine filling in the cillin bottle of cleaning, the false add plug is put into the freeze dryer lyophilization.
10. according to the preparation method of the described tirofiban hydrochloride injection of claim 9 freeze-dried powder, it is characterized in that the preparation process of the described solid dispersion of step (1) comprises following steps:
(1) takes by weighing tirofiban hydrochloride, solid dispersion carrier, join in the ethanol stirring and dissolving;
(2) evaporating solvent, the preparation solid dispersion.
11., it is characterized in that described freezing dry process comprises the steps: according to the preparation method of the described tirofiban hydrochloride injection of claim 9 freeze-dried powder
(1) pre-freeze: sample is placed on the freeze dryer shelf, open freeze dried refrigeration system and sample is freezed, cool the temperature to-60～-35 ℃, kept this temperature 3～9 hours with 0.5～3 ℃/min rate of cooling;
(2) sublimation drying: after treating that product freezes in fact fully, the open cold condenser is reduced to below-40 ℃ its temperature, the beginning evacuation, and the sample temperature that progressively raises under the vacuum state makes the basic lyophilizing of moisture in the sample to-10～-5 ℃;
(3) parsing-desiccation: keep vacuum state, sample is warming up to 25～40 ℃, and keeps a period of time under this temperature, lyophilizing finishes, total head plug outlet.
12. according to the preparation method of the described tirofiban hydrochloride injection of claim 10 freeze-dried powder, the temperature that it is characterized in that stirring and dissolving described in the step (1) is 30～75 ℃, the temperature of evaporating solvent is 40～80 ℃ described in the step (2).
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101756915A (en) * | 2010-02-25 | 2010-06-30 | 山东新时代药业有限公司 | Tirofiban hydrochloride lyophilized powder injection and preparation method thereof |
| CN108785261A (en) * | 2018-07-03 | 2018-11-13 | 马现梅 | A kind of pharmaceutical preparation and preparation method thereof containing tirofiban hydrochloride |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1820751A (en) * | 2005-02-18 | 2006-08-23 | 华中科技大学 | Tirofiban powder injection and its preparing method |
| CN100367961C (en) * | 2005-09-30 | 2008-02-13 | 天津南开允公医药科技有限公司 | Tirofiban hydrochloride freeze-dried powder injecta and preparing method |
-
2009
- 2009-12-08 CN CN2009102312331A patent/CN101716148B/en active Active
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101756915A (en) * | 2010-02-25 | 2010-06-30 | 山东新时代药业有限公司 | Tirofiban hydrochloride lyophilized powder injection and preparation method thereof |
| CN101756915B (en) * | 2010-02-25 | 2011-06-22 | 山东新时代药业有限公司 | Tirofiban hydrochloride lyophilized powder injection and preparation method thereof |
| CN108785261A (en) * | 2018-07-03 | 2018-11-13 | 马现梅 | A kind of pharmaceutical preparation and preparation method thereof containing tirofiban hydrochloride |
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| CN101716148B (en) | 2012-03-07 |
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Assignee: SHANDONG NEW TIME PHARMACEUTICAL Co.,Ltd. Assignor: LUNAN PHARMACEUTICAL Group Corp. Contract record no.: 2010370000509 Denomination of invention: Tirofiban hydrochloride freeze-dried powder injection preparation and preparation method thereof License type: Exclusive License Open date: 20100602 Record date: 20100908 |
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