CN105748458B - A kind of freeze-drying composition for injection for treating advanced ovarian cancer and preparation method thereof - Google Patents
A kind of freeze-drying composition for injection for treating advanced ovarian cancer and preparation method thereof Download PDFInfo
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- CN105748458B CN105748458B CN201610225160.5A CN201610225160A CN105748458B CN 105748458 B CN105748458 B CN 105748458B CN 201610225160 A CN201610225160 A CN 201610225160A CN 105748458 B CN105748458 B CN 105748458B
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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Abstract
The invention belongs to pharmaceutical technology fields, and in particular to a kind of freeze-drying composition for injection for treating advanced ovarian cancer and preparation method thereof：Mainly it is made of active constituent carboplatin, excipient, Tween 80 and pH adjusting agent.Invention formulation stable quality, simple for process, during the storage of freeze-drying composition for injection preparation, significant change does not occur for 1,1 cyclobutane dicarboxylic acid of impurity and related substance, improves the safety of preparation Clinical practice.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of freeze-drying composition for injection for treating advanced ovarian cancer and
Preparation method.
Background technology
Women of the whole world every year there are about more than 200,000 endures the torment of oophoroma to the fullest extent at present.Although its incidence is relatively
It is low, but case fatality rate is very high.In female cancer illness, case fatality rate has ranked the 7th.In American Women, the 5th is ranked
Position, every year there are about the death of 15,000 many cases, its case fatality rate is even more than lung cancer within 2008.The high main original of oophoroma case fatality rate
One of cause is that early diagnosis is difficult, and the patient of III/IV phase accounts for about the 75% of patient populations, and 5 years survival rates of these patients only have
30%。
Carboplatin is controlled available for the two wires after the first-line treatment of the oophoroma in treatment advanced epithelial source and other treatment failures
It treats, it is a kind of iridium-platinum complex of cytotoxicity as cis-platinum, and different from cis-platinum, carboplatin does not generate serious pair generally
Effect, such as renal toxicity, ototoxicity and neurotoxicity.Carboplatin is resistant to aquation, therefore this makes it have relatively low toxicity,
Carboplatin（Carboplatin）It by discoveries such as Clear, is listed first in Britain within 1986 within 1980, U.S. FDA is ratified for 1989
Listing is promoted using gradual.China's nineteen ninety approval production carboplatin powder, injection.Its entitled cis- 1,1- cyclobutane dicarboxylic acid of chemistry
Diamino conjunction platinum, molecular weight 371.3, molecular formula C6H12N2O4Pt, structural formula are as follows：
The liposome, emulsion and compound preparation about carboplatin at present disclosed in document is more, normal injection and common
The patent of freeze-dried composition is less.Chinese Patent Application No. 94109528.2 discloses platinum（Ⅱ）Stablizing for antitumor knurl agent is molten
Liquid, the present invention prepare 1, the 1- cyclobutane dicarboxylic acids containing stationary action or salt, the carboplatin that pH value is 4-8 and other malonic acid
Eka-platinium（Ⅱ）The solution of antitumor agent；This stabilizer inhibits unacceptable discoloration and precipitation；With air or oxygen purging and
Optionally it can also make solution-stabilizedization with oxygen or air covering headspace.
Due to carboplatin storage process easily in by environment temperature and illumination influenced, impurity 1,1-cyclobutane dicarboxyl
Acid and increase in relation to substance with the extension of standing time, carboplatin for injection equally exists similar problem, this is resulted in
The reduction of curative effect in preparation Clinical practice, while also increase security risk of the patient in Clinical practice.
Invention content
For above deficiency, the present invention provides a kind of freeze-drying composition for injection for treating advanced ovarian cancer：Mainly by
Active constituent carboplatin, excipient, Tween-80 and pH adjusting agent composition.
Freeze-drying composition for injection provided by the invention：The excipient for maltose, lactose, glucose, trehalose,
One or several kinds in sucrose, Dextran-20, Dextran 40, macrodex and sodium chloride, further preferably wheat
Bud sugar.
Freeze-drying composition for injection provided by the invention：The mass ratio of the active constituent carboplatin and excipient maltose
It is 1:1.0 ~ 2.0, further preferably 1:1.5.
Freeze-drying composition for injection provided by the invention：The active constituent carboplatin and the mass ratio of Tween-80 are 1:
0.5 ~ 0.9, further preferably 1:0.7.
Freeze-drying composition for injection provided by the invention：The pH value is the solution after freeze-drying composition for injection redissolution,
In the range of 3.8 ~ 4.2, further preferably 4.0.
Freeze-drying composition for injection provided by the invention：The pH adjusting agent is hydrochloric acid, acetic acid, phosphoric acid, lactic acid, citron
It is a kind of or several in acid or ammonium hydroxide and sodium hydroxide, further preferably hydrochloric acid or ammonium hydroxide.
Invention further provides the preparation methods of above-mentioned freeze-drying composition for injection, mainly include the following steps that：
1st, it prepares
A. it weighs the maltose of recipe quantity and Tween-80 is dissolved in suitable water for injection, be uniformly mixed, at addition
The carboplatin just measured, stirring and dissolving；
B. stirring and dissolving finishes, and pH value is adjusted with the dilute hydrochloric acid solution of 0.1mol/L or the dilute ammonia solution of 0.1mol/L；
C. it adjusts pH value to finish, is settled to full dose with water for injection, sampling detection intermediate products solution prepares to fill after qualified
Envelope.
2nd, wash bottle is dried
By neutral boron silica glass tubular injection bottle by bottle washing machine washes clean, 300 DEG C or more sterilizing and dryings reach filling
It is spare between dress.
3rd, rubber plug is handled
Injection freeze-drying aseptic powdery is cleaned up with chlorinated butyl rubber bung through rubber plug cleaning machine, 121 DEG C of steamings
Vapour pressure sterilizing 15 minutes, it is spare after dry.
4th, aluminium-plastic cap is handled
The cleaned machine washing of antibiotic bottle aluminium-plastic combined cover is washed, is sterilized, after dry, is taken out spare.
5th, it is filling
Liquid carries out filling after 0.22 μm of filtering with microporous membrane；Half adds rubber plug, and it is dry to be put into freezing in freeze drier
It is dry.
6th, it is lyophilized
Rubber plug is compressed after freeze-drying, abolishes freeze dryer vacuum, takes out product.
7th, lid, washout are rolled
The intermediate products of tamponade qualification after freeze-drying are rolled into lid, washout through Cover-rolling machine.
8th, visual inspection, packaging
By bottle visual inspection, breakage is rejected, rolls and covers the defective works such as bad, abnormal appearance.Certified products are packed.
The present invention also provides a kind of freeze-drying methods of above-mentioned freeze-drying composition for injection；
The following three phases of the freeze-drying method point carry out：
A. the pre-freeze stage：Pre-freeze is carried out, and make on the partition board that semi-finished product that are filling and partly jumping a queue are placed in freeze-drying cabinet
Semi-finished product reach pre-freezing temperature in the shortest possible time, and pre-freezing temperature is ranging between -50~-40 DEG C, and the time about 90 ~
150min；Pre-freezing temperature is preferably -45 DEG C, and the pre-freeze time is preferably 120min；
B. the lyophilization stage：When vacuum degree in drying box reaches 80mTorr~120mTorr, preferably
100mTorr；Main drying temperature is risen into -18.0 ~ -14.0 DEG C, preferably -16 DEG C；Used time about 60~120min, preferably
90min；Soaking time about 480min~720min, preferably 600min；
C. the re-dry stage：Re-dry temperature is increased to 25 ~ 35 DEG C, preferably 30 DEG C；Used time about 90 ~ 150min, it is excellent
It is selected as 120min；Vacuum degree in drying box is evacuated to end vacuum, soaking time about 210~270min, preferably 240min,
Obtain freeze-drying composition for injection.
Above-mentioned freeze-drying composition for injection of the present invention has the following advantages compared with prior art：Present invention system
Agent stable quality, it is simple for process, during the storage of freeze-drying composition for injection preparation, impurity 1,1-cyclobutane dicarboxylic acid
Significant change does not occur with related substance, improves the safety of preparation Clinical practice.
Specific embodiment
Embodiment 1：
Prescription
Preparation process
1st, it prepares
A. it weighs the maltose of recipe quantity and Tween-80 is dissolved in suitable water for injection, be uniformly mixed, at addition
The carboplatin just measured, stirring and dissolving；
B. stirring and dissolving finishes, and pH value is adjusted with the dilute hydrochloric acid solution of 0.1mol/L or the dilute ammonia solution of 0.1mol/L；
C. it adjusts pH value to finish, is settled to full dose with water for injection, sampling detection intermediate products solution prepares to fill after qualified
Envelope.
2nd, wash bottle is dried
By neutral boron silica glass tubular injection bottle by bottle washing machine washes clean, 300 DEG C or more sterilizing and dryings reach filling
It is spare between dress.
3rd, rubber plug is handled
Injection freeze-drying aseptic powdery is cleaned up with chlorinated butyl rubber bung through rubber plug cleaning machine, 121 DEG C of steamings
Vapour pressure sterilizing 15 minutes, it is spare after dry.
4th, aluminium-plastic cap is handled
The cleaned machine washing of antibiotic bottle aluminium-plastic combined cover is washed, is sterilized, after dry, is taken out spare.
5th, it is filling
Liquid carries out filling after 0.22 μm of filtering with microporous membrane；Half adds rubber plug, and it is dry to be put into freezing in freeze drier
It is dry.
6th, it is lyophilized
Rubber plug is compressed after freeze-drying, abolishes freeze dryer vacuum, takes out product.
7th, lid, washout are rolled
The intermediate products of tamponade qualification after freeze-drying are rolled into lid, washout through Cover-rolling machine.
8th, visual inspection, packaging
By bottle visual inspection, breakage is rejected, rolls and covers the defective works such as bad, abnormal appearance.Certified products are packed.
The present invention also provides a kind of freeze-drying methods of freeze-drying composition for injection；
The following three phases of the freeze-drying method point carry out：
A. the pre-freeze stage：Pre-freeze is carried out, and make on the partition board that semi-finished product that are filling and partly jumping a queue are placed in freeze-drying cabinet
Semi-finished product reach pre-freezing temperature in the shortest possible time, and pre-freezing temperature is -45 DEG C, and the pre-freeze time is 120min；
B. the lyophilization stage：Vacuum degree in drying box reaches 100mTorr；Main drying temperature is risen to -16 DEG C；With
When 90min；Soaking time 600min；
C. the re-dry stage：Re-dry temperature is risen to 30 DEG C；Used time 120min；Vacuum degree in drying box is evacuated to pole
Vacuum is limited, soaking time 240min obtains freeze-drying composition for injection.
Embodiment 2：
Prescription
Preparation process:With embodiment 1
Embodiment 3：
Prescription
Preparation process:With embodiment 1
Embodiment 4：
Prescription
Preparation process:With embodiment 1
Embodiment 5：
Prescription
Preparation process:With embodiment 1
Comparative example 1：
Prescription
Preparation process:
1st, it prepares
A. the Tween-80 for weighing recipe quantity is dissolved in suitable water for injection, is uniformly mixed, and adds in the card of recipe quantity
Platinum, stirring and dissolving；
B. stirring and dissolving finishes, and pH value is adjusted with the dilute hydrochloric acid solution of 0.1mol/L or the dilute ammonia solution of 0.1mol/L；
C. it adjusts pH value to finish, is settled to full dose with water for injection, sampling detection intermediate products solution prepares to fill after qualified
Envelope.
2nd, wash bottle is dried
By neutral boron silica glass tubular injection bottle by bottle washing machine washes clean, 300 DEG C or more sterilizing and dryings reach filling
It is spare between dress.
3rd, rubber plug is handled
Injection freeze-drying aseptic powdery is cleaned up with chlorinated butyl rubber bung through rubber plug cleaning machine, 121 DEG C of steamings
Vapour pressure sterilizing 15 minutes, it is spare after dry.
4th, aluminium-plastic cap is handled
The cleaned machine washing of antibiotic bottle aluminium-plastic combined cover is washed, is sterilized, after dry, is taken out spare.
5th, it is filling
Liquid carries out filling after 0.22 μm of filtering with microporous membrane；Half adds rubber plug, and it is dry to be put into freezing in freeze drier
It is dry.
6th, it is lyophilized
Rubber plug is compressed after freeze-drying, abolishes freeze dryer vacuum, takes out product.
7th, lid, washout are rolled
The intermediate products of tamponade qualification after freeze-drying are rolled into lid, washout through Cover-rolling machine.
8th, visual inspection, packaging
By bottle visual inspection, breakage is rejected, rolls and covers the defective works such as bad, abnormal appearance.Certified products are packed.
The present invention also provides a kind of freeze-drying methods of freeze-drying composition for injection；
The following three phases of the freeze-drying method point carry out：
A. the pre-freeze stage：Pre-freeze is carried out, and make on the partition board that semi-finished product that are filling and partly jumping a queue are placed in freeze-drying cabinet
Semi-finished product reach pre-freezing temperature in the shortest possible time, and pre-freezing temperature is -45 DEG C, and the pre-freeze time is 120min；
B. the lyophilization stage：Vacuum degree in drying box reaches 100mTorr；Main drying temperature is risen to -18 DEG C；With
When 90min；Soaking time 600min；
C. the re-dry stage：Re-dry temperature is risen to 30 DEG C；Used time 120min；Vacuum degree in drying box is evacuated to pole
Vacuum is limited, soaking time 240min obtains freeze-drying composition for injection.
Comparative example 2：
Prescription
Preparation process:
1st, it prepares
A. it weighs the maltose of recipe quantity and Tween-80 is dissolved in suitable water for injection, be uniformly mixed, at addition
The carboplatin just measured, stirring and dissolving；
B. stirring and dissolving finishes, and pH value is adjusted with the dilute hydrochloric acid solution of 0.1mol/L or the dilute ammonia solution of 0.1mol/L；
C. it adjusts pH value to finish, is settled to full dose with water for injection, sampling detection intermediate products solution prepares to fill after qualified
Envelope.
2nd, wash bottle is dried
By neutral boron silica glass tubular injection bottle by bottle washing machine washes clean, 300 DEG C or more sterilizing and dryings reach filling
It is spare between dress.
3rd, rubber plug is handled
Injection freeze-drying aseptic powdery is cleaned up with chlorinated butyl rubber bung through rubber plug cleaning machine, 121 DEG C of steamings
Vapour pressure sterilizing 15 minutes, it is spare after dry.
4th, aluminium-plastic cap is handled
The cleaned machine washing of antibiotic bottle aluminium-plastic combined cover is washed, is sterilized, after dry, is taken out spare.
5th, it is filling
Liquid carries out filling after 0.22 μm of filtering with microporous membrane；Half adds rubber plug, and it is dry to be put into freezing in freeze drier
It is dry.
6th, it is lyophilized
Rubber plug is compressed after freeze-drying, abolishes freeze dryer vacuum, takes out product.
7th, lid, washout are rolled
The intermediate products of tamponade qualification after freeze-drying are rolled into lid, washout through Cover-rolling machine.
8th, visual inspection, packaging
By bottle visual inspection, breakage is rejected, rolls and covers the defective works such as bad, abnormal appearance.Certified products are packed.
The present invention also provides a kind of freeze-drying methods of freeze-drying composition for injection；
The following three phases of the freeze-drying method point carry out：
A. the pre-freeze stage：Pre-freeze is carried out, and make on the partition board that semi-finished product that are filling and partly jumping a queue are placed in freeze-drying cabinet
Semi-finished product reach pre-freezing temperature in the shortest possible time, and pre-freezing temperature is -45 DEG C, and the pre-freeze time is 120min；
B. the lyophilization stage：Vacuum degree in drying box reaches 100mTorr；Main drying temperature is risen to -16 DEG C；With
When 90min；Soaking time 600min；
C. the re-dry stage：Re-dry temperature is risen to 30 DEG C；Used time 120min；Vacuum degree in drying box is evacuated to pole
Vacuum is limited, soaking time 240min obtains freeze-drying composition for injection.
Comparative example 3：
Prescription
Preparation process：
1st, it prepares
A. the maltose for weighing recipe quantity is dissolved in suitable water for injection, is uniformly mixed, and adds in the card of recipe quantity
Platinum, stirring and dissolving；
B. stirring and dissolving finishes, and pH value is adjusted with the dilute hydrochloric acid solution of 0.1mol/L or the dilute ammonia solution of 0.1mol/L；
C. it adjusts pH value to finish, is settled to full dose with water for injection, sampling detection intermediate products solution prepares to fill after qualified
Envelope.
2nd, wash bottle is dried
By neutral boron silica glass tubular injection bottle by bottle washing machine washes clean, 300 DEG C or more sterilizing and dryings reach filling
It is spare between dress.
3rd, rubber plug is handled
Injection freeze-drying aseptic powdery is cleaned up with chlorinated butyl rubber bung through rubber plug cleaning machine, 121 DEG C of steamings
Vapour pressure sterilizing 15 minutes, it is spare after dry.
4th, aluminium-plastic cap is handled
The cleaned machine washing of antibiotic bottle aluminium-plastic combined cover is washed, is sterilized, after dry, is taken out spare.
5th, it is filling
Liquid carries out filling after 0.22 μm of filtering with microporous membrane；Half adds rubber plug, and it is dry to be put into freezing in freeze drier
It is dry.
6th, it is lyophilized
Rubber plug is compressed after freeze-drying, abolishes freeze dryer vacuum, takes out product.
7th, lid, washout are rolled
The intermediate products of tamponade qualification after freeze-drying are rolled into lid, washout through Cover-rolling machine.
8th, visual inspection, packaging
By bottle visual inspection, breakage is rejected, rolls and covers the defective works such as bad, abnormal appearance.Certified products are packed.
The present invention also provides a kind of freeze-drying methods of freeze-drying composition for injection；
The following three phases of the freeze-drying method point carry out：
A. the pre-freeze stage：Pre-freeze is carried out, and make on the partition board that semi-finished product that are filling and partly jumping a queue are placed in freeze-drying cabinet
Semi-finished product reach pre-freezing temperature in the shortest possible time, and pre-freezing temperature is -45 DEG C, and the pre-freeze time is 120min；
B. the lyophilization stage：Vacuum degree in drying box reaches 100mTorr；Main drying temperature is risen to -16 DEG C；With
When 90min；Soaking time 600min；
C. the re-dry stage：Re-dry temperature is risen to 30 DEG C；Used time 120min；Vacuum degree in drying box is evacuated to pole
Vacuum is limited, soaking time 240min obtains freeze-drying composition for injection.
Comparative example 4：
Prescription
Preparation process：
A. it weighs the maltose of recipe quantity and Tween-80 is dissolved in suitable water for injection, be uniformly mixed, at addition
The carboplatin just measured, stirring and dissolving；
B. stirring and dissolving finishes, and pH value is adjusted with the dilute hydrochloric acid solution of 0.1mol/L or the dilute ammonia solution of 0.1mol/L；
C. it adjusts pH value to finish, is settled to full dose with water for injection, sampling detection intermediate products solution prepares to fill after qualified
Envelope.
2nd, wash bottle is dried
By neutral boron silica glass tubular injection bottle by bottle washing machine washes clean, 300 DEG C or more sterilizing and dryings reach filling
It is spare between dress.
3rd, rubber plug is handled
Injection freeze-drying aseptic powdery is cleaned up with chlorinated butyl rubber bung through rubber plug cleaning machine, 121 DEG C of steamings
Vapour pressure sterilizing 15 minutes, it is spare after dry.
4th, aluminium-plastic cap is handled
The cleaned machine washing of antibiotic bottle aluminium-plastic combined cover is washed, is sterilized, after dry, is taken out spare.
5th, it is filling
Liquid carries out filling after 0.22 μm of filtering with microporous membrane；Half adds rubber plug, and it is dry to be put into freezing in freeze drier
It is dry.
6th, it is lyophilized
Rubber plug is compressed after freeze-drying, abolishes freeze dryer vacuum, takes out product.
7th, lid, washout are rolled
The intermediate products of tamponade qualification after freeze-drying are rolled into lid, washout through Cover-rolling machine.
8th, visual inspection, packaging
By bottle visual inspection, breakage is rejected, rolls and covers the defective works such as bad, abnormal appearance.Certified products are packed.
The present invention also provides a kind of freeze-drying methods of freeze-drying composition for injection；
The following three phases of the freeze-drying method point carry out：
A. the pre-freeze stage：Pre-freeze is carried out, and make on the partition board that semi-finished product that are filling and partly jumping a queue are placed in freeze-drying cabinet
Semi-finished product reach pre-freezing temperature in the shortest possible time, and pre-freezing temperature is -45 DEG C, and the pre-freeze time is 120min；
B. the lyophilization stage：Vacuum degree in drying box reaches 100mTorr；Main drying temperature is risen to -16 DEG C；With
When 90min；Soaking time 600min；
C. the re-dry stage：Re-dry temperature is risen to 30 DEG C；Used time 120min；Vacuum degree in drying box is evacuated to pole
Vacuum is limited, soaking time 240min obtains freeze-drying composition for injection.
Comparative example 5：
Prescription
Preparation process：
A. the Dextran 40 for weighing recipe quantity is dissolved in suitable water for injection, is uniformly mixed, and adds in recipe quantity
Carboplatin, stirring and dissolving；
B. stirring and dissolving finishes, and pH value is adjusted with the dilute hydrochloric acid solution of 0.1mol/L or the dilute ammonia solution of 0.1mol/L；
C. it adjusts pH value to finish, is settled to full dose with water for injection, sampling detection intermediate products solution prepares to fill after qualified
Envelope.
2nd, wash bottle is dried
By neutral boron silica glass tubular injection bottle by bottle washing machine washes clean, 300 DEG C or more sterilizing and dryings reach filling
It is spare between dress.
3rd, rubber plug is handled
Injection freeze-drying aseptic powdery is cleaned up with chlorinated butyl rubber bung through rubber plug cleaning machine, 121 DEG C of steamings
Vapour pressure sterilizing 15 minutes, it is spare after dry.
4th, aluminium-plastic cap is handled
The cleaned machine washing of antibiotic bottle aluminium-plastic combined cover is washed, is sterilized, after dry, is taken out spare.
5th, it is filling
Liquid carries out filling after 0.22 μm of filtering with microporous membrane；Half adds rubber plug, and it is dry to be put into freezing in freeze drier
It is dry.
6th, it is lyophilized
Rubber plug is compressed after freeze-drying, abolishes freeze dryer vacuum, takes out product.
7th, lid, washout are rolled
The intermediate products of tamponade qualification after freeze-drying are rolled into lid, washout through Cover-rolling machine.
8th, visual inspection, packaging
By bottle visual inspection, breakage is rejected, rolls and covers the defective works such as bad, abnormal appearance.Certified products are packed.
The present invention also provides a kind of freeze-drying methods of freeze-drying composition for injection；
The following three phases of the freeze-drying method point carry out：
A. the pre-freeze stage：Pre-freeze is carried out, and make on the partition board that semi-finished product that are filling and partly jumping a queue are placed in freeze-drying cabinet
Semi-finished product reach pre-freezing temperature in the shortest possible time, and pre-freezing temperature is -45 DEG C, and the pre-freeze time is 120min；
B. the lyophilization stage：Vacuum degree in drying box reaches 100mTorr；Main drying temperature is risen to -20 DEG C；With
When 90min；Soaking time 600min；
C. the re-dry stage：Re-dry temperature is risen to 30 DEG C；Used time 120min；Vacuum degree in drying box is evacuated to pole
Vacuum is limited, soaking time 240min obtains freeze-drying composition for injection.
Comparative example 6：
Prescription
Preparation process：
A. the mannitol for weighing recipe quantity is dissolved in suitable water for injection, is uniformly mixed, and adds in the card of recipe quantity
Platinum, stirring and dissolving；
B. stirring and dissolving finishes, and pH value is adjusted with the dilute hydrochloric acid solution of 0.1mol/L or the dilute ammonia solution of 0.1mol/L；
C. it adjusts pH value to finish, is settled to full dose with water for injection, sampling detection intermediate products solution prepares to fill after qualified
Envelope.
2nd, wash bottle is dried
By neutral boron silica glass tubular injection bottle by bottle washing machine washes clean, 300 DEG C or more sterilizing and dryings reach filling
It is spare between dress.
3rd, rubber plug is handled
Injection freeze-drying aseptic powdery is cleaned up with chlorinated butyl rubber bung through rubber plug cleaning machine, 121 DEG C of steamings
Vapour pressure sterilizing 15 minutes, it is spare after dry.
4th, aluminium-plastic cap is handled
The cleaned machine washing of antibiotic bottle aluminium-plastic combined cover is washed, is sterilized, after dry, is taken out spare.
5th, it is filling
Liquid carries out filling after 0.22 μm of filtering with microporous membrane；Half adds rubber plug, and it is dry to be put into freezing in freeze drier
It is dry.
6th, it is lyophilized
Rubber plug is compressed after freeze-drying, abolishes freeze dryer vacuum, takes out product.
7th, lid, washout are rolled
The intermediate products of tamponade qualification after freeze-drying are rolled into lid, washout through Cover-rolling machine.
8th, visual inspection, packaging
By bottle visual inspection, breakage is rejected, rolls and covers the defective works such as bad, abnormal appearance.Certified products are packed.
The present invention also provides a kind of freeze-drying methods of freeze-drying composition for injection；
The following three phases of the freeze-drying method point carry out：
A. the pre-freeze stage：Pre-freeze is carried out, and make on the partition board that semi-finished product that are filling and partly jumping a queue are placed in freeze-drying cabinet
Semi-finished product reach pre-freezing temperature in the shortest possible time, and pre-freezing temperature is -45 DEG C, and the pre-freeze time is 120min；
B. the lyophilization stage：Vacuum degree in drying box reaches 100mTorr；Main drying temperature is risen to -18 DEG C；With
When 90min；Soaking time 600min；
C. the re-dry stage：Re-dry temperature is risen to 30 DEG C；Used time 120min；Vacuum degree in drying box is evacuated to pole
Vacuum is limited, soaking time 240min obtains freeze-drying composition for injection.
Verify embodiment
Long term test is investigated
The embodiment of the present invention 1~5 and 1~6 gained finished product preparation of comparative example are placed in 25 DEG C of climatic chambers, point
Appearance character, moisture, pH, 1 are not investigated in sampling in the 0th, 12,24 month, 1-cyclobutane dicarboxylic acid, in relation to substance and content
Variation, result of the test are shown in Table 1
1 Examples 1 to 5 of table investigates result with 1~6 preparation long term test of comparative example
By experiment investigation result it is found that 1~5 gained finished product preparation of the embodiment of the present invention at ambient temperature, is stored for a long time
24 months appearance characters, pH, 1,1-cyclobutane dicarboxylic acid do not occur significantly to become in relation to the indices such as substance and content
Change, it is with obvious effects to be better than comparative example.
Claims (3)
1. a kind of freeze-drying composition for injection for treating advanced ovarian cancer, it is characterised in that mainly by active constituent carboplatin, figuration
Agent, Tween-80 and pH adjusting agent composition；The excipient is maltose；The active constituent carboplatin and excipient malt
The mass ratio of sugar is 1：（1.0~2.0）；The active constituent carboplatin and the mass ratio of Tween-80 are 1：（0.5~0.9）；Institute
The solution after pH value is redissolved for freeze-drying composition for injection is stated, in the range of 3.8~4.2；The pH adjusting agent for hydrochloric acid or
Ammonium hydroxide.
2. a kind of freeze-drying composition for injection for treating advanced ovarian cancer according to claim 1, which is characterized in that it is made
Preparation Method includes the following steps：
（1）It prepares
A. it weighs the excipient of recipe quantity and Tween-80 is dissolved in suitable water for injection, be uniformly mixed, add in recipe quantity
Carboplatin, stirring and dissolving；
B. stirring and dissolving finishes, and pH value is adjusted with pH adjusting agent；
C. it adjusts pH value to finish, is settled to full dose with water for injection, sampling detection intermediate products solution prepares embedding after qualified；
（2）Wash bottle is dried
By neutral boron silica glass tubular injection bottle by bottle washing machine washes clean, 300 DEG C or more sterilizing and dryings reach bottling department
It is spare；
（3）Rubber plug processing
Injection freeze-drying aseptic powdery is cleaned up with chlorinated butyl rubber bung through rubber plug cleaning machine, 121 DEG C of steam heats
Pressure sterilizing 15 minutes, it is spare after dry；
（4）Aluminium-plastic cap processing
The cleaned machine washing of antibiotic bottle aluminium-plastic combined cover is washed, is sterilized, after dry, is taken out spare；
（5）It is filling
Liquid carries out filling after 0.22 μm of filtering with microporous membrane；Half adds rubber plug, is put into freeze drier and is freeze-dried；
（6）Freeze-drying
Rubber plug is compressed after freeze-drying, abolishes freeze dryer vacuum, takes out product；
（7）Roll lid, washout
The intermediate products of tamponade qualification after freeze-drying are rolled into lid, washout through Cover-rolling machine；
（8）Visual inspection, packaging
By bottle visual inspection, breakage is rejected, rolls and covers the defective works such as bad, abnormal appearance；Certified products are packed.
3. a kind of freeze-drying composition for injection for treating advanced ovarian cancer according to claim 2, which is characterized in that described
The following three phases of freeze-drying method point carry out：
（1）The pre-freeze stage：Carry out pre-freeze on the partition board that semi-finished product that are filling and partly jumping a queue are placed in freeze-drying cabinet, and make half into
Product reach pre-freezing temperature in the shortest possible time, and pre-freezing temperature is ranging between -50~-40 DEG C, 90~150min of time；
（2）The lyophilization stage：When vacuum degree in drying box reaches 80mTorr~120mTorr, main drying temperature is risen to-
18.0~-14.0 DEG C；60~120min of used time, soaking time 480min~720min；
（3）The re-dry stage：Re-dry temperature is increased to 25~35 DEG C, 90~150min of used time, by the vacuum in drying box
Degree is evacuated to end vacuum, and 210~270min of soaking time obtains freeze-drying composition for injection.
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| CN201810192050.2A CN108143721A (en) | 2016-04-12 | 2016-04-12 | A kind of freeze-drying composition for injection for treating advanced ovarian cancer and preparation method thereof |
| CN201610225160.5A CN105748458B (en) | 2016-04-12 | 2016-04-12 | A kind of freeze-drying composition for injection for treating advanced ovarian cancer and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1435167A (en) * | 2002-01-31 | 2003-08-13 | 清华大学 | Carboplatin precursor liposome injection and preparing process thereof |
| CN1969824A (en) * | 2006-09-28 | 2007-05-30 | 山东蓝金生物工程有限公司 | Anticancer sustained release agent containing fluorouracil and synergist thereof |
| CN104042572A (en) * | 2013-03-12 | 2014-09-17 | 江苏奥赛康药业股份有限公司 | Composition for injection containing fosaprepitant dimeglumine and preparation method thereof |
-
2016
- 2016-04-12 CN CN201610225160.5A patent/CN105748458B/en active Active
- 2016-04-12 CN CN201810192050.2A patent/CN108143721A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1435167A (en) * | 2002-01-31 | 2003-08-13 | 清华大学 | Carboplatin precursor liposome injection and preparing process thereof |
| CN1969824A (en) * | 2006-09-28 | 2007-05-30 | 山东蓝金生物工程有限公司 | Anticancer sustained release agent containing fluorouracil and synergist thereof |
| CN104042572A (en) * | 2013-03-12 | 2014-09-17 | 江苏奥赛康药业股份有限公司 | Composition for injection containing fosaprepitant dimeglumine and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 制备工艺对卡铂白蛋白微球性质的影响;主皓 等;《中国药学杂志》;19980331;第33卷(第3期);第151-153页 * |
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| CN108143721A (en) | 2018-06-12 |
| CN105748458A (en) | 2016-07-13 |
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