CN102617584B - Irinotecan hydrochloride compound and medicinal composition thereof - Google Patents
Irinotecan hydrochloride compound and medicinal composition thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicine, and relates to an irinotecan hydrochloride compound and a medicinal composition thereof. The molecular formula of irinotecan hydrochloride is C33H38N4O6.HCl.1.5H2O. A preparation method of the irinotecan hydrochloride comprises the following steps of: adding a mixed solvent of water/ethylene glycol into an irinotecan hydrochloride bulk pharmaceutical, wherein the volume ratio of water to ethylene glycol is (2-4):1; stirring and heating to 40-60 DEG C; adding active carbon; stirring and adsorbing; filtering, removing carbon and degerming to obtain a clear solution; transferring the clear solution into a reaction kettle; standing at the temperature of 160-180 DEG C for 24-36 hours; uniformly cooling to 55-75 DEG C; opening a reaction kettle; dropwise adding acetone slowly; devitrifying; slowly cooling to 0-5 DEG C; filtering; washing with deionized water; and drying under reduced pressure to obtain the irinotecan hydrochloride compound. The irinotecan hydrochloride provided by the invention does not absorb moisture easily, and has low impurity content, high storage stability and higher safety performance.
Description
Technical field
The invention belongs to medical technical field, relate to a kind of U 101440E compound and pharmaceutical composition thereof.
Background technology
U 101440E, English name: Irinotecan Hydrochloride Injection, molecular formula is C
33H
38N
4O
6HCl3H
2O, molecular weight are 677.19, and its chemical name is (+)-(4S)-4,11-diethyl-4-hydroxyl-9-[(4-piperidinyl piperidine) carbonyl]-1H-pyrans also [3,4:6,7] indolizine [1,2b] quinoline-3,14-(4H, 12H)-and the dione hydrochloride trihydrate, be pale yellow powder or light yellow crystalline powder under the room temperature, odorless, slightly soluble in water, ethanol or chloroform, insoluble in acetone.Be Japanese the first pharmacy and Yakult Honsha company in the antitumor drug of exploitation listing in 1994, antitumour activity is strong, exists with the form of hydrochloride, and structural formula is as follows:
U 101440E (CPT-11) is a kind of semisynthetic solubility camptothecin derivative, and Main Function by suppressing topoisomerase I, disturbs dna replication dna and cell fission in the S phase of cell cycle.Through the katalysis of Procaine esterase, be metabolized to active result SN38 (SN-38) in vivo, its antitumour activity is the former 100～1000 times.The U 101440E injection liquid is a kind of effective, representative anti-cancer agent, as specific topoisomerase I (Topo I) inhibitor, different from traditional enzyme inhibitors, it does not hinder the combination of Topo I, but this ribozyme is transformed into the material harmful to DNA, with the mixture mortise of Topo I enzyme and DNA formation, specificity suppresses DNA and reconnects step, cause the dna single splitting of chain, make DNA produce irreversible damage, cause necrocytosis.
The mortality ratio that China's tumour causes occupies the 2nd (accounting for 17.9%) in all causes of disease, and sickness rate is in rising trend, and wherein the sickness rate of lung cancer, intestinal cancer is higher.U 101440E is the specific medicament for the treatment of advanced CRC, and it is still effective that 5 FU 5 fluorouracil is produced chemical sproof case, and is also effective in cure to minicell and nonsmall-cell lung cancer and cervical cancer and ovarian cancer simultaneously.This medicine has obtained the common approval of U.S. FDA and European Union, more than 100 country's listings in the whole world, and it is that U.S. FDA has continued over more than 40 year since the 5 FU 5 fluorouracil (5-FU), unique approval is used for the chemotherapeutic of advanced CRC first-line treatment.
Interaction between irinotecan and the neuromuscular blocking agent is very important, has anticholinesterase activity, can prolong the neuromuscular blockade effect of lake choline, and the neuromuscular blockade effect of non depolarization medicine may be by antagonism.
CN101277694A discloses a kind of new crystal of U 101440E, and new crystal formation of U 101440E and preparation method thereof is provided, and contains the pharmaceutical composition of described new crystal formation and utilizes the method for its treatment colon or rectum metastatic carcinoma.
CN101318964A discloses a kind of crystal of U 101440E, and the U 101440E of this crystal formation has preferably stability in storage, and foreign matter content is few.
In the prior art, the U 101440E of different crystal forms is all with 3 crystal water, and the change crystal formation that passes through that has has improved stability, and the change crystal formation that passes through that has has improved water-soluble, in order to find the more good irinotecan hydrochloride medicines of a kind of performance, special proposition the present invention.
Summary of the invention
The object of the present invention is to provide a kind of U 101440E compound, the U 101440E compound that provides is easily dilutable not, is easy to store, and has better stability in storage, and foreign matter content is few, has greatly improved drug safety.
Another object of the present invention is to provide the pharmaceutical composition that contains above-mentioned U 101440E compound.
In order to realize the foregoing invention purpose, the present invention takes following technical scheme:
A kind of U 101440E, the molecular formula of described U 101440E are C
33H
38N
4O
6HCl1.5H
2O.
In the U 101440E compound provided by the invention, only with 1.5 crystal water, individual molecule is in the process of piling up crystallization in its molecular formula, because the minimizing of crystal water, variation has also occured its internal crystal structure.The easy moisture absorption of U 101440E in the prior art, the unexpected special crystallized form of U 101440E compound provided by the present invention of finding is difficult for moisture absorption, has stronger stability in storage.
The X-ray powder diffraction that described U 101440E crystal uses the Cu-K alpha-ray to measure is 9.7 °, 10.1 °, 13.1 °, 13.3 °, 16.1 °, 19.0 °, 20.5 °, 21.6 °, 23.4 °, 28.6 °, 29.2 °, 30.7 °, 33.2 °, 35.7 ° at 2 θ and locates to show characteristic peak.
The fusing point of described U 101440E is 278-280 ℃.
The preparation of described U 101440E comprises: get the U 101440E bulk drug, the mixed solvent that adds entry/ethylene glycol, wherein the volume ratio of water and ethylene glycol is 2～4: 1, stirs and be heated to 40～60 ℃, adds gac again, whip attachment, filter the decarburization degerming, obtain settled solution, settled solution is moved in the reactor, in 160～180 ℃ of lower 24～36h that place, reactor is opened in uniform decrease in temperature to 55～75 ℃, slowly drips acetone, crystallization, filter slow cooling to 0～5 ℃, uses deionized water wash, drying under reduced pressure, and get final product.
Among the above-mentioned preparation method, the ratio of the weight of described U 101440E and the volume of mixed solvent is 1g: 10～15ml.
Among the above-mentioned preparation method, described dropping is at the uniform velocity to drip under mixing speed 25～30rmp.
Among the above-mentioned preparation method, the volume ratio of described acetone and mixed solvent is 3～4: 1.
The degerming of described adding activated carbon is this area common technology means, can process referring to any decolouring, those skilled in the art need not to pay any creative work, can carry out appropriate selection according to the prior art of himself grasping, and realize the object of the invention.
In order further to improve the formulation products quality, the present invention also can be preferably be filtered into the use ultrafiltration membrance filter after decolouring.
The contriver passes through experiment repeatedly, finally comprises under the experiment conditions such as temperature, pressure, pH, solvent, with C in change
33H
38N
4O
6HCl3H
2O is that raw material has obtained C
33H
38N
4O
6HCl1.5H
2O, because variation has occured in position and the environment of water molecules in the compound, huge variation has occured in this new U 101440E compound inner solid-state structure in the process of packing of molecules crystallization, the contriver draws by water absorbability experiment and stability experiment, the invention provides not easily dilutable of U 101440E, stability in storage is good.
The present invention also provides a kind of pharmaceutical composition that contains foregoing U 101440E.
Described pharmaceutical composition is the U 101440E injection liquid, and by weight, described U 101440E injection liquid comprises U 101440E 30-100 part, Sorbitol Powder 50-250 part, lactic acid 1-5 part, water for injection 150-2000 part.
Preferably, by weight, described U 101440E injection liquid comprises 40 parts of U 101440Es, 90 parts of Sorbitol Powders, 1.8 parts of lactic acid, 2000 parts of waters for injection.
Preferably, by weight, described U 101440E injection liquid comprises 100 parts of U 101440Es, 225 parts of Sorbitol Powders, 4.5 parts of lactic acid, 2000 parts of waters for injection.
The preparation method of described U 101440E injection liquid comprises the steps:
(1) water for injection preparation: purified water is carried out multi-effect distilling prepare sterile water for injection;
(2) dosing: after recipe quantity U 101440E, Sorbitol Powder, lactic acid mixed, in stirring lower slowly the adding in 90% the water for injection, be 3.0～4.0 with pH adjusting agent regulator solution pH value, add remaining 10% water for injection;
(3) sterilization: stir lower solution and be warming up to 117～125 ℃, stopped heating insulation 10～15min is cooled to 40～50 ℃;
(4) decolouring: add gac in clear and bright solution, whip attachment 30min filters through taking off charcoal and sterilization filter, and the secondary terminals degerming filters filter, gained filtrate to medicinal liquid bottle, can after the passed examination, tamponade and get final product.
Among the preparation method of above-mentioned U 101440E injection liquid, step (2), (3) described stirring are that rotating speed 100～160 turns/min.
Among the preparation method of above-mentioned U 101440E injection liquid, the described water for injection temperature of step (2) is 70～75 ℃.
Among the preparation method of above-mentioned U 101440E injection liquid, the described multiple-effect of step (1) is 3～6 effects.
Among the preparation method of above-mentioned U 101440E injection liquid, the activated carbon consumption is 0.3～0.5% (g/ml) of liquor capacity in the described decolouring of step (4).
Among the preparation method of above-mentioned U 101440E injection liquid, millipore filtration aperture described in the step (4) is 0.22 μ m.
PH adjusting agent of the present invention is well known in the art, and those skilled in the art know the concrete kind of pH adjusting agent usually, such as mineral acid or mineral alkali, but the present invention's one or more combination in sodium hydroxide, potassium hydroxide or the hydrochloric acid preferably.With the pH regulator to 3.0 of liquid～4.0, U 101440E all being in the more stable system from be formulated into the whole process of can in this scope, this has been conducive to improve the stability of U 101440E injection liquid.
Among the present invention, activated carbon dosage and adsorption time have been carried out strict control, it is proper that gac uses, can the active adsorption degerming, can reduce again gac to the adsorption of bulk drug, so that the clarification of prepared U 101440E injection liquid solution.
Preparation technology's simple possible of U 101440E injection liquid provided by the invention, good reproducibility, easily realize industrialized production, save manpower, the production cycle of lacking, lower scrap rate and lower human cost make the production cost decrease, can produce considerable economic and social benefit, prepared U 101440E clarity of injection is good, and foreign matter content is low, and little to human body side effect and potential harm.
Compared with prior art, U 101440E provided by the invention and composition thereof have following advantage:
(1) U 101440E of the present invention is difficult for moisture absorption, and foreign matter content is few, and stability in storage is good;
(2) U 101440E safety performance of the present invention is higher.
Description of drawings
The X-powder diagram of the U 101440E that Fig. 1 provides for the embodiment of the invention 1;
The thermogravimetric curve of the U 101440E that Fig. 2 provides for the embodiment of the invention 1.
Embodiment
Below by specific embodiment summary of the invention of the present invention is described further, but does not therefore limit content of the present invention.
Embodiment 1
Get U 101440E bulk drug 50g, the mixed solvent 500ml that adds entry/ethylene glycol, wherein the volume ratio of water and ethylene glycol is 2: 1, stirs and be heated to 40 ℃, adds the 0.15g gac again, whip attachment, filter the decarburization degerming, obtain settled solution, settled solution is moved in the reactor, in 160 ℃ of lower 24h that place, uniform decrease in temperature to 55 ℃ is opened reactor, slowly drips 1500ml acetone and stirs with the speed of 25rmp, crystallization, slow cooling to 0 ℃ filters, with deionized water wash 3 times, drying under reduced pressure 3h, and get final product.Yield 65.4%, HPLC content 99.74%.mp：278-280℃。
The X-ray powder diffraction that the U 101440E crystal that obtains uses the Cu-K alpha-ray to measure is 9.7 °, 10.1 °, 13.1 °, 13.3 °, 16.1 °, 19.0 °, 20.5 °, 21.6 °, 23.4 °, 28.6 °, 29.2 °, 30.7 °, 33.2 °, 35.7 ° at 2 θ and locates to show characteristic peak.
Adopt the U.S. PE Pyris Diamond TG of Perkin-Elmer company thermal analyzer, the thermogravimetric analysis experiment shows: the U 101440E crystal of present embodiment 1 preparation loses 1.5 H in the time of 137～161 ℃
2The O molecule.
Embodiment 2
Get U 101440E bulk drug 50g, the mixed solvent 750ml that adds entry/ethylene glycol, wherein the volume ratio of water and ethylene glycol is 4: 1, stirs and be heated to 60 ℃, adds the 0.3g gac again, whip attachment, filter the decarburization degerming, obtain settled solution, settled solution is moved in the reactor, in 180 ℃ of lower 36h that place, uniform decrease in temperature to 75 ℃ is opened reactor, slowly drips 3000ml acetone and stirs with the speed of 30rmp, crystallization, slow cooling to 5 ℃ filters, with deionized water wash 3 times, drying under reduced pressure 3h, and get final product.Yield 68.5%, HPLC content 99.79%.mp：278-280℃。
X-ray powder diffraction collection of illustrative plates, the thermogravimetric curve of the U 101440E crystal that obtains and embodiment 1 product have identical parameters.
Embodiment 3
Get U 101440E bulk drug 50g, the mixed solvent 600ml that adds entry/ethylene glycol, wherein the volume ratio of water and ethylene glycol is 3: 1, stirs and be heated to 55 ℃, adds the 0.2g gac again, whip attachment, filter the decarburization degerming, obtain settled solution, settled solution is moved in the reactor, in 170 ℃ of lower 30h that place, uniform decrease in temperature to 70 ℃ is opened reactor, slowly drips 2400ml acetone and stirs with the speed of 30rmp, crystallization, slow cooling to 0 ℃ filters, with deionized water wash 3 times, drying under reduced pressure 3h, and get final product.Yield 68.8%, HPLC content 99.77%.mp：278-280℃。
X-ray powder diffraction collection of illustrative plates, the thermogravimetric curve of the U 101440E crystal that obtains and embodiment 1 product have identical parameters.
Embodiment 4
The preparation of U 101440E injection liquid
Purified water is carried out distillation preparation sterile water for injection 3 times; After U 101440E 30g, Sorbitol Powder 50g, the lactic acid 1g that gets embodiment 1 preparation mixes, in stirring the lower 70 ℃ of water for injection 135ml that slowly add, the rotating speed that stirs is 100 to turn/min, is 3.0 with sodium hydroxide or hydrochloric acid conditioning solution pH value, adds 70 ℃ water for injection 15ml; Stir lower solution and be warming up to 117 ℃, the rotating speed of stirring is 100 to turn/min, and stopped heating insulation 10min is cooled to 40 ℃; In clear and bright solution, add gac 0.45g, whip attachment 30min, the rotating speed that stirs is 100 to turn/min, through taking off charcoal and a sterilization filter filtration, the secondary terminals degerming filters filter, and the millipore filtration aperture of filtration is 0.22 μ m, and gained filtrate is to medicinal liquid bottle, can after the passed examination, tamponade and get final product.Every bottle loading amount is 0.4g: 2ml.
Embodiment 5
The preparation of U 101440E injection liquid
Purified water is carried out distillation preparation sterile water for injection 6 times; After U 101440E 100g, Sorbitol Powder 250g, the lactic acid 5g that gets embodiment 2 preparation mixes, in stirring the lower 75 ℃ of water for injection 1800ml that slowly add, the rotating speed that stirs is 100 to turn/min, be 4.0 with sodium hydroxide or hydrochloric acid conditioning solution pH value, add 75 ℃ water for injection 200ml; Stir lower solution and be warming up to 125 ℃, the rotating speed of stirring is 100 to turn/min, and stopped heating insulation 15min is cooled to 50 ℃; Add gac 10g in the clear and bright solution, whip attachment 30min, the rotating speed of stirring 100 turn/min, through taking off charcoal and a sterilization filter filtration, the secondary terminals degerming filters filter, and the millipore filtration aperture of filtration is 0.22 μ m, gained filtrate to medicinal liquid bottle, can after the passed examination, tamponade and get final product.Every bottle loading amount is 0.1g: 2ml.
Embodiment 6
The preparation of U 101440E injection liquid
Purified water is carried out distillation preparation sterile water for injection 4 times; After U 101440E 40g, Sorbitol Powder 90g, the lactic acid 1.8g that gets embodiment 3 preparation mixes, in stirring the lower 75 ℃ of water for injection 1800ml that slowly add, the rotating speed that stirs is 160 to turn/min, be 4.0 with sodium hydroxide or hydrochloric acid conditioning solution pH value, add 75 ℃ water for injection 200ml; Stir lower solution and be warming up to 125 ℃, the rotating speed of stirring is 160 to turn/min, and stopped heating insulation 15min is cooled to 50 ℃; Add gac 6g in the clear and bright solution, whip attachment 30min, the rotating speed of stirring 160 turn/min, through taking off charcoal and a sterilization filter filtration, the secondary terminals degerming filters filter, and the millipore filtration aperture of filtration is 0.22 μ m, gained filtrate to medicinal liquid bottle, can after the passed examination, tamponade and get final product.Every bottle loading amount is 0.1g: 5ml.
Embodiment 7
The preparation of U 101440E injection liquid
Purified water is carried out distillation preparation sterile water for injection 4 times; After U 101440E 40g, Sorbitol Powder 90g, the lactic acid 1.8g that gets embodiment 3 preparation mixes, in stirring the lower 75 ℃ of water for injection 1800ml that slowly add, the rotating speed that stirs is 160 to turn/min, be 4.0 with sodium hydroxide or hydrochloric acid conditioning solution pH value, add 75 ℃ water for injection 200ml; Stir lower solution and be warming up to 125 ℃, the rotating speed of stirring is 160 to turn/min, and stopped heating insulation 15min is cooled to 50 ℃; Add gac 6g in the clear and bright solution, whip attachment 30min, the rotating speed of stirring 160 turn/min, through taking off charcoal and a sterilization filter filtration, the secondary terminals degerming filters filter, and the millipore filtration aperture of filtration is 0.22 μ m, gained filtrate to medicinal liquid bottle, can after the passed examination, tamponade and get final product.Every bottle loading amount is 0.04g: 2ml.
Embodiment 8
The preparation of U 101440E injection liquid
Purified water is carried out distillation preparation sterile water for injection 4 times; After U 101440E 100g, Sorbitol Powder 225g, the lactic acid 4.5g that gets embodiment 3 preparation mixes, in stirring the lower 75 ℃ of water for injection 1800ml that slowly add, the rotating speed that stirs is 160 to turn/min, be 4.0 with sodium hydroxide or hydrochloric acid conditioning solution pH value, add 75 ℃ water for injection 200ml; Stir lower solution and be warming up to 125 ℃, the rotating speed of stirring is 160 to turn/min, and stopped heating insulation 15min is cooled to 50 ℃; Add gac 6g in the clear and bright solution, whip attachment 30min, the rotating speed of stirring 160 turn/min, through taking off charcoal and a sterilization filter filtration, the secondary terminals degerming filters filter, and the millipore filtration aperture of filtration is 0.22 μ m, gained filtrate to medicinal liquid bottle, can after the passed examination, tamponade and get final product.Every bottle loading amount is 0.1g: 2ml.
Experimental example 1
This test example detects related substance in the prepared U 101440E of embodiment 1～3, this test is carried out according to 2010 editions second appendix VIII P of Chinese Pharmacopoeia residual solvent assay method, appendix XIX F medicine impurity analysis governing principle, and it the results are shown in Table 1:
The assay of table 2 related substance
| Preparation | Ethylene glycol | Acetone | Other related substance |
| Embodiment 1 product | Up to specification | Up to specification | Up to specification |
| Embodiment 2 products | Up to specification | Up to specification | Up to specification |
| Embodiment 3 products | Up to specification | Up to specification | Up to specification |
Experimental example 2
This test example has been investigated the water absorbability of U 101440E provided by the invention.
Under the condition of humidity 80% and 90%, each sample thief 1g places on the electronic balance this test example respectively, and time recording weight is to detect the moisture absorption degree.
Table 2 wettability test result
Wherein sample 1 is embodiment 1 product;
Sample 2 is embodiment 2 products;
Sample 3 is that HPLC content is 99.58% with reference to the U 101440E crystal of CN201110247797.1 embodiment 1 preparation;
Sample 4 is commercially available U 101440E, originates from Shanghai Ya Ji bio tech ltd, and content is 98.8%.
This test example has also been investigated other embodiment preparing products, draws and upper table rule identical result, i.e. the prepared U 101440E water absorbability of the present invention is little.
Experimental example 3
This test example has been investigated the stability of U 101440E provided by the invention
This test is carried out according to 2005 editions second appendix XIX C of Chinese Pharmacopoeia medicine stability test governing principle, and the result is as follows:
Table 3, accelerated test result
| 1 month | 2 months | 3 months | 6 months | 12 months | |
| 1 | 99.86％ | 99.86％ | 99.84％ | 99.82％ | 99.61％ |
| 2 | 99.80％ | 99.79％ | 99.76％ | 99.73％ | 99.56％ |
| 3 | 99.85％ | 99.84％ | 99.78％ | 99.47％ | 98.64％ |
| 4 | 99.86％ | 99.83％ | 99.77％ | 99.44％ | 97.63％ |
| 5 | 99.84％ | 99.82％ | 99.72％ | 99.40％ | 98.58％ |
Table 4, long-term test results
| 3 months | 6 months | 9 months | 12 months | 18 months | |
| 1 | 99.86％ | 99.86％ | 99.86％ | 99.85％ | 99.83％ |
| 2 | 99.80％ | 99.80％ | 99.80％ | 99.78％ | 99.75％ |
| 3 | 99.85％ | 99.85％ | 99.84％ | 99.80％ | 99.48％ |
| 4 | 99.86％ | 99.86％ | 99.84％ | 99.79％ | 99.41％ |
| 5 | 99.84％ | 99.84％ | 99.82％ | 99.75％ | 99.35％ |
Wherein sample 1 is embodiment 1 product, and sample 2 is embodiment 2 products;
Sample 3 is for getting commercially available common U 101440E, the water recrystallization, and recrystallization repeatedly approaches to HPLC content and embodiment 1;
Sample 4 is that HPLC content is 99.62% with reference to the U 101440E of CN200710041738.2 embodiment 1 preparation;
Sample 5 originates from Shanghai Ya Ji bio tech ltd for getting commercially available common U 101440E, and content is 98.8%;
This description of test, compared with prior art, U 101440E good stability provided by the invention accelerates, test of long duration purity content is little.
The other embodiments of the invention product has also carried out identical experiment, and obtains the experimental result of same trend, but length limits, and the present invention enumerates no longer one by one.
Claims (9)
1. a U 101440E is characterized in that, the molecular formula of described U 101440E is C
33H
38N
4O
6HCl1.5H
2O;
The X-ray powder diffraction spectrogram that described U 101440E use Cu-K alpha-ray measures as shown in Figure 1.
2. the preparation method of a U 101440E claimed in claim 1 is characterized in that, the preparation of described U 101440E comprises: get the U 101440E bulk drug, the mixed solvent that adds entry/ethylene glycol, wherein the volume ratio of water and ethylene glycol is 2～4:1, stirs and be heated to 40～60 ℃, adds gac again, whip attachment, filter the decarburization degerming, obtain settled solution, settled solution is moved in the reactor, in 160～180 ℃ of lower 24～36h that place, reactor is opened in uniform decrease in temperature to 55～75 ℃, slowly drips acetone, crystallization, filter slow cooling to 0～5 ℃, uses deionized water wash, drying under reduced pressure, and get final product.
3. the preparation method of U 101440E according to claim 2 is characterized in that, the ratio of the weight of described U 101440E and the volume of mixed solvent is 1g:10～15ml.
4. the preparation method of U 101440E according to claim 2 is characterized in that, described dropping is at the uniform velocity to drip under mixing speed 25～30rmp.
5. the preparation method of U 101440E according to claim 2 is characterized in that, the volume ratio of described acetone and mixed solvent is 3～4:1.
6. pharmaceutical composition that contains U 101440E claimed in claim 1.
7. pharmaceutical composition according to claim 6, it is characterized in that, described pharmaceutical composition is the U 101440E injection liquid, by weight, consisting of of described U 101440E injection liquid: U 101440E 30-100 part, Sorbitol Powder 50-250 part, lactic acid 1-5 part, water for injection 150-2000 part.
8. pharmaceutical composition according to claim 7 is characterized in that, by weight, and the consisting of of described U 101440E injection liquid: 40 parts of U 101440Es, 90 parts of Sorbitol Powders, 1.8 parts of lactic acid, 2000 parts of waters for injection.
9. pharmaceutical composition according to claim 7 is characterized in that, by weight, and the consisting of of described U 101440E injection liquid: 100 parts of U 101440Es, 225 parts of Sorbitol Powders, 4.5 parts of lactic acid, 2000 parts of waters for injection.
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| CN102824345B (en) * | 2012-09-20 | 2014-03-26 | 江苏奥赛康药业股份有限公司 | Irinotecan hydrochloride composition and preparation method thereof |
| CN102885765B (en) * | 2012-10-25 | 2013-11-06 | 哈药集团生物工程有限公司 | Irinotecan hydrochloride injection and preparation method thereof |
| RU2552289C1 (en) * | 2014-02-05 | 2015-06-10 | ФЕДЕРАЛЬНОЕ ГОСУДАРСТВЕННОЕ БЮДЖЕТНОЕ УЧРЕЖДЕНИЕ "РОССИЙСКИЙ НАУЧНЫЙ ЦЕНТР РАДИОЛОГИИ И ХИРУРГИЧЕСКИХ ТЕХНОЛОГИЙ" МИНИСТЕРСТВА ЗДРАВООХРАНЕНИЯ РОССИЙСКОЙ ФЕДЕРАЦИИ /ФГБУ "РНЦРХТ" Минздрава России/ | Method of treating locally advanced stomach cancer with high metabolic and proliferative activity |
| KR102293907B1 (en) | 2015-06-30 | 2021-08-26 | 한미약품 주식회사 | Solid formulation for for oral administration containing irinotecan and a process for the preparation thereof |
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| CN102311443A (en) * | 2011-08-24 | 2012-01-11 | 上海北卡医药技术有限公司 | Novel crystal form of irinotecan hydrochloride and preparation method thereof |
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| CN102617584A (en) | 2012-08-01 |
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