CN100522167C - Palonosetron injection and its powder injection preparation of salt receptable on medicine and its preparing method - Google Patents
Palonosetron injection and its powder injection preparation of salt receptable on medicine and its preparing method Download PDFInfo
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- CN100522167C CN100522167C CNB2004100647249A CN200410064724A CN100522167C CN 100522167 C CN100522167 C CN 100522167C CN B2004100647249 A CNB2004100647249 A CN B2004100647249A CN 200410064724 A CN200410064724 A CN 200410064724A CN 100522167 C CN100522167 C CN 100522167C
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Abstract
The present invention relates to palonosetron as medicine for treating chemotherapy caused vomiting and its pharmaceutically acceptable salt, and is especially medicine powder of palonosetron and its pharmaceutically acceptable salt for injection and its preparation process. The medicine powder for injection consists of palonosetron and its pharmaceutically acceptable salt and excipient, and may have also pH regulator, antioxidant and other supplementary material.
Description
Technical field
The present invention relates to a kind of medicine palonosetron (palonosetron) and pharmaceutically acceptable salt thereof for the treatment of the vomiting that chemotherapy causes, specifically is powder injection formulation of injection palonosetron and pharmaceutically acceptable salt thereof and preparation method thereof.
Background technology
Palonosetron (palonosetron) is a kind of new 5-hydroxytryptamine receptor antagonist, is mainly used in to prevent the inductive nausea and vomiting disease of chemotherapy.The injection hydro-acupuncture preparation is arranged in the market, and the vomiting that causes has extraordinary curative effect to said preparation for the treatment chemotherapy clinically, but hydro-acupuncture preparation pH value, light stability are relatively poor relatively, thereby exerts a certain influence for clinical drug safety and effectiveness.
Summary of the invention
The purpose of this invention is to provide a kind of injection palonosetron of the vomiting that chemotherapy causes and powder injection formulation of pharmaceutically acceptable salt thereof of being used for the treatment of.
Another object of the present invention provides the preparation method of the powder injection formulation of a kind of injection palonosetron that is used for the treatment of the vomiting that chemotherapy causes and pharmaceutically acceptable salt thereof.
Purpose of the present invention can reach by following measure:
The powder injection formulation of injection palonosetron of the present invention and pharmaceutically acceptable salt thereof can be made up of principal agent palonosetron and pharmaceutically acceptable salt thereof and excipient.
The present invention also can add the pH regulator agent, is used to regulate the pH value of preparation.
According to characteristics such as stability of formulation, can also add adjuvants such as antioxidant.
Add the diluent of excipient as the powder injection formulation of injection palonosetron and pharmaceutically acceptable salt thereof, be convenient to packing and raising stability of drug and be fit to injection use, excipient is polyhydric alcohol, organic acid and the salt thereof that allows on the physiology, inorganic salts etc.; Promptly can adopt: the combination of one or several in mannitol, lactose, glycine, sorbitol, sucrose, low molecule dextrose, gelatin hydrolysate, vitamin C, citric acid, sodium citrate, sodium deoxycholate, sodium chloride, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydroxide, sodium carbonate, sodium bicarbonate, the glucose.
Described excipient is preferably one or several combination of following formula: mannitol, glycine, sodium dihydrogen phosphate, sodium chloride.
Add the pH regulator agent, be used to regulate the pH value of preparation, increase stability, can be hydrochloric acid, sulphuric acid, citric acid, the combination of one or several in tartaric acid, maleic acid, sodium hydroxide, sodium bicarbonate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium citrate, acetic acid, sodium acetate, lactic acid, sodium lactate, malic acid, natrium malicum, the phosphoric acid.
Described pH regulator agent is preferably one or several combination of following formula:
Sodium dihydrogen phosphate, maleic acid, tartaric acid.
Above-mentioned antioxidant can be sodium sulfite, sodium sulfite, sodium pyrosulfite, potassium metabisulfite, sodium formaldehyde sulphoxylate, sodium thiosulfate, sodium dithionite, 2-hydroxy-2-propane-sulfonic acid sodium salt, hydroxyl Loprazolam sodium, L-ascorbic acid, the D ascorbic acid, the combination of one or several in ascorbyl palmitate, L-cysteine, L-methionine, L-network propylhomoserin, L-valine, L-arginine, the L-leucine.
Described antioxidant is preferably one or several combination of following formula:
Sodium sulfite, sodium pyrosulfite, L-ascorbic acid.
After can dissolving with solvent, principal agent in the above-mentioned prescription and excipient carry out the preparation of sterilized powder.
Carry out the preparation of sterilized powder after also can dissolving the principal agent in the above-mentioned prescription, excipient, pH regulator agent with solvent.
If antioxidant is arranged, then dissolve preceding adding at the adding solvent.
Above-mentioned solution can carry out obtaining sterile solution behind aseptic filtration or the pressure sterilizing.
But above-mentioned sterile solution lyophilizing or spray drying obtain sterile solid, are packed as the sterile powder injection that is fit to clinical use.
Above-mentioned sterile solution also can packing after lyophilizing, become freeze-dried powder.
The invention of the powder injection formulation of described palonosetron and pharmaceutically acceptable salt thereof, every consist of:
Principal agent 0.01-10mg,
Excipient 0.5-1000mg.
In the preparation if pH regulator agent, then every consist of arranged:
Principal agent 0.01-10mg,
Excipient 0.5-1000mg,
PH regulator agent 0.1-200mg.
In the preparation if antioxidant, then every consist of arranged:
Principal agent 0.01-10mg
Excipient 0.5-1000mg
Antioxidant 0.001-200mg
Perhaps: principal agent 0.01-10mg, excipient 0.5-1000mg, pH regulator agent 0.1-200mg, antioxidant 0.001-200mg.
Principal agent in the above-mentioned composition all calculates by the amount of palonosetron, if its pharmaceutically acceptable salt then is converted into palonosetron and calculates.
The powder injection formulation invention of described palonosetron and pharmaceutically acceptable salt thereof, when having only principal agent and excipient, every composition is preferably:
Principal agent 0.01-10mg,
Mannitol 0.5-1000mg.
More preferably: principal agent: 0.25mg, mannitol: 250mg.
Described palonosetron and the invention of pharmaceutically acceptable salt powder injection formulation thereof, when being made up of principal agent, excipient and pH regulator agent, every composition is preferably: principal agent 0.01-10mg, mannitol 0.5-1000mg, sodium dihydrogen phosphate 0.1-200mg.
More preferably: palonosetron and pharmaceutically acceptable salt 0.25mg thereof, mannitol 230mg, sodium dihydrogen phosphate 40mg.
The powder injection formulation invention of described palonosetron and pharmaceutically acceptable salt thereof, when in the prescription antioxidant being arranged, every composition is preferably:
Principal agent 0.01-10mg,
Mannitol 0.5-1000mg,
Sodium sulfite 0.001-200mg.
Perhaps: principal agent 0.01-10mg,
Mannitol 0.5-1000mg,
Sodium dihydrogen phosphate 0.1-200mg,
Sodium pyrosulfite 0.001-200mg.
More preferably: principal agent 0.25mg
Mannitol 250mg
Sodium sulfite 5mg
Perhaps: principal agent 0.25mg
Mannitol 220mg
Sodium dihydrogen phosphate 40mg
Sodium pyrosulfite 10mg.
Above-mentioned principal agent all calculates by the amount of palonosetron, if its pharmaceutically acceptable salt then is converted into palonosetron and calculates.
The preparation method of injection palonosetron and pharmaceutically acceptable salt powder injection formulation thereof, mainly take following steps:
A. by above-mentioned preparation prescription batching, get the palonosetron of recipe quantity and pharmaceutically acceptable salt raw material thereof, excipient, add an amount of solvent dissolving;
B. above-mentioned solution adds activated carbon decolorizing, filters carbon removal;
C. be diluted to amount of preparation with above-mentioned solvent, measure liquor strength, liquor strength pH value scope is 3.5～6.0;
D. pass through the filter membrane filtration sterilization to receiver, packing according to the preset temperature lyophilizing, is rolled lid, packing.
When needing to add pH regulator agent or antioxidant in the prescription, before adding the solvent dissolving, add.The preparation process of above-mentioned steps d is lyophilizing after the first packing.
Also can take following steps:
A. press preparation prescription amount batching, get the palonosetron of recipe quantity and pharmaceutically acceptable salt raw material thereof, excipient, add an amount of solvent dissolving;
B. above-mentioned solution adds activated carbon decolorizing, filters carbon removal;
C. be diluted to amount of preparation with above-mentioned solvent, measure liquor strength;
D. pass through the filter membrane filtration sterilization to receiver, according to the preset temperature lyophilizing, lid is rolled in packing, packing.
When needing to add pH regulator agent or antioxidant in the prescription, before adding the solvent dissolving, add.The preparation process of above-mentioned steps d is packing after the first lyophilizing.
The present invention can adopt also that spray drying prepares sterilized powder under the gnotobasis, carries out packing again, makes the aseptic powder injection preparation, and concrete steps are as follows:
A. press preparation prescription amount batching, get the palonosetron of recipe quantity and pharmaceutically acceptable salt raw material thereof, excipient, add an amount of solvent dissolving;
B. above-mentioned solution adds activated carbon decolorizing, filters carbon removal;
C. be diluted to amount of preparation with above-mentioned solvent, measure liquor strength;
D. pass through the filter membrane filtration sterilization to receiver;
E. medicinal liquid spray drying under gnotobasis, relative density of medicine liquid is controlled between 1.05～1.28 for 60 ℃, and inlet temperature is controlled at 70～200 ℃, and leaving air temp is controlled at 50～90 ℃, collects dry sterilized powder;
F. with above-mentioned sterilized powder packing, jump a queue, roll lid, packing is made aseptic powder injection.
When needing to add pH regulator agent or antioxidant in the prescription, before adding the solvent dissolving, add.
Overall process of the present invention is carried out the sterile working, adopts the micropore filtering film degerming, cold drying, and product has and is difficult for ruined advantage; Vacuum or noble gas are filled, and are difficult for oxidation takes place, and period of storage is long, and stability is improved, thereby has prolonged the effect duration of this medicine, are convenient to store, transport and sell, and also are convenient to guarantee the quality of product.
Description of drawings
Fig. 1 is embodiment 1 a medicinal liquid freeze temperature curve chart.
Fig. 2 is embodiment 2 medicinal liquid freeze temperature curve charts.
Fig. 3 is embodiment 3 medicinal liquid freeze temperature curve charts.
The specific embodiment
Embodiment 1: palonosetron powder injection formulation prescription
Palonosetron 0.25g,
Mannitol 230g,
Sodium dihydrogen phosphate 40g,
Water for injection adds to 3000ml, makes 1000 altogether.
Embodiment 2: palonosetron powder injection formulation prescription
Palonosetron 0.25g,
Mannitol 240g,
Ascorbic acid 12g,
Water for injection adds to 2000ml, makes 1000 altogether.
Embodiment 3: palonosetron hydrochlorate powder injection formulation prescription
Palonosetron hydrochlorate (in palonosetron) 0.25g,
Mannitol 250g,
Water for injection adds to 800ml, makes 1000 altogether.
Embodiment 4: palonosetron powder injection formulation prescription
Palonosetron sulfate (in palonosetron) 0.25g
Mannitol 250g
Sodium sulfite 5g
Water for injection adds to 3000ml, makes 1000 altogether.
Embodiment 5: palonosetron powder injection formulation prescription:
Palonosetron 0.25g
Mannitol 220g
Sodium dihydrogen phosphate 40g
Sodium pyrosulfite 10g
Water for injection adds to 3000ml, makes 1000 altogether.
Embodiment 6: palonosetron powder injection formulation prescription
Palonosetron lactate (in palonosetron) 0.25g,
Mannitol 50g,
Water for injection adds to 3000ml, makes 1000 altogether.
Embodiment 7: palonosetron powder injection formulation prescription
Palonosetron maleate (in palonosetron) 0.55g,
Mannitol 30g,
Sodium dihydrogen phosphate 500g,
Glycine 20g,
Water for injection adds to 3000ml, makes 1000 altogether.
Embodiment 8: palonosetron and pharmaceutically acceptable salt powder injection formulation prescription thereof
Palonosetron and pharmaceutically acceptable salt 5g thereof,
Lactose 30g,
Sodium dihydrogen phosphate 50g,
Maleic acid 1g,
Water for injection adds to 3000ml, makes 1000 altogether.
Embodiment 9: palonosetron and pharmaceutically acceptable salt powder injection formulation prescription thereof
Palonosetron and pharmaceutically acceptable salt 10g thereof,
Sodium dihydrogen phosphate 250g,
Maleic acid 1g,
Tartaric acid 5g,
Water for injection adds to 3000ml, makes 1000 altogether.
Execute example 10: palonosetron and pharmaceutically acceptable salt powder injection formulation prescription thereof
Palonosetron and pharmaceutically acceptable salt 0.1g thereof,
Sodium dihydrogen phosphate 10g,
L-tyrosine 30g,
Tartaric acid 5g,
Water for injection adds to 3000ml, makes 1000 altogether.
Embodiment 11: palonosetron and pharmaceutically acceptable salt powder injection formulation prescription thereof
Palonosetron and pharmaceutically acceptable salt 0.25g thereof,
Sodium dihydrogen phosphate 40g,
Pyrosulfurous acid 30g,
Tartaric acid 5g,
Water for injection adds to 3000ml, makes 1000 altogether.
Embodiment 12: palonosetron and pharmaceutically acceptable salt powder injection formulation prescription thereof
Palonosetron and pharmaceutically acceptable salt 0.25mg thereof
Mannitol 50mg
Sodium dihydrogen phosphate 40mg
Sodium sulfite 10mg.
Embodiment 13: palonosetron and the preparation of pharmaceutically acceptable salt powder injection formulation thereof
The following steps preparation is taked in the preparation of the palonosetron of embodiment 1 and pharmaceutically acceptable salt powder injection formulation thereof:
A. by above-mentioned preparation prescription, get mannitol and the sodium dihydrogen phosphate 24g of the palonosetron of 0.25g and pharmaceutically acceptable salt raw material thereof, 200g, with the water for injection dissolving of 2400ml.
B. 1% the activated carbon decolorizing that adds the injection water yield filters carbon removal.
C. be diluted to amount of preparation with above-mentioned water for injection, measure liquor strength.
D. pass through the filter membrane filtration sterilization to receiver, packing according to the preset temperature lyophilizing, is rolled lid, packing.
Degerming measure: medicinal liquid disposable filtering membrane filtration degerming; Plugs etc. adopt the sterilization of vacuum and steam sterilization cabinet, drying; Material-compound tank, equipment such as receiver, injection water pot, freeze dryer and pipeline adopt online sterilization.
This example adopts general freeze dryer lyophilizing.
Temperature descending section temperature low spot :-52 ℃ keep in 7 hours lyophilizing this moment casings not evacuation
The section that heats up heating rate: 5 ℃ of/hour vacuums are 25～8Pa
The high point of the section temperature that heats up: 25 ℃ of vacuums are 8Pa
The high some retention time of temperature: 10 hours vacuum is 8Pa
The medicinal liquid freeze-drying curve as shown in Figure 1.
Embodiment 14: palonosetron and the preparation of pharmaceutically acceptable salt powder injection formulation thereof
The following steps preparation is taked in the preparation of the palonosetron of embodiment 2 and pharmaceutically acceptable salt powder injection formulation thereof:
A. by above-mentioned preparation prescription, get the palonosetron of 0.25g and pharmaceutically acceptable salt raw material thereof, the mannitol of 240g, 12g ascorbic acid, with the water for injection dissolving of 2000ml.
B. 1% the activated carbon decolorizing that adds the injection water yield filters carbon removal.
C. be diluted to amount of preparation with above-mentioned water for injection, measure liquor strength.
D. pass through the filter membrane filtration sterilization to receiver, packing according to the preset temperature lyophilizing, is rolled lid, packing.
This example adopts general freeze dryer lyophilizing.
Temperature descending section temperature low spot :-51 ℃ keep in 7 hours lyophilizing this moment casings not evacuation
A first intensification section heating rate: 4 ℃ of/hour vacuums are 10～8Pa
The high point of the first intensification section temperature: 10 ℃ keep 10 hours vacuum is 8Pa
A second intensification section heating rate: 4 ℃ of/hour vacuums are 8Pa
The high point of the second intensification section temperature: 30 ℃ keep 7 hours vacuum is 8Pa
The medicinal liquid freeze-drying curve as shown in Figure 2.
Embodiment 15: palonosetron and the preparation of pharmaceutically acceptable salt powder injection formulation thereof
The following steps preparation is taked in the preparation of the palonosetron of embodiment 3 and pharmaceutically acceptable salt powder injection formulation thereof:
A. by above-mentioned preparation prescription, get the palonosetron of 0.25g and the mannitol of pharmaceutically acceptable salt raw material and 250g thereof, with the water for injection dissolving of 800ml.
A. add activated carbon decolorizing, filter carbon removal.
B. be diluted to amount of preparation with above-mentioned water for injection, measure liquor strength.
C. pass through the filter membrane filtration sterilization to receiver, packing according to the preset temperature lyophilizing, is rolled lid, packing.
This example adopts general freeze dryer lyophilizing.
Temperature descending section temperature low spot :-52 ℃ keep in 7 hours lyophilizing this moment casings not evacuation
A first intensification section heating rate: 5 ℃ of/hour vacuums are 9～8Pa
The high point of the first intensification section temperature: 4 ℃ keep 15 hours vacuum is 8Pa
A second intensification section heating rate: 4 ℃ of/hour vacuums are 8Pa
The high point of the second intensification section temperature: 30 ℃ keep 6 hours vacuum is 8Pa
The 3rd an intensification section heating rate: 5 ℃ of/hour vacuums are 8Pa
The medicinal liquid freeze-drying curve as shown in Figure 3.
Embodiment 16: palonosetron and the preparation of pharmaceutically acceptable salt powder injection formulation thereof
Palonosetron and pharmaceutically acceptable salt 5g thereof, mannitol 230g, sodium dihydrogen phosphate 24g, sodium pyrosulfite 1g,
Water for injection adds to 1000ml, makes 1000 altogether.
Take the following steps preparation:
A. press preparation prescription amount batching, get the palonosetron of recipe quantity and pharmaceutically acceptable salt raw material thereof, excipient, pH regulator agent, antioxidant adds an amount of solvent dissolving.
B. above-mentioned solution adds activated carbon decolorizing, filters carbon removal.
C. be diluted to amount of preparation with above-mentioned solvent, measure liquor strength.
D. pass through the filter membrane filtration sterilization to receiver.
E. medicinal liquid spray drying under gnotobasis is carried out smoothly for guaranteeing spray drying, and is improved its efficient, relative density of medicine liquid is controlled between 1.05～1.28 (60 ℃), inlet temperature is controlled at 70～200 ℃, and leaving air temp is controlled at 50～90 ℃, collects dry sterilized powder.
With above-mentioned sterilized powder packing, jump a queue, roll lid, packing is made aseptic powder injection.
Embodiment 17: and palonosetron and pharmaceutically acceptable salt injectable powder thereof and palonosetron and pharmaceutically acceptable saline injection (injection) accelerated test result comparison thereof (40 ℃, RH75%)
Palonosetron and pharmaceutically acceptable saline injection accelerated test result thereof
Palonosetron and pharmaceutically acceptable salt injectable powder accelerated test result thereof
Can see from above result: palonosetron and pharmaceutically acceptable saline injection thereof accelerated test (40 ℃, RH75%) just against regulation during the condition next year.Palonosetron and pharmaceutically acceptable salt powder injection formulation thereof are then still stable in the time of 2 years.Therefore our invention advantage aspect period of storage, stable raising is outstanding.
Claims (2)
1. the powder injection formulation of an injection palonosetron and pharmaceutically acceptable salt thereof is characterized in that consisting of of every of described powder injection formulation:
Principal agent 0.25mg,
Mannitol 230mg,
Sodium dihydrogen phosphate 40mg.
2. the powder injection formulation of palonosetron as claimed in claim 1 and pharmaceutically acceptable salt thereof is characterized in that taking following steps:
A. press preparation prescription amount batching, get the palonosetron of recipe quantity and pharmaceutically acceptable salt raw material thereof, excipient, add an amount of solvent dissolving;
B. above-mentioned solution adds activated carbon decolorizing, filters carbon removal;
C. be diluted to amount of preparation with above-mentioned solvent, measure liquor strength, liquor strength pH value scope is: 3.5～6.0;
D. pass through the filter membrane filtration sterilization to receiver, packing according to the preset temperature lyophilizing, is rolled lid, packing.
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| CNB2004100647249A CN100522167C (en) | 2004-09-23 | 2004-09-23 | Palonosetron injection and its powder injection preparation of salt receptable on medicine and its preparing method |
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| CNB2004100647249A CN100522167C (en) | 2004-09-23 | 2004-09-23 | Palonosetron injection and its powder injection preparation of salt receptable on medicine and its preparing method |
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| CN100522167C true CN100522167C (en) | 2009-08-05 |
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2008146283A2 (en) * | 2007-05-29 | 2008-12-04 | Chemagis Ltd. | Novel palonosetron salts and processes for preparation and purification thereof |
| CN102670495B (en) * | 2012-05-23 | 2014-03-19 | 南京正大天晴制药有限公司 | Azasetron hydrochloride injection and preparation method thereof |
| CN103040762B (en) * | 2012-07-12 | 2014-08-13 | 姚云 | Pharmaceutical composition containing granisetron hydrochloride compound |
| JP6768404B2 (en) * | 2016-08-12 | 2020-10-14 | 武田テバファーマ株式会社 | A pharmaceutical composition comprising palonosetron or a pharmaceutically acceptable salt thereof. |
| KR101802183B1 (en) * | 2016-11-16 | 2017-11-28 | 주식회사 유영제약 | Pharmaceutical compositions comprising palonosetron as active ingredient |
| JP2019038758A (en) * | 2017-08-23 | 2019-03-14 | 武田テバファーマ株式会社 | Pharmaceutical composition containing palonosetron or pharmaceutically acceptable salt thereof |
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| 2003年美国FDA批准上市的新分子实体药物. 陆志城.医药经济报. 2004 |
| 2003年美国FDA批准上市的新分子实体药物. 陆志城.医药经济报. 2004 * |
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