CN101428035B - Gemcitabine hydrochloride or gemcitabine composition - Google Patents
Gemcitabine hydrochloride or gemcitabine composition Download PDFInfo
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- CN101428035B CN101428035B CN2008101830926A CN200810183092A CN101428035B CN 101428035 B CN101428035 B CN 101428035B CN 2008101830926 A CN2008101830926 A CN 2008101830926A CN 200810183092 A CN200810183092 A CN 200810183092A CN 101428035 B CN101428035 B CN 101428035B
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Abstract
The invention belongs to the field of pharmacy, which discloses hydrochloric gemcitabine or gemcitabine composition. The composition comprises components in the following weight ratio: the ratio of hydrochloric gemcitabine or gemcitabine, polymer and protein is 0.1 to 20:0.00 to 50:0.00 to 20, wherein, the weight of polymer and protein is not zero at the same time. The composition can effectivelyprevent hydrochloric gemcitabine or gemcitabine from loosing the activity in vivo, and has the advantages of good stability, low toxicity and good efficacy.
Description
Technical field
The invention belongs to pharmaceutical field, relate to that a kind of good stability, toxicity are low, the antitumor gemcitabine hydrochloride or the gemcitabine compositions of high curative effect.
Background technology
Gemcitabine hydrochloride or gemcitabine are antitumoral compounds, drugs approved by FDA in 1996 the line medicine of the gemcitabine hydrochloride produced of U.S. Lilly company as the treatment cancer of pancreas.Approval in 1998 is as treatment nonsmall-cell lung cancer medicine.China's approval of import gemcitabine hydrochloride antitumor drug in 1999, homemade imitation products and approval listing in 2003.
United States Patent (USP) 4808614 has write down gemcitabine hydrochloride or gemcitabine as a kind of antiviral chemical compound, and its antitumor characteristic is recorded in United States Patent (USP) 5464826, and this two patent is drawn at this and is reference.The formula technique of gemcitabine hydrochloride or gemcitabine has been described it and can be mixed with freeze-dried powder and be used for injection in this two patent, and this freeze-dried powder need aquation before injection is used become solution.At present, domestic and international commercially available gemcitabine hydrochloride is lyophilized injectable powder, must aquation become solution before injection or transfusion.
Caused gemcitabine hydrochloride or gemcitabine can only prolong the life and the moderate ground quality of making the life better of cancer patient a little to gemcitabine hydrochloride or the limited understanding of gemcitabine anti entity tumour mechanism.Main cause is the active anticancer that its very short in vivo serum half-life (about 8-12 minute) has suppressed it.Very fast in vivo the deaminizing of gemcitabine hydrochloride or gemcitabine is reacted into does not have active metabolite.In addition, the toxicity of commercially available gemcitabine hydrochloride product has also limited the dosage of patient.
Data shows that liposome can prevent that as the drug-loading system of gemcitabine hydrochloride or gemcitabine it from losing activity rapidly in vivo.Yet at present traditional liposome technology also is difficult to gemcitabine hydrochloride or gemcitabine are stably wrapped up in the liposome system, because gemcitabine is in vivo during pH neutral, and the little and liposome duplicature of freely coming in and going out soon of its molecular weight.Therefore, soon, gemcitabine hydrochloride or gemcitabine can diffuse out the liposome duplicature apace, thereby have reduced the stability and the clinical efficacy of product after gemcitabine hydrochloride or gemcitabine liposome preparation.
Summary of the invention
The purpose of this invention is to provide that a kind of good stability, toxicity are low, the antitumor gemcitabine hydrochloride or the gemcitabine compositions of high curative effect.
The objective of the invention is to realize by following technical measures:
A kind of gemcitabine hydrochloride or gemcitabine compositions is characterized in that said composition contains the component of following percentage by weight:
Gemcitabine hydrochloride or gemcitabine: polymer: protein is 0.1～20:0.00～50:0.00～20.
Wherein: polymer and protein are not zero simultaneously; Polymer be following one or more: polyvinylpyrrolidone, Polyethylene Glycol, polyvinylpyrrolidone and poly-copolymer, the poloxamer of handing over fat; Polymer molecular weight is 300-100,000Da.Further, polymer preferably polyethylene ketopyrrolidine.The copolymer of polyvinylpyrrolidone and poly-friendship fat is (C
6H
9NO) m-(C
3H
6O
3) n, m wherein, n is 30-80.
Protein be following one or more: human serum albumin, bovine serum albumin, alpha-globulin, betaglobulin, gamma globulin, Fibrinogen, siderophillin, ferritin.Protein molecular weight is 5000-500,000Da.Further, the preferred human serum albumin of protein.
Described compositions, its dosage form are injection solution or freeze-dried powder.
Described compositions, said composition also comprise one or more of buffer solution, osmotic pressure regulator, antioxidant, antiseptic.
Wherein:
Buffer solution be in phosphate, citrate, acetate, succinate, histidine, glycine, carbonate, the HEPES buffer solution one or more, concentration is 0.1-1000mM, pH is 3-12.
Osmotic pressure regulator be in sodium chloride, calcium chloride, sucrose, maltose, sorbitol, trehalose, glucose, mannitol, lactose, the hydroxypropyl-B-cyclodextrin (HPBCD) one or more, consumption is the 0.0%-20% of composition total weight.
Antioxidant is one or more in anti-hematic acid vitamin C, sodium bisulfate, sodium pyrosulfite, cysteine, N-ethoxycarbonyl cysteine, EDTA, the sodium citrate, and consumption is the 0.0%-1.5% of composition total weight.
Antiseptic is one or more in ethylparaben, propyl p-hydroxybenzoate, methyl parahydroxybenzoate, chlorocresol, the benzyl alcohol, and consumption is the 0.0%-2.0% of composition total weight.
Can add following one or more freeze drying protectants during the preparation freeze-dried powder: mannitol, sucrose, lactose, trehalose, consumption are the 0.1%-30% of composition total weight.
The concentration of gemcitabine is 1mg/ml to 100mg/ml in the injection solution, and its solution pH value is 3.0 to 9.0.
Said composition can be used from the medicine of preparation treatment cancer and hyperplasia with other antineoplastic agent one, for example: cisplatin, paclitaxel, amycin, 5-fluorouracil etc.
" gemcitabine " is meant 2 '-deoxidation-2 ' among the present invention, the form of various sta-salts, acid or the free alkali of 2 '-difluoro cytidine (β-isomer).Preferably among the present invention is gemcitabine hydrochloride.
Compositions provided by the present invention can be mixed use with intravenous fluid commonly used.For example, but be not limited in: one or more mixed liquors such as glucose injection, sodium chloride injection, lactate buffer.
The preparation of compositions method that provides among the present invention is for being dissolved in polymer, protein and an amount of one or more osmotic pressure regulators, antioxidant, antiseptic etc. in the suitable buffer solution, add gemcitabine hydrochloride or gemcitabine, treat that thoroughly pH value is regulated in the dissolving back.Aseptic filtration sterilization and envelope are filled in vial or the plastic bag.This prescription also can be selected the high temperature sterilize sterilization for use.Final products can be solution or further are prepared into lyophilized powder.
Compositions provided by the present invention can be used for the oncotherapy of the mankind and animal.Gemcitabine hydrochloride or the medicable tumor of gemcitabine compositions with the present invention's preparation include but not limited to: pulmonary carcinoma, and ovarian cancer, the cancer of gastrointestinal system comprises rectal cancer, colorectal cancer, cancer of pancreas and gastric cancer, liver cell tumor, head and neck cancer, carcinoma of prostate, kidney cell canceration, adenoacanthoma, sarcomata, lymphoma, leukemia, melanoma, the glioblastoma and the brain cancer etc.
Compositions provided by the present invention can be used with other preparation, as antifungal preparation, anti-tumor agent and antibiotic etc.
Clearly, can carry out some changes or improvement to the technology of the present invention, as raw material and method, but this and do not mean that these changes exceed the category of disclosure invention.
Beneficial effect of the present invention:
Patent of the present invention is actual to have comprised three formula systems: formula system one: contain gemcitabine hydrochloride or gemcitabine, polymer and albuminous solution or lyophilized powder; Formula system two: the solution or the lyophilized powder that contain gemcitabine hydrochloride or gemcitabine and polymer; Formula system three: contain gemcitabine hydrochloride or gemcitabine and albuminous solution or lyophilized powder; Three formula systems that this patent invention is developed can prevent effectively that all gemcitabine hydrochloride or gemcitabine from losing activity rapidly in vivo, and reduce toxic and side effects effectively, thereby have improved its antitumor curative effect.It is bonding to the present invention relates to gemcitabine hydrochloride or gemcitabine, polymer and albumin formation molecule; or gemcitabine hydrochloride or gemcitabine are bonding with polymer or albumin formation molecule separately; thereby protected gemcitabine hydrochloride or gemcitabine in vivo rapidly deaminizing reaction become the metabolite of non-activity; improve gemcitabine hydrochloride or the gemcitabine half-life in vivo, improved its curative effect greatly.In addition, bonding this system of the formed molecule of gemcitabine hydrochloride or gemcitabine helps gemcitabine hydrochloride or gemcitabine to act on cancerous cell in the body effectively, and its toxic and side effects is reduced, and has also improved curative effect simultaneously.With respect to the commercial like product, the gemcitabine hydrochloride of three formula systems provided by the invention or gemcitabine compositions significantly reduce human toxicity, and its curative effect also obviously improves.
Three formula systems of patent of the present invention all have identical stability.Formula system three has higher Drug tolerance but its gemcitabine hydrochloride or gemcitabine and albuminous bonding rate are relatively low, so its mouse heteroplastic transplantation model curative effect of investigating is low relatively slightly.Gemcitabine hydrochloride or gemcitabine have relative high slightly bonding rate so it is more stable relatively when deoxidation cytidine deaminase exists with polymer in the formula system two.Thereby the product of this formula system can guarantee the aseptic of product to greatest extent with high temperature sterilize in addition.And this formula system production technology is simple, and cost is low and clinical easy to use.But the Drug tolerance of this formula system is relatively low.The mouse heteroplastic transplantation model curative effect that the bonding rate of molecule is higher and it is investigated that gemcitabine hydrochloride or gemcitabine, polymer and albumin form in the formula system one is relative high slightly, but stability and drug resistance sex expression were general when it existed at deoxidation cytidine deaminase, and this formula system cost is higher.But three formula systems of patent of the present invention have all improved Drug tolerance significantly with respect to the commercial like product, have improved gemcitabine hydrochloride or the gemcitabine stability when deoxidation cytidine deaminase exists to a great extent, thereby have improved curative effect greatly.
Description of drawings
Fig. 1: the concentration of gemcitabine and time relation in the blood.
The specific embodiment
The invention will be further elaborated by the following examples.
Adopt in following examples "～" expression " pact " or " about " the meaning, also comprise " equaling ".
Preparation embodiment 1:100ml Jixitabing hydrochloride solution and 100mg/ bottle gemcitabine hydrochloride lyophilized powder
Preparation is formed: gemcitabine hydrochloride 1000mg
Human serum albumin (～MW66K) 10000mg
Polyvinylpyrrolidone (K17) 10000mg
Sodium hydrogen phosphate 1420mg
Mannitol 3000mg
Vitamin C 0.5mg
Injection water is an amount of
Hydrochloric acid or sodium hydroxide are an amount of
Preparation method: sodium hydrogen phosphate is dissolved in the injection water, is prepared into disodium hydrogen phosphate buffer solution behind the adjusting pH value to 7.5.With the human serum albumin, polyvinylpyrrolidone, mannitol, vitamin C is dissolved in the disodium hydrogen phosphate buffer solution, the dissolving back adds gemcitabine hydrochloride fully, treat that pH value to 7.5 is regulated in thorough dissolving back and with the buffer solution standardize solution of preparation, make the lyophilized powder product after behind the filtration sterilization filled with solution being become final products or vacuum lyophilization in type I vial.
Preparation embodiment 2:10ml Jixitabing hydrochloride solution
Preparation is formed: gemcitabine hydrochloride 150mg
Bovine serum albumin (～MW69K) 600mg
Polyvinylpyrrolidone (K17) 1000mg
Sodium dihydrogen phosphate 120mg
Sucrose 300mg
EDTA 0.05mg
Injection water is an amount of
Hydrochloric acid or sodium hydroxide are an amount of
Preparation method: sodium dihydrogen phosphate is dissolved in the injection water, is prepared into sodium dihydrogen phosphate buffer behind the adjusting pH value to 7.4.With bovine serum albumin, polyvinylpyrrolidone, sucrose and EDTA are dissolved in the sodium dihydrogen phosphate buffer, the dissolving back adds gemcitabine hydrochloride fully, treat that thoroughly pH value to 7.4 is regulated also with the buffer solution standardize solution of preparation in the dissolving back, behind the filtration sterilization filled with solution is become final products in type I vial.
Preparation embodiment 3:10ml Jixitabing hydrochloride solution
Preparation is formed: gemcitabine hydrochloride 50mg
Human serum albumin (～MW66K) 1000mg
Polyvinylpyrrolidone (K17) 500mg
Citric acid 154mg
Sodium chloride 500mg
Vitamin C 0.05mg
Mannitol 100mg
Injection water is an amount of
Hydrochloric acid or sodium hydroxide are an amount of
Preparation method: citric acid is dissolved in the injection water, is prepared into citric acid solution behind the adjusting pH value to 7.0.With the human serum albumin, polyvinylpyrrolidone, sodium chloride, vitamin C and mannitol are dissolved in the citric acid solution, the dissolving back adds gemcitabine hydrochloride fully, treat that thoroughly pH value to 7.0 is regulated also with the buffer solution standardize solution of preparation in the dissolving back, behind the filtration sterilization filled with solution is become final products in type I vial.
Preparation embodiment 4:100mg/ bottle gemcitabine hydrochloride lyophilized powder
Preparation is formed: gemcitabine hydrochloride 100mg
Alpha-globulin (～100K) 1000mg
Polyvinylpyrrolidone (K17) 1000mg
Histidine 155mg
Lactose 1000mg
Injection water is an amount of
Hydrochloric acid or sodium hydroxide are an amount of
Preparation method: histidine is dissolved in the injection water, is prepared into histidine buffer solution behind the adjusting pH value to 6.5.With alpha-globulin, polyvinylpyrrolidone and lactose are dissolved in the histidine buffer solution, the dissolving back adds gemcitabine hydrochloride fully, treat thoroughly to dissolve the back and regulate pH value to 6.5 also with the buffer solution standardize solution for preparing, behind the filtration sterilization with filled with solution in type I vial, make the lyophilized powder product after the vacuum lyophilization.
Preparation embodiment 5:10ml Jixitabin solution
Preparation is formed: gemcitabine 200mg
Siderophillin (～MW75K) 1000mg
Polyethylene Glycol (～MW600) 250mg
Histidine 155mg
Glucose 300mg
Methyl parahydroxybenzoate 10mg
Propyl p-hydroxybenzoate 0.5mg
Hydrochloric acid or sodium hydroxide are an amount of
Preparation method: histidine is dissolved in the injection water, is prepared into histidine buffer solution behind the adjusting pH value to 5.5.With siderophillin, Polyethylene Glycol, glucose, methyl parahydroxybenzoate and propyl p-hydroxybenzoate are dissolved in the histidine buffer solution, the dissolving back adds gemcitabine fully, treat that thoroughly pH value to 5.5 is regulated also with the buffer solution standardize solution of preparation in the dissolving back, behind the filtration sterilization filled with solution is become final products in type I vial.
Preparation embodiment 6:10ml Jixitabing hydrochloride solution
Preparation is formed: gemcitabine hydrochloride 100mg
Human serum albumin (～MW66K) 1000mg
Polyvinylpyrrolidone and the poly-copolymer m=n=50 that hands over fat (～MW100K) 1000mg
Sodium acetate 50mg
Lactose 500mg
EDTA 0.05mg
Chlorocresol 5.0mg
Injection water is an amount of
Hydrochloric acid or sodium hydroxide are an amount of
Preparation method: sodium acetate is dissolved in the injection water, is prepared into sodium acetate buffer solution behind the adjusting pH value to 6.0.With polyvinylpyrrolidone and the poly-copolymer of handing over fat, lactose, EDTA and chlorocresol are dissolved in the sodium acetate buffer solution, the dissolving back adds gemcitabine hydrochloride fully, treat that thoroughly pH value to 6.0 is regulated also with the buffer solution standardize solution of preparation in the dissolving back, behind the filtration sterilization filled with solution is become final products in type I vial.
Preparation embodiment 7:200mg/ bottle gemcitabine hydrochloride lyophilized powder
Preparation is formed: gemcitabine hydrochloride 200mg
Human serum albumin (～MW66K) 800mg
Poloxamer 188 1200mg
Histidine 155mg
Vitamin C 0.1mg
Glucose 2000mg
Injection water is an amount of
Hydrochloric acid or sodium hydroxide are an amount of
Preparation method: histidine is dissolved in the injection water, regulates pH value to 7.0 and be prepared into histidine buffer solution.With the human serum albumin, poloxamer 188, vitamin C and glucose are dissolved in the histidine buffer solution, the dissolving back adds gemcitabine hydrochloride fully, treat thoroughly to dissolve the back and regulate pH value to 7.0 also with the buffer solution standardize solution for preparing, behind the filtration sterilization with filled with solution in type I vial, make the lyophilized powder product after the vacuum lyophilization.
Preparation embodiment 8:10ml Jixitabing hydrochloride solution
Preparation is formed: gemcitabine hydrochloride 200mg
Polyvinylpyrrolidone (K17) 1500mg
Sodium hydrogen phosphate 142mg
Vitamin C 0.5mg
Injection water is an amount of
Hydrochloric acid or sodium hydroxide are an amount of
Preparation method: sodium hydrogen phosphate is dissolved in the injection water, is prepared into disodium hydrogen phosphate buffer solution behind the adjusting pH value to 8.0.Polyvinylpyrrolidone, vitamin C are dissolved in the disodium hydrogen phosphate buffer solution, the dissolving back adds gemcitabine hydrochloride fully, treat that thoroughly pH value to 7.0 is regulated also with the disodium hydrogen phosphate buffer solution standardize solution of preparation in the dissolving back, behind the filtration sterilization filled with solution is become final products in type I cillin bottle.
Preparation embodiment 9:10ml Jixitabing hydrochloride solution
Preparation is formed: gemcitabine hydrochloride 400mg
Polyvinylpyrrolidone (K17) 2000mg
Sodium dihydrogen phosphate 71mg
Sodium chloride 30mg
EDTA 0.5mg
Injection water is an amount of
Hydrochloric acid or sodium hydroxide are an amount of
Preparation method: sodium dihydrogen phosphate is dissolved in the injection water, is prepared into sodium dihydrogen phosphate buffer behind the adjusting pH value to 7.4.With polyvinylpyrrolidone, sodium chloride and EDTA are dissolved in the sodium dihydrogen phosphate buffer, the dissolving back adds gemcitabine hydrochloride fully, treat that thoroughly pH value to 7.4 is regulated also with the sodium dihydrogen phosphate buffer standardize solution of preparation in the dissolving back, behind the high temperature sterilize filled with solution is become final products in type I cillin bottle.
Preparation embodiment 10:400mg/ bottle gemcitabine hydrochloride lyophilized powder
Preparation is formed: gemcitabine hydrochloride 400mg
Bovine serum albumin (～MW69K) 600mg
Polyvinylpyrrolidone (K17) 1000mg
Sucrose 2000mg
Injection water is an amount of
Preparation method: with bovine serum albumin, polyvinylpyrrolidone and sucrose dissolved are in aqueous solution, the dissolving back adds gemcitabine hydrochloride fully, treats thoroughly dissolving back standardize solution, behind the filtration sterilization filled with solution is become final products after the vacuum lyophilization in type I vial.
Preparation embodiment 11:250mg/ bottle gemcitabine hydrochloride lyophilized powder
Preparation is formed: gemcitabine hydrochloride 250mg
Human serum albumin (～MW66K) 500mg
Sucrose 2500mg
Injection water is an amount of
Preparation method: in aqueous solution, the dissolving back adds gemcitabine hydrochloride fully with human serum albumin and sucrose dissolved, treats thoroughly dissolving back standardize solution, behind the filtration sterilization filled with solution is become final products after the vacuum lyophilization in type I vial.
Preparation embodiment 12:400mg/ bottle gemcitabine hydrochloride lyophilized powder
Preparation is formed: gemcitabine hydrochloride 400mg
Polyvinylpyrrolidone (K17) 2000mg
Sucrose 2500mg
Injection water is an amount of
Preparation method: in polyvinylpyrrolidone and the water-soluble solution of sucrose, the dissolving back adds gemcitabine hydrochloride fully, treats thoroughly dissolving back water standardize solution, behind the filtration sterilization filled with solution is become final products after the vacuum lyophilization in type I vial.
Preparation embodiment 13:400mg/ bottle gemcitabine hydrochloride lyophilized powder
Preparation is formed: gemcitabine hydrochloride 400mg
Bovine serum albumin (～MW69K) 1000mg
Polyvinylpyrrolidone (K17) 3000mg
Injection water is an amount of
Preparation method: bovine serum albumin and polyvinylpyrrolidone are dissolved in the aqueous solution, the dissolving back adds gemcitabine hydrochloride fully, treat that thoroughly the aqueous solution standardize solution is used in the dissolving back, behind the filtration sterilization filled with solution is become final products after the vacuum lyophilization in type I vial.
Preparation embodiment 14:400mg/ bottle gemcitabine hydrochloride lyophilized powder
Preparation is formed: gemcitabine hydrochloride 400mg
Human serum albumin (～MW66K) 1000mg
Sodium dihydrogen phosphate 142mg
EDTA 0.5mg
Sucrose 2500mg
Injection water is an amount of
Hydrochloric acid or sodium hydroxide are an amount of
Preparation method: sodium dihydrogen phosphate is dissolved in the injection water, is prepared into sodium dihydrogen phosphate buffer behind the adjusting pH value to 5.5.With the human serum albumin, sucrose, be dissolved in the sodium dihydrogen phosphate buffer with EDTA, the dissolving back adds gemcitabine hydrochloride fully, treat that thoroughly pH value to 4.5 is regulated also with the buffer solution standardize solution of preparation in the dissolving back, behind the filtration sterilization filled with solution is become final products after the vacuum lyophilization in type I vial.
Effect embodiment 1: the bonding rate test of gemcitabine hydrochloride or gemcitabine among the present invention
Separating bonding and non-bonding gemcitabine hydrochloride or gemcitabine can finish by filtration and centrifugation technique.Specifically, 0.5ml gemcitabine hydrochloride or Jixitabin solution (this effect embodiment has investigated embodiment 1 respectively, and embodiment 9, embodiment 11 and with the gemcitabine hydrochloride aqueous solution of concentration) being inserted one filters in the tubule on the filter membrane.The filter membrane that is equipped with in this filtration tubule is that 3000 molecular weight are held back filter membrane, the filtration tubule of having adorned sample put into the polypropylene sleeve pipe of another about 1.5ml and add cover, this polypropylene sleeve pipe is used to collect filtrate filtered, this is equipped with the polypropylene sleeve pipe that filters tubule puts into centrifugal 45 minutes of centrifuge, collects centrifugal back solution (be non-bonding gemcitabine hydrochloride or Jixitabin solution) and also use liquid chromatography (Phenomenex Luna C8 column with from sample separately with unbonded gemcitabine hydrochloride or gemcitabine; UV detection wavelength 275nm; Mobile phase A is a methanol, and Mobile phase B is a phosphate buffer; Use the gradient method analysis, 55% during methanol component 95% to 20 minute when initial.) analyze its content, its bonding rate is calculated as: gemcitabine hydrochloride or gemcitabine total amount x100% in (gemcitabine hydrochloride or bonding gemcitabine hydrochloride of gemcitabine total amount-non-or gemcitabine in the sample)/sample.The bonding rate of gemcitabine hydrochloride is all greater than 70% (seeing Table 1) among the embodiment 1,9 and 11, and is 0.1%. with its bonding rate of gemcitabine hydrochloride aqueous solution of concentration
Table 1: the bonding rate test of gemcitabine hydrochloride prescription
Effect embodiment 2: gemcitabine hydrochloride or the gemcitabine stability when deoxidation cytidine deaminase exists
Gemcitabine hydrochloride composition (is pressed embodiment 1, embodiment 9 and embodiment 11 preparations) and the gemcitabine hydrochloride lyophilized powder " Gemzar " (200 milligrams/bottle) produced of commercially available Lilly company use phosphate buffered saline(PBS) (pH7.4) to be mixed with solution respectively, its gemcitabine hydrochloride or gemcitabine concentration are 0.1mg/ml in each solution.(50 units/ml) add in the solution after above each dilution with deoxidation cytidine deaminase, the final concentration of its deoxidation cytidine deaminase is adjusted to 5 units/ml, this two mixed liquor was hatched 24 hours down at 37 ℃, respectively extract certain amount of mixed solution and use liquid chromatography (Phenomenex Luna C8 column in the different time; UV detection wavelength 275nm; Mobile phase A is a methanol, and Mobile phase B is a phosphate buffer; Use the gradient method analysis, 55% during methanol component 95% to 20 minute when initial) detect the content of its gemcitabine hydrochloride or gemcitabine.Calculate gemcitabine hydrochloride or gemcitabine concentration at different test points.Data show (seeing Table 2), three formula systems of patent of the present invention are more stable in deoxidation cytidine deaminase solution than the gemcitabine hydrochloride lyophilized powder " Gemzar " (200 milligrams/bottle) that commercially available Lilly company produces.
Table 2: gemcitabine hydrochloride or the gemcitabine stability when deoxidation cytidine deaminase exists
Effect embodiment 3: the stability test of gemcitabine hydrochloride prescription
Leave Jixitabing hydrochloride solution and lyophilized powder (pressing embodiment 1, embodiment 9 and embodiment 11 preparation preparations) in 2-8 ℃, 25 ℃ and 40 ℃, at different measuring points liquid chromatography (Phenomenex Luna C8 column; UV detection wavelength 275nm; Mobile phase A is a methanol, and Mobile phase B is a phosphate buffer; Analyze with gradient method, during methanol component 95% to 20 minute when initial 55%) detect the content of its gemcitabine hydrochloride, three formula systems of data show (see Table 3 and table 4) patent of the present invention all have suitable stability in six months under the investigation temperature.
Table 3: stability test-----embodiment 1 of gemcitabine hydrochloride prescription
Table 4: stability test-----embodiment 9 and 11 of gemcitabine hydrochloride prescription
Effect embodiment 4: the maximum tolerated dose test
The gemcitabine hydrochloride lyophilized powder " Gemzar " (200 milligrams/bottle) that this The effects gemcitabine hydrochloride composition of the present invention (pressing embodiment 1, embodiment 9 and embodiment 11 preparations) and commercially available Lilly company produce is to the maximum tolerated dose of neonatal rat.Investigate under the dosage in difference, male neonatal rat is divided into four groups, every group each 10, all neonatal rats are by the Jixitabing hydrochloride solution of being investigated of caudal vein injection same dose in each group.First group of neonatal rat injected the solution after gemcitabine hydrochloride lyophilized powder " Gemzar " (200 milligrams/bottle) aquation that commercially available Lilly company produces, solution after the gemcitabine hydrochloride lyophilized powder aquation that second group of neonatal rat injection embodiment 1 is prepared, the 3rd group of Jixitabing hydrochloride solution that neonatal rat injection embodiment 9 is prepared, solution after the gemcitabine hydrochloride lyophilized powder aquation that the 4th group of neonatal rat injection embodiment 11 is prepared. the lowest dose level (10mg/kg) that injection in the 1st day is investigated, injected dose was every corresponding increase in seven days.Neonatal rat until all investigations is all dead.Observe all neonatal rats mortality rate to the different gemcitabine hydrochloride compositions investigated under various dose.Table 5 is that data are summed up.
Table 5: maximum tolerated dose test
Effect embodiment 5: the mice pharmacokinetic
The gemcitabine hydrochloride lyophilized powder " Gemzar " (200 milligrams/bottle) that this The effects Jixitabing hydrochloride solution of the present invention (embodiment 1) and commercially available Lilly company produce is to the pharmacokinetic of neonatal rat.32 male neonatal rats are divided into two groups, and every group each 16, wherein one group to of the present invention Jixitabing hydrochloride solution of all neonatal rats by 20 milligrams/kilogram of caudal vein injections.Other one group of all neonatal rat " Gemzar " lyophilized powder after with same procedure injection same dose aquation.At each testing time point, get 2 neonatal rats at random and gather every neonatal rat blood in the collecting bottle of heparinization from each group.After treating that erythrocyte separates, with liquid chromatography (Phenomenex Luna C8 column; UV detection wavelength 275nm; Mobile phase A is a methanol, and Mobile phase B is a phosphate buffer; Use the gradient method analysis, 55% during methanol component 95% to 20 minute when initial) concentration of gemcitabine hydrochloride or gemcitabine the analysed for plasma.The concentration of gemcitabine hydrochloride or gemcitabine in each group blood plasma is obtained two curves with respect to individual testing time point mapping.Determine the half-life of each area under curve (AUC) and gemcitabine hydrochloride, see Table 6 and Fig. 1.The AUC of data show Jixitabing hydrochloride solution of the present invention and half-life are apparently higher than commercially available gemcitabine hydrochloride lyophilized powder.
Table 6: pharmacokinetic
| Investigate sample | Dosage (milligram/kilogram) | AUC (microgram hour/milliliter) | Half-life (hour) |
| Gemzar | 20 | 89 | 0.2 |
| The present composition | 20 | 4570 | 13.0 |
Effect embodiment 6: mouse heteroplastic transplantation model clinical trial
The lung carcinoma cell (A549) that cultivation is grown up (is injected in the SCID mouse under 2 * 106cells) the routine Pericarpium Arecae, when the lung carcinoma cell of inoculation is grown up to 65-120mm
3The time, the Jixitabing hydrochloride solution that start injection is investigated.The mouse of all inoculations is divided into different groups, every group 5, inject respectively solution after placebo, Jixitabing hydrochloride solution of the present invention (pressing embodiment 1 and 9 preparations), gemcitabine hydrochloride lyophilized powder of the present invention (press the embodiment 11 preparations) aquation, and gemcitabine hydrochloride lyophilized powder " Gemzar " (200 milligrams/bottle) aquation of commercially available Lilly company production after solution, it investigates dosage is 20mg/kg and 30mg/kg, injection once week about, continuously three weeks of injection, observations in every 2-3 days detect the volume of cancerous cell.The curative effect of gemcitabine hydrochloride is estimated with the percent by volume that the volume of injecting the back cancerous cell accounts for the preceding cancerous cell of injection, and data are summarized as follows (seeing Table 7,8).The result shows that the curative effect of three formula systems of patent of the present invention is apparently higher than commercially available gemcitabine hydrochloride.
Table 7: mouse heteroplastic transplantation model clinical trial-----embodiment 1
Table 8: mouse heteroplastic transplantation model clinical trial-----embodiment 9 and 11
Claims (6)
1. gemcitabine hydrochloride or gemcitabine compositions is characterized in that said composition contains the component of following weight ratio:
Gemcitabine hydrochloride or gemcitabine: polymer: protein is 0.1～20: 0.00～50: 0.00～20;
Wherein:
Polymer and protein are all non-vanishing;
Polymer be following one or more: polyvinylpyrrolidone, Polyethylene Glycol, poloxamer, polyvinylpyrrolidone and the poly-copolymer (C that hands over fat
6H
9NO) m-(C
3H
6O
3) n, m wherein, n is 30-80;
Protein be following one or more: human serum albumin, bovine serum albumin, alpha-globulin, betaglobulin, gamma globulin, Fibrinogen, siderophillin, ferritin.
2. compositions according to claim 1 is characterized in that polymer molecular weight is 300-100,000Da.
3. compositions according to claim 1 is characterized in that polymer is a polyvinylpyrrolidone.
4. compositions according to claim 1 is characterized in that protein molecular weight is 5000-500,000Da.
5. compositions according to claim 1 is characterized in that protein is the human serum albumin.
6. compositions according to claim 1, the dosage form that it is characterized in that said composition is injection solution or freeze-dried powder.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008101830926A CN101428035B (en) | 2007-12-11 | 2008-12-04 | Gemcitabine hydrochloride or gemcitabine composition |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007101911844A CN101185654A (en) | 2007-12-11 | 2007-12-11 | Gemcitabine hydrochloride or gemcitabine composition |
| CN200710191184.4 | 2007-12-11 | ||
| CN2008101830926A CN101428035B (en) | 2007-12-11 | 2008-12-04 | Gemcitabine hydrochloride or gemcitabine composition |
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| Publication Number | Publication Date |
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| CN101428035A CN101428035A (en) | 2009-05-13 |
| CN101428035B true CN101428035B (en) | 2010-12-22 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNA2007101911844A Pending CN101185654A (en) | 2007-12-11 | 2007-12-11 | Gemcitabine hydrochloride or gemcitabine composition |
| CN2008101830926A Expired - Fee Related CN101428035B (en) | 2007-12-11 | 2008-12-04 | Gemcitabine hydrochloride or gemcitabine composition |
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| Application Number | Title | Priority Date | Filing Date |
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| CNA2007101911844A Pending CN101185654A (en) | 2007-12-11 | 2007-12-11 | Gemcitabine hydrochloride or gemcitabine composition |
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101732258B (en) * | 2008-11-19 | 2013-12-25 | 复旦大学附属华山医院 | Nano microsphere preparation used for chemotherapy of tumors and preparation method thereof |
| CA2871061C (en) * | 2012-04-27 | 2017-06-20 | Sun Pharmaceutical Industries Ltd | Ready to be infused gemcitabine solution |
| CN102614137B (en) * | 2012-05-02 | 2013-12-11 | 南京臣功制药股份有限公司 | Gemcitabine hydrochloride freeze-dried powder injection and preparation method thereof |
| CN104434948B (en) * | 2014-11-11 | 2016-11-23 | 滨州医学院附属医院 | The pharmaceutical composition of a kind of anti-pancreatic cancer and application thereof |
| CN109758467B (en) * | 2019-03-08 | 2020-12-25 | 中国农业科学院兰州兽医研究所 | Application of gemcitabine in preparation of drugs for preventing foot-and-mouth disease virus infection |
| WO2023076878A1 (en) * | 2021-10-26 | 2023-05-04 | Emphascience Inc. | Ready-to-dilute formulation |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060089328A1 (en) * | 2004-10-22 | 2006-04-27 | Edgar Schridde | Ready-to-use gemcitabine solutions |
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| US20060089328A1 (en) * | 2004-10-22 | 2006-04-27 | Edgar Schridde | Ready-to-use gemcitabine solutions |
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| CN101185654A (en) | 2008-05-28 |
| CN101428035A (en) | 2009-05-13 |
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