CN102764260B - Pharmaceutical composition of camptothecin derivative and preparation method thereof - Google Patents
Pharmaceutical composition of camptothecin derivative and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a pharmaceutical composition, which comprises (+)-(4S)-11-succinyl oxyethyl-4-ethyl-4-hydroxy-1H pyran[3',4',6,7]indolizine[1,2-b]quinoline-3,14-(4H,12H)-dione or its pharmaceutically acceptable salt, a stabilizing agent and a pH conditioning agent, wherein the pH value is 6.0-7.2.
Description
Technical field
The invention belongs to field of medicaments, relate in particular to pharmaceutical composition of a kind of camptothecin derivative and preparation method thereof, and the purposes for the treatment of tumor.
Background technology
Camptothecine (camptothecin, CPT) be the alkaloid extracting from the distinctive Nyssaceae plant camptotheca acuminata of China (camptotheca acuminata), by selectively acting DNA topoisomerase I (Top I), stop cancerous cell to copy and bring into play antitumaous effect.Camptothecine and hydroxy camptothecin are restricted its application greatly because of poorly soluble, toxic and side effects.Hundreds of camptothecin derivants and analog are synthesized from separating first the whole world so far, the position of structural modification is many at 7 of camptothecine, 9 and 10 carbon, by introducing different substituent groups in these positions to improve drug effect, reduce toxicity and improve dissolubility etc., ratified and clinically widely used representative drugs have irinotecan hydrochloride (irinotecan, CPT-11), topotecan (topotecan), Belotecan (belotecan), 10-hydroxycamptothecine etc., there is a lurtotecan (lurtotecan in the clinical research stage, GG211), Rubitecan (rubitecan), Diflomotecan (diilomotecan), the multi-medicaments such as gefitinib (gimatecan).
The camptothecin antineoplastic agents of listing at present, as irinotecan, topotecan, Belotecan are water soluble drug, but water soluble drug is difficult for entering tumor cell, causes IC lower, and retention time is shorter.Fat-soluble medicine curative effect is better, but be difficult to make stable intravenous injection, although as fat-soluble in hydroxy camptothecin better, but its preparation is not ideal enough, current sodium salt is the product after lactonic ring is opened, as everyone knows, the lactonic ring in camptothecine compounds molecule is opened while becoming water soluble compound activity and is obviously weakened.
Compound (+)-(4S)-11-succinum acyl-oxygen ethyl-4-ethyl-4-hydroxyl-1H pyrans also [3 ' is disclosed in Chinese patent ZL03142241.1,4 ', 6,7] indolizine [1,2-b] quinoline-3,14-(4H, 12H)-diketone (structural formula as shown in Equation 1, below sometimes also referred to as formula 1 compound).
Formula 1 compound is a kind of camptothecin anti-tumor prodrug of new high-efficiency low-toxicity, and it obtains 7-ethoxy camptothecine through succinic anhydride acylation, and hydrolysis is sloughed after succinic acid forms 7-ethoxy camptothecine and brought into play antitumor action in vivo.It is fat-soluble medicine, but has following problem while being prepared into injection preparation: the one, because this compound is fat-soluble medicine, so poorly soluble; The 2nd, the hexa-atomic lactonic ring of this compound is easily open loop in aqueous solution, therefore poor stability in aqueous solution, thus cause drug effect to reduce.Applicant finds in further studying, in the time that dissolubility increases, the open loop speed of hexa-atomic lactonic ring is also accelerated, the stability that is medicine becomes extreme difference, therefore, need to meet to reach the open loop catabolite of minimizing formula 1 compound of trying one's best in injection requires at the dissolubility that improves this product, this is conflict, is also difficult point and the key point of this product preparation.
Can be made into although disclose in Chinese patent ZL03142241.1 the various preparations that comprise pharmaceutical carrier, and specifically disclose sugar (as glucose, sucrose, lactose etc.), but do not carry out deep research, comprise that impact on drug solubility and stability such as sugared consumption, other factors etc. all do not study, there is no to obtain available effective, the stable preparation of reality that can solve above-mentioned contradiction, the report that other prior art is not also studied the preparation of this compound.
Therefore people expect to obtain a kind of pharmaceutical composition with good dissolubility and stability, especially stable injection preparation.
Summary of the invention
One aspect of the present invention provides a kind of pharmaceutical composition, it comprises (+)-(4S)-11-succinum acyl-oxygen ethyl-4-ethyl-4-hydroxyl-1H pyrans also [3 ', 4 ', 6,7] indolizine [1,2-b] quinoline-3,14-(4H, 12H)-diketone or its pharmaceutically acceptable salt, stabilizing agent and pH adjusting agent, wherein pH value is 6.0～7.2.
Wherein, (+)-(4S)-11-succinum acyl-oxygen ethyl-4-ethyl-4-hydroxyl-1H-pyrans also [3 ', 4 ', 6,7] indolizine [1,2-b] quinoline-3,14-(4H, 12H)-diketone or its pharmaceutically acceptable salt can be crystal, solvate or the hydrates of amorphous article, different crystal habits.
Wherein, stabilizing agent refers to the pharmaceutically acceptable material that can increase the chemistry of reactive compound in preparation and physical stability, and suitable stabilizing agent is selected from one or more in lactose, sucrose, mannitol, hetastarch, threonine, histidine.Be preferably lactose and sucrose, most preferably be lactose, comprise the lactose of different solid forms, for example the lactose of Lactis Anhydrous, lactose monohydrate or any other hydrate or solvation form is all in protection scope of the present invention.
In pharmaceutical composition of the present invention, the weight ratio (W/W) of formula 1 compound and stabilizing agent is 1: 5～1: 50, is preferably 1: 10～1: 40, more preferably 1: 15～1: 30.
PH adjusting agent of the present invention refers to for the organic salt of regulator solution pH value or inorganic salt, comprises one or more in phosphate, acetate, citrate, tartrate, lactate, succinate, sodium hydroxide, hydrochloric acid, sodium chloride, sodium carbonate, sodium bicarbonate, potassium carbonate, sodium sulfite, sodium sulfite, sodium deoxycholate, sodium nitrite, Disodium oxalate., ammonium oxalate, potassium hydroxide, sodium sulfide etc.
The pH value of pharmaceutical composition of the present invention refers to the aqueous solution of pharmaceutical composition or by the freeze-drying medicinal composition measured pH value that is dissolved in the water, is preferably 6.0～7.2, most preferably is 6.2～6.8.
Compositions of the present invention also can further contain one or more materials in adjuvant for the pharmaceutically acceptable regular injection agent such as freeze-dried excipient, isoosmotic adjusting agent, analgesics, and wherein freeze-dried excipient can be one or more the mixture that is selected from mannitol, sodium chloride, glucose, lactose, sucrose, gelatin hydrolysate, trehalose, glucosan, dextran, glycine, Glycine sodium, alanine, albumin, Polyethylene Glycol, polyvinylpyrrolidone, sodium dihydrogen phosphate, sorbitol, maltose, cyclodextrin, citric acid.The consumption of freeze-dried excipient by weight, can be 0～50 times of formula 1 compound 1.
Pharmaceutical composition of the present invention comprises freeze-dried preparation and aseptic subpackaged product.
The invention still further relates to by above-mentioned freeze-dried preparation or aseptic subpackaged product are dissolved to the aqueous compositions of making.
The preparation method of pharmaceutical composition of the present invention, can be that formula 1 compound or its pharmaceutically acceptable salt, stabilizing agent and pH adjusting agent are mixed in water, carries out aseptic filtration, then carries out lyophilization, obtains freeze-dried product.
The preparation method of the present composition can also be that formula 1 compound or its pharmaceutically acceptable salt, stabilizing agent and pH adjusting agent are mixed, and then carries out aseptic subpackagedly, obtains aseptic subpackaged product.
The preparation method of the present composition further can comprise: (1) adds pH adjusting agent in water, the solution of preparation pH6.0-7.2, (2) in this solution, add stabilizing agent, (3) add (+)-(4S)-11-succinum acyl-oxygen ethyl-4-ethyl-4-hydroxyl-1H pyrans also [3 ', 4 ', 6,7] indolizine [1,2-b] quinoline-3,14-(4H, 12H)-diketone or its pharmaceutically acceptable salt, dissolve, (4) aseptic filtration, lyophilization.
The preparation method of the present composition also can comprise: (1) is by the aqueous solution of preparing soluble in water stabilizing agent; (2) regulate pH value to 6.0～7.2 by pH adjusting agent; (3) dissolve (+)-(4S)-also [3 ', 4 ', 6,7] indolizines [1,2-b] quinoline-3 of 11-succinum acyl-oxygen ethyl-4-ethyl-4-hydroxyl-1H pyrans, 14-(4H, 12H)-diketone or its pharmaceutically acceptable salt; (4) aseptic filtration, lyophilization.
In above-mentioned preparation method, prepare (+)-(4S)-11-succinum acyl-oxygen ethyl-4-ethyl-4-hydroxyl-1H pyrans also [3 ', 4 ', 6,7] indolizine [1,2-b] quinoline-3, after the solution of 14-(4H, 12H)-diketone or its pharmaceutically acceptable salt, optionally, can further regulate pH value to 6.0～7.2 by pH adjusting agent, then carry out aseptic filtration lyophilization.
In above-mentioned preparation method, the weight ratio (W/W) of formula 1 compound and stabilizing agent is 1: 5～1: 50, is preferably 1: 10～1: 40, more preferably 1: 15～1: 30.PH value is preferably 6.0～7.2, most preferably is 6.2～6.8.
Lyophilized powder of the present invention can dilute or reconstruct with the acceptable diluent of any pharmacy, to patient is carried out to parenteral.This class diluent includes but not limited to water for injection, saline (as 0.9% normal saline), 5% or 10% D/W, sodium lactate ringer's injection etc., preferably water for injection, normal saline and D/W.In one embodiment, dissolve with the water for injection of 5 milliliters, obtain the ultimate density of 2mg/mL, general reconstitution time is less than 1 minute, and gained solution can further be diluted in intravenous drip solution for example in 5% D/W before administration.
Herein, " pharmaceutically acceptable salt " includes but not limited to alkali metal or the alkali salts such as sodium, potassium, calcium, aluminum, ammonium salt, methylamine salt, ethylamine salt, ethanolamine salt etc.
Pharmaceutical composition of the present invention, the dissolubility of its Chinese style 1 compound or its salt improves greatly, and the concentration in pharmaceutical composition aqueous solution of the present invention can reach 0.2mg/ml～50mg/ml, preferably 0.5mg/ml～30mg/ml, more preferably 1mg/ml～10mg/ml, most preferably 1mg/ml～5mg/ml.
Pharmaceutical composition of the present invention, has ensured time prepared by preparation and freeze-dried powder redissolution is rear and the long-term stability of placing of freeze-dried powder, and its related substances of pharmaceutical composition of the present invention is lower than 1.5% weight, preferably lower than 1.0% weight.
By the present invention, not only solve drug solubility problem, ensured the complete of hexa-atomic lactonic ring simultaneously.Specifically, applicant finds that Cucumber has Stabilization to formula 1 compound unexpectedly, and selects specific pH value scope, thereby can meet the dissolubility that preparation preparation requires in acquisition, increases the stability of this product lactonic ring simultaneously.Applicant has made more effective, stable compositions thus.Both significantly increased the dissolubility of formula 1 compound in water, solve again the stability problem in preparation preparation process and in put procedure, make dissolubility and stability obtain balance, realize in solution formula 1 compound dissolution, still can be prepared into stable preparation used for intravenous injection, meet the requirements such as clinical use, preparation, placement.
Detailed description of the invention
To contribute to understand the present invention by following embodiment, but not limit the scope of the invention.
Embodiment 1 (+)-(4S)-also [3 ', 4 ', 6,7] indolizines [1,2-b] quinoline-3 of 11-succinum acyl-oxygen ethyl-4-ethyl-4-hydroxyl-1H pyrans, the preparation of 14-(4H, 12H)-diketone
1g7-ethoxy camptothecine is dissolved in the dry dimethyl sulfoxine of 40mL, adds succinic anhydrides 2g, then add after 2mL dry pyridine, stirring and refluxing 12 hours.By in reactant mixture impouring separatory funnel, add distilled water 50mL, dichloromethane extraction for aqueous solution (200mL*3), after merging by evaporated under reduced pressure after anhydrous sodium sulfate drying.Recycle silicon plastic column chromatography separates, and with 50: 1.5 eluting of methylene chloride/methanol, obtains 840mg faint yellow solid (productive rate 66%).
Embodiment 2
Sodium dihydrogen phosphate, sodium hydrogen phosphate and sodium chloride are dissolved in 500mL water for injection, are adjusted to the solution of pH6.6.25g lactose is joined in above-mentioned solution, be stirred to completely after dissolving and in solution, add 0.2% active carbon again, after boiling, be cooled to 60 DEG C and maintain 30 minutes, de-charcoal.1g (by dry product) formula 1 compound is joined after above-mentioned de-charcoal in solution, be dissolved to clarification.By medicinal liquid after initial filter again through 0.22 μ m filter aseptic filtration, obtain semi-finished product solution.Semi-finished product solution checks visible foreign matters, content and pH, qualified rear subpackage, and the laggard freeze drying box of half tamponade, carries out lyophilization.
Embodiment 3
Dissolution of sodium hydroxide, in 500mL water for injection, is adjusted to the solution of pH 7.2.5g threonine is joined in above-mentioned solution, be stirred to completely after dissolving and in solution, add 0.2% active carbon again, after boiling, be cooled to 60 DEG C and maintain 30 minutes, de-charcoal.1g (by dry product) formula 1 compound is joined after above-mentioned de-charcoal in solution, be dissolved to clarification.By medicinal liquid after initial filter again through 0.22 μ m filter aseptic filtration, obtain semi-finished product solution.Semi-finished product solution checks visible foreign matters, content and pH, qualified rear subpackage, the laggard freeze drying box of half tamponade, lyophilization.
Embodiment 4
Sodium carbonate, sodium bicarbonate are dissolved in 500mL water for injection, are adjusted to the solution of pH 6.8.10g mannitol is joined in above-mentioned solution, be stirred to completely after dissolving and in solution, add 0.2% active carbon again, after boiling, be cooled to 60 DEG C and maintain 30 minutes, de-charcoal.1g (by dry product) formula 1 compound is joined after above-mentioned de-charcoal in solution, be dissolved to clarification.By medicinal liquid after initial filter again through 0.22 μ m filter aseptic filtration, obtain semi-finished product solution.Semi-finished product solution checks visible foreign matters, content and pH, qualified rear subpackage, the laggard freeze drying box of half tamponade, lyophilization.
Embodiment 5
Sodium bicarbonate is dissolved in 500mL water for injection, is adjusted to the solution of pH 6.2.15g hetastarch is joined in above-mentioned solution, be stirred to completely after dissolving and in solution, add 0.2% active carbon again, after boiling, be cooled to 60 DEG C and maintain 30 minutes, de-charcoal.1g (by dry product) formula 1 compound is joined after above-mentioned de-charcoal in solution, be dissolved to clarification.By medicinal liquid after initial filter again through 0.22 μ m filter aseptic filtration, obtain semi-finished product solution.Semi-finished product solution checks visible foreign matters, content and pH, qualified rear subpackage, the laggard freeze drying box of half tamponade, lyophilization.
Embodiment 6
Sodium citrate is dissolved in 500mL water for injection, is adjusted to the solution of pH 6.0.20g sucrose is joined in above-mentioned solution, be stirred to completely after dissolving and in solution, add 0.2% active carbon again, after boiling, be cooled to 60 DEG C and maintain 30 minutes, de-charcoal.1g (by dry product) formula 1 compound is joined after above-mentioned de-charcoal in solution, be dissolved to clarification.By medicinal liquid after initial filter again through 0.22 μ m filter aseptic filtration, obtain semi-finished product solution.Semi-finished product solution checks visible foreign matters, content and pH, qualified rear subpackage, the laggard freeze drying box of half tamponade, lyophilization.
Embodiment 7
Sodium acetate is dissolved in 500mL water for injection, is adjusted to the solution of pH 7.0.30g histidine is joined in above-mentioned solution, be stirred to completely after dissolving and in solution, add 0.2% active carbon again, after boiling, be cooled to 60 DEG C and maintain 30 minutes, de-charcoal.1g (by dry product) formula 1 compound is joined after above-mentioned de-charcoal in solution, be dissolved to clarification.By medicinal liquid after initial filter again through 0.22 μ m filter aseptic filtration, obtain semi-finished product solution.Semi-finished product solution checks visible foreign matters, content and pH, qualified rear subpackage, the laggard freeze drying box of half tamponade, lyophilization.
Embodiment 8
Sodium lactate is dissolved in 500mL water for injection, is adjusted to the solution of pH6.4.20g lactose and 20g threonine are joined in above-mentioned solution, be stirred to completely after dissolving and in solution, add 0.2% active carbon again, after boiling, be cooled to 60 DEG C and maintain 30 minutes, de-charcoal.1g (by dry product) formula 1 compound is joined after above-mentioned de-charcoal in solution.Be dissolved to clarification.By medicinal liquid after initial filter again through 0.22 μ m filter aseptic filtration, obtain semi-finished product solution.Semi-finished product solution checks visible foreign matters, content and pH, qualified rear subpackage, the laggard freeze drying box of half tamponade, lyophilization.
Embodiment 9
Potassium Suceinate is dissolved in 500mL water for injection, is adjusted to the solution of pH6.5.30g lactose and 20g sucrose are joined in above-mentioned solution, be stirred to completely after dissolving and in solution, add 0.2% active carbon again, after boiling, be cooled to 60 DEG C and maintain 30 minutes, de-charcoal.1g (by dry product) formula 1 compound is joined after above-mentioned de-charcoal in solution, be dissolved to clarification.By medicinal liquid after initial filter again through 0.22 μ m filter aseptic filtration, obtain semi-finished product solution.Semi-finished product solution checks visible foreign matters, content and pH, qualified rear subpackage, the laggard freeze drying box of half tamponade, lyophilization.
Embodiment 10
Sodium bicarbonate and sodium sulfite are dissolved in 500mL water for injection, are adjusted to the solution of pH6.7.23g lactose is joined in above-mentioned solution, be stirred to completely after dissolving and in solution, add 0.2% active carbon again, after boiling, be cooled to 60 DEG C and maintain 30 minutes, de-charcoal.1g (by dry product) formula 1 compound is joined after above-mentioned de-charcoal in solution, be dissolved to clarification.By medicinal liquid after initial filter again through 0.22 μ m filter aseptic filtration, obtain semi-finished product solution.Semi-finished product solution checks visible foreign matters, content and pH, qualified rear subpackage, the laggard freeze drying box of half tamponade, lyophilization.
Dissolubility and the stability of embodiment 11 formula 1 compounds in different pH value aqueous solutions
Modus ponens 1 compound joins in following different pH value aqueous solution (each 5ml), if all dissolvings, continue to add the compound dissolution of formula 1, until there is excessive solid to exist, make solution be hypersaturated state, use HPLC method to detect the saturation solubility of formula 1 compound in different pH solution.Adopt HPLC method to detect its related substances simultaneously.Result is as shown in table 1.
HPLC method: with octadecylsilane chemically bonded silica be filler; Taking acetonitrile-2% formic acid solution (25: 75) as mobile phase; Detection wavelength is 254nm.Number of theoretical plate calculates and is not less than 4000 by the compound of formula 1, and the separating degree of formula 1 compound and adjacent impurity peaks should meet the requirements.
Table 1
As seen from the above table, the dissolubility of formula 1 compound in water increases along with the rising of pH, but in aqueous solution also variation of stability, related substance increases obviously.In pH value 6.0～7.2 scopes, dissolubility meets preparation and prepares requirement, and stability is more satisfactory.
The impact of embodiment 12 different stabilizers on formula 1 compound stability
Freeze-dried powder according to the method preparation of embodiment 2 containing formula 1 compound, wherein stabilizing agent is respectively lactose, threonine, sucrose, mannitol, hetastarch, histidine.Use HPLC method to detect sealing, lucifuge, the related substance of room temperature (25 DEG C) placement after 10 days.Result is as shown in table 2.
Table 2
From table, can find out compared with not adding the pharmaceutical composition of stabilizing agent, lactose, threonine, sucrose, mannitol, hetastarch and histidine all can effectively improve its stability, but the stablizing effect of lactose is best.
Embodiment 13 impacts of lactose consumption on formula 1 compound stability
According to the method for embodiment 2, formula 1 compound is 1g, the phosphate solution that solution is pH6.6, and lactose consumption is respectively 0 times, 5 times, 10 times, 15 times, 20 times, 25 times, 30 times, 40 times, 50 times of formula 1 compound, makes different freeze-dried compositions.Use HPLC method to detect sealing, lucifuge, the related substance of room temperature (25 DEG C) placement after 10 days.The results are shown in Table 3
Table 3
Visible, add after lactose, related substance obviously reduces, and stablizing effect is obvious, and along with lactose consumption increases, stablizing effect strengthens, but when being greater than a certain consumption (25g), related substance is substantially constant, and stablizing effect is stable.
Stability after embodiment 14 redissolves
Use 0.9% sodium chloride or 5% glucose injection to redissolve the pharmaceutical composition of preparation in embodiment 2.After all dissolving, obtain the drug solution that concentration is 2mg/ml, this solution is kept 8 hours under room temperature (25 DEG C).Meanwhile, use 0.9% sodium chloride or 5% glucose injection 250ml to dilute redissolution solution, after dilution, solution was the lower maintenance of room temperature (25 DEG C) 5 hours.Solution after redissolving and after dilution all uses HPLC to analyze.The results are shown in Table 4.
Table 4
As can be seen here, the stabilization time after present composition redissolution and dilution is long.After redissolution, at least stablize 8 hours, after dilution, at least stablize 5 hours.Make the stabilization time of these prolongations formula 1 compound be highly susceptible to using in hospital environment.
Embodiment 15 stability tests
By the phosphate solution of sodium dihydrogen phosphate, sodium hydrogen phosphate and sodium chloride preparation pH6.6; Lactose is joined in this solution, be stirred to completely after dissolving and in solution, add 0.2% active carbon again, after boiling, be cooled to 60 DEG C and maintain 30 minutes, de-charcoal; The compound of formula 1 is joined after above-mentioned de-charcoal in solution, be dissolved to clarification; By medicinal liquid after initial filter again through 0.22 μ m filter aseptic filtration, obtain semi-finished product solution; Semi-finished product solution checks visible foreign matters, content and pH, and qualified rear subpackage, carries out lyophilization.
Influence factor's test:
The above-mentioned freeze-dried composition preparing is investigated under 40 DEG C (shadings) of high temperature, 60 DEG C (shading) and strong illumination (25 DEG C, 4500 ± 500Lx) condition to outward appearance, related substance and the content of dried frozen aquatic products.Investigate 5 days and 10 days.Result of the test is in table 5.
Table 5 influence factor test
From above-mentioned result of the test, under various influence factor's conditions, the prescription of lactose used as stabilizers all meets the requirements.Long term test
The above-mentioned freeze-dried composition preparing, 40 DEG C ± 2 DEG C of temperature, is placed 6 months under relative humidity 75% ± 5% accelerated test condition; 25 DEG C ± 2 DEG C of temperature, under relative humidity 60% ± 10% room temperature condition, place 24 months simultaneously.And compare with initial detecting result, all can meet clinical instructions for use.The results are shown in Table 6.
Table 6
| Investigation project | 0 month | Accelerate June | Room temperature 24 months |
| PH | 6.4 | 6.4 | 6.4 |
| Related substance (%) | 0.74 | 1.25 | 1.14 |
Claims (6)
1. a pharmaceutical composition, it comprises (+)-(4S)-11-succinum acyl-oxygen ethyl-4-ethyl-4-hydroxyl-1H pyrans also [3 ', 4 ', 6,7] indolizine [1,2-b] quinoline-3,14-(4H, 12H)-diketone or its pharmaceutically acceptable salt, lactose and pH adjusting agent, wherein pH value is 6.0～7.2, described pharmaceutical composition is freeze-dried preparation.
2. compositions according to claim 1, wherein pH value 6.2～6.8.
3. compositions according to claim 1 and 2, wherein (+)-(4S)-11-succinum acyl-oxygen ethyl-4-ethyl-4-hydroxyl-1H pyrans also [3 ', 4 ', 6,7] indolizine [1,2-b] quinoline-3, the weight ratio (W/W) of 14-(4H, 12H)-diketone and lactose is 1:5～1:50.
4. compositions according to claim 1 and 2, wherein (+)-(4S)-11-succinum acyl-oxygen ethyl-4-ethyl-4-hydroxyl-1H pyrans also [3 ', 4 ', 6,7] indolizine [1,2-b] quinoline-3, the weight ratio (W/W) of 14-(4H, 12H)-diketone and lactose is 1:10～1:40.
5. compositions according to claim 1 and 2, wherein (+)-(4S)-11-succinum acyl-oxygen ethyl-4-ethyl-4-hydroxyl-1H pyrans also [3 ', 4 ', 6,7] indolizine [1,2-b] quinoline-3, the weight ratio (W/W) of 14-(4H, 12H)-diketone and lactose is 1:15～1:30.
6. the preparation method of pharmaceutical composition claimed in claim 1, by (+)-(4S)-11-succinum acyl-oxygen ethyl-4-ethyl-4-hydroxyl-1H pyrans also [3 ', 4 ', 6,7] indolizine [1,2-b] quinoline-3,14-(4H, 12H)-diketone or its pharmaceutically acceptable salt, lactose and pH adjusting agent are mixed in water, carry out aseptic filtration, then carry out lyophilization, obtain freeze-dried product.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1580057A (en) * | 2003-08-13 | 2005-02-16 | 中国科学院上海药物研究所 | 20(S) camptotheca alkaloid derivatives, their preparing methods and uses |
| CN1646172A (en) * | 2002-04-16 | 2005-07-27 | 田边制药株式会社 | Liquid preparation comprising camptothecin derivative and pharmaceutical composition producible by lyophilizing the preparation |
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| CN1646172A (en) * | 2002-04-16 | 2005-07-27 | 田边制药株式会社 | Liquid preparation comprising camptothecin derivative and pharmaceutical composition producible by lyophilizing the preparation |
| CN1580057A (en) * | 2003-08-13 | 2005-02-16 | 中国科学院上海药物研究所 | 20(S) camptotheca alkaloid derivatives, their preparing methods and uses |
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