CN102600077A - Gemcitabine or gemcitabine salt nano-emulsion injecta and preparation method thereof - Google Patents
Gemcitabine or gemcitabine salt nano-emulsion injecta and preparation method thereof Download PDFInfo
- Publication number
- CN102600077A CN102600077A CN2012100885491A CN201210088549A CN102600077A CN 102600077 A CN102600077 A CN 102600077A CN 2012100885491 A CN2012100885491 A CN 2012100885491A CN 201210088549 A CN201210088549 A CN 201210088549A CN 102600077 A CN102600077 A CN 102600077A
- Authority
- CN
- China
- Prior art keywords
- oil
- gemcitabine
- injection
- water
- emulsion
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a gemcitabine or gemcitabine salt nano-emulsion injecta and a preparation method of the gemcitabine or gemcitabine salt nano-emulsion injecta. The injecta specifically includes gemcitabine or a gemcitabine salt, oil for injection, a surface active agent and water for injection, wherein the weight ratio of gemcitabine or the gemcitabine salt to the oil for injection to the surface active agent is 1:(10-100):(10-100), and the average particle size of an emulsion droplet in the emulsion is 1-100nm. The injecta provided by the invention is high in entrapment efficiency and stability and low in side effect.
Description
Technical field
The present invention relates to a kind of gemcitabine or its salt new formulation and preparation method thereof, specifically relate to nano-emulsion injection of gemcitabine or its salt and preparation method thereof.
Background technology
Gemcitabine is a kind of Difluoronucleosides class antimetabolite anticarcinogen that destroys cellular replication; It is the water-soluble analogues of cytosine deoxyriboside; To ribonucleotide reductase is a kind of substitute of substrate of inhibition; This kind of enzyme DNA synthetic with repair process in, be vital to the generation of needed Deoxydization nucleotide.Have that antitumor spectra is wide, mechanism of action is unique, do not have crossing drug resistant with other chemotherapeutics and toxic reaction does not have characteristics such as stack.
Gemcitabine is the good substrates of thymine deoxyriboside kinase phosphorylation in cell as a kind of prodrug, under the effect of enzyme, changes into following metabolite: gemcitabine monophosphate (dFdCMP), gemcitabine diphosphate (dFdCDP) and gemcitabine triphosphate (dFdCTP) wherein dFdCDP and dFdCTP are activated product.DFdCDP suppresses ribonucleotide reductase, thereby has reduced the amount (especially dCTP) of the required Deoxydization nucleotide of the synthetic reparation of DNA, and low-level dCTP has reversed the normal negative feedback inhibition of deoxidation glycosides kinases, cause dFdCTP more to gather.Simultaneously dFdCDP has suppressed the deamination of the inductive deoxidation born of the same parents of dCTP ammonia enzyme to dFdCMP, and dFdCTP directly suppresses deoxycytidine and take off enzyme, thereby makes more dFdCMP change into the deamination of active metabolite dFdCMP; And dFdCTP directly suppresses deoxycytidine deaminase; Thereby make more dFdCMP change into active metabolite dFdCDP, dFd-CTP dFdCTP then combines to get into the DNA chain with the dCTP competition, is inserted into the site of deoxycytidine in the DNA chain; And permission guanosine and its pairing; The gemcitabine molecule just " is sheltered " by this guanosine and is made its reparation that removes of avoiding exoribonuclease, and the DNA chain is synthetic then stops, and then dna break, cell death.
Confirm that at present gemcitabine is remarkable to multiple treatment of solid tumors effect, especially to nonsmall-cell lung cancer, cancer of pancreas and breast carcinoma, single drug or unite other cancer therapy drug and all obtain very high curative effect.Gemcitabine is short (between 32～94min) in the intracellular half-life; Must heavy dose of (RD be 1000mg/m2), continue that intravenously administrable is kept its effective medicinal concentration and to the toxicity of cancerous cell; But this toxicity also works to normal structure simultaneously, and this dose-limiting toxicity influences clinical efficacy.In addition, the inorganizable specificity of gemcitabine, the whole body toxic and side effects is big; Internal metabolism is rapid, and plasma half-life is short; Shortcomings such as drug resistance of tumor.
Therefore, it is stronger to seek a kind of drug targeting property that can make, and the medication that toxic and side effects is littler is the emphasis and the difficult point of current research.The medicine-carried nano particles that contains active drug is a kind of novel slow-released system, can change conventional administering mode, and utmost point wide prospect is arranged; It is medicine and pharmacology hot research fields in recent years; The nanometer medicine in getting into body after, medicine slowly discharges in the target area, to alleviate the untoward reaction of medicine.
Huang Lesong, Chunxia WANG, Chen Zhiliang etc. " targeting of gemcitabine poly-alkyl-alfa-cyanoacrylate nanoparticles in mouse brain distributes " (Chinese Hospitals pharmaceutical journal; 2008,28 (16): 1332), and Huang Lesong; Chunxia WANG; Chen Zhi very waits " the gemcitabine poly-alkyl-alfa-cyanoacrylate nanoparticles is transplanted glioma to mouse brain influence research " (China Dispensary, 2009,20 (19): introduced a kind of nanoparticle of gemcitabine 1457) and to the influence of animal.Huang Junqin, Kong Liwen " the mensuration character of the preparation of gemcitabine hydrochloride liposome and content and envelop rate " (Chinese antibiotic magazine, 2010,35 (1): 30) introduced a kind of preparation and content assaying method of gemcitabine liposome.CN101444485B discloses a kind of gemcitabine liposome, and this liposome comprises gemcitabine, phospholipid, cholesterol, but the envelop rate of this liposome and dispersibility all perform poor, and stability of drug and bioavailability are all had adverse effect.CN101926779A discloses a kind of gemcitabine solid lipid nanospheres and preparation method thereof, and said preparation still exists entrapment efficiency not high, and the not good problem of stability, stores about 3 months medicines the part degraded promptly takes place.Though the research of the liposome of part medicine or nanometer medicine has obtained bigger progress even in clinical, has obtained application.But because the difference of physical and chemical properties of drugs and pharmacological action, the technology that liposome or nanometer medicine are used in the gemcitabine field does not obtain to break through yet.
From the achievement of present research, the gemcitabine liposome of existing method preparation or Nano microsphere exist be prone in poor stability, the aqueous solution assemble, problems such as whole corrosion or superficial degradation, can't in clinical, obtain practical application.
Summary of the invention
The objective of the invention is to solve the problems of the technologies described above; A kind of envelop rate and stability, minimizing gemcitabine or the side effect of its salt in clinical practice that can strengthen drug targeting property, raising medicine is provided, and is suitable for gemcitabine or its salt nano-emulsion injection of wide clinical application.
The object of the present invention is to provide the nano-emulsion injection of a kind of gemcitabine or its salt; Said injection contains gemcitabine or its salt, oil for injection, surfactant and water for injection; Wherein the weight ratio of gemcitabine or its salt, oil for injection, surfactant is 1: 10～100: 10～100;, the mean diameter of emulsion droplet is 1～100nm in the Emulsion.
Said nano-emulsion injection is an oil-in-water type, and wherein the weight ratio of gemcitabine or its salt, oil for injection, surfactant is 1: 20～50: 10～20.
The salt of said gemcitabine is hydrochlorate.
Said oil for injection is selected from one or more in mineral oil, vegetable oil, animal oil or the artificial oil; Said vegetable oil is selected from one or more in soybean oil, Oleum Arachidis hypogaeae semen, Semen Maydis oil, Oleum sesami, safflower oil, Oleum Ricini, Petiolus Trachycarpi oil, Oleum Gossypii semen, Oleum Cocois, the medium-chain fatty acid triglyceride, one or more in preferred soybean oil, Oleum Arachidis hypogaeae semen, Oleum sesami or the medium-chain fatty acid triglyceride; Said animal oil is selected from fish oil, sperm oil or its mixture.
Said surfactant is selected from phospholipid, nonionic surfactant or its mixture.
Said phospholipid is selected from lecithin, fabaceous lecithin or its mixture, preferably lecithin or fabaceous lecithin; Said non-ionic surface active agent is selected from polyoxyethylene and polyethylene glycols non-ionic surface active agent; Said polyoxyethylene non-ionic surface active agent is selected from polysorbas20, polysorbate40, polysorbate60, Tween 80, polysorbate85, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, poloxamer 188 or its mixture; Preferred Tween 80 or poloxamer 188, said polyethylene glycols non-ionic surface active agent is selected from Pegylation and gathers hexadecane cyanoacrylate, Polyethylene Glycol stearic acid, Polyethylene Glycol vitamin e succinate or its mixture.
The mean diameter of emulsion droplet is 1～70nm in the said Emulsion, preferred 1～50nm, more preferably 1～20nm.
The injection of described gemcitabine or its salt also comprises one or more in antioxidant or the stabilizing agent.
Said antioxidant is selected from water solublity antioxidant or oil-soluble antioxidant, and wherein water solublity antioxidant is selected from sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium ascorbate, L-cysteine or its mixture; Oil-soluble antioxidant is selected from BHA (butylated hydroxyarisol), BHT (2; 6-di-t-butyl hydroxy-methylbenzene), vitamin E, ascorbyl palmitate or its mixture; Preferred ascorbyl palmitate, wherein said antioxidant accounts for 0%～1w/v% of injection.
Said stabilizing agent is selected from oleic acid, enuatrol, cholic acid, sodium cholate, dextran-70, deoxycholic acid, sodium deoxycholate or its mixture, 0%～1.5w/v% of wherein said stabilizer comprises injection.
The present invention also aims to provide a kind of method for preparing above-mentioned gemcitabine or its salt nano-emulsion injection, comprise the steps:
Under inert gas shielding, oil for injection is stirred into oil phase;
Surfactant is added proper amount of water for injection, be stirred into water;
Under the high-speed stirred, oil phase is mixed with water evenly, and process colostrum through the high pressure homogenizer homogenize;
Add gemcitabine or its salt to first Ruzhong;
Regulating pH value is 4～9, continues to add water and is settled to full dose, fully stirs or makes the emulsion droplet mean diameter meet the requirements of nanorize through the high pressure homogenizer homogenize.
The present invention also provides other a kind of method for preparing above-mentioned gemcitabine or its salt nano-emulsion injection, comprises the steps:
Under inert gas shielding, oil for injection, oil-soluble antioxidant are stirred into oil phase;
Water solublity antioxidant stabilizers and surfactant are added in the proper amount of water for injection, be stirred into water;
Under high-speed stirred, oil phase is mixed with water evenly, and process colostrum through the high pressure homogenizer homogenize;
Add gemcitabine or its salt to first Ruzhong;
Regulate pH value 4～9. continue to add water to be settled to full dose, fully stir or meet the requirements of nanorize through high pressure homogenization machine homogenize to emulsion droplet mean diameter.
Research according to the inventor shows that pH value is good especially at 4～7 o'clock.
Above-mentioned preparation has been opened up the new way of gemcitabine or its salt administration; Screening through each constituent content proportioning in the compositions; And the processing of emulsion droplet grain size nanometer grade improved the envelop rate and the stability of medicine greatly, reduced medicine toxic and side effects in use, and it is painful to have alleviated patient's medication.
The specific embodiment
Should to invent in order more specifically describing, and will combine specific embodiment to further specify this invention below, but content of the present invention to be not limited to specific embodiment.
Embodiment one
Method for preparing: under inert gas shielding, 200g stirs into oil phase with the injection soybean oil, in addition soybean phospholipid 200g is added in the 500ml water for injection; Stir into water, under high-speed stirred that oil phase is mixed with water evenly, and process colostrum through the homogenize of high pressure homogenization machine; Add gemcitabine hydrochloride 10g, regulating pH value is 5.0, adds water and is settled to 1000ml; Change in the high pressure homogenization machine fully and stir, to mean diameter below 40nm; Fill, the inflated with nitrogen encapsulation.
Embodiment two
Method for preparing: under inert gas shielding, 200g stirs into oil phase with injection Oleum Arachidis hypogaeae semen, in addition soybean phospholipid 200g is added in the 500ml water for injection; Stir into water, under high-speed stirred that oil phase is mixed with water evenly, and process colostrum through the homogenize of high pressure homogenization machine; Add gemcitabine hydrochloride 10g, regulating pH value is 5.0, adds water and is settled to 1000ml; Change in the high pressure homogenization machine fully and stir, to mean diameter below 40nm; Fill, the inflated with nitrogen encapsulation.
Embodiment three
Method for preparing: under inert gas shielding, 200g stirs into oil phase with the injection Oleum sesami, in addition soybean phospholipid 200g is added in the 500ml water for injection; Stir into water, under high-speed stirred that oil phase is mixed with water evenly, and process colostrum through the homogenize of high pressure homogenization machine; Add gemcitabine hydrochloride 10g, regulating pH value is 5.0, adds water and is settled to 1000ml; Change in the high pressure homogenization machine fully and stir, to mean diameter below 40nm; Fill, the inflated with nitrogen encapsulation.
Embodiment four
Method for preparing: under inert gas shielding, 200g stirs into oil phase with the injection soybean oil, in addition soybean phospholipid 200g is added in the 500ml water for injection; Stir into water, under high-speed stirred that oil phase is mixed with water evenly, and process colostrum through the homogenize of high pressure homogenization machine; Add gemcitabine hydrochloride 10g, regulating pH value is 5.0, adds water and is settled to 1000ml; Change in the high pressure homogenization machine fully and stir, to mean diameter below 20nm; Fill, the inflated with nitrogen encapsulation.
Embodiment five
Method for preparing: under inert gas shielding, 225g stirs into oil phase with the injection soybean oil, is preheated to 60 ℃; Soybean phospholipid 125g, sodium sulfite 4g are joined in the 600ml water for injection, be stirred into water, be preheated to 60 ℃; Under high-speed stirred that oil phase is mixed with water evenly; And process colostrum through the homogenize of high pressure homogenization machine, and add gemcitabine hydrochloride 10g, regulate pH value to 6.0; Add water and be settled to 1000ml, it is transferred to continue emulsifying to mean diameter in the high pressure homogenization machine about 20nm; Fill, the inflated with nitrogen sealing by fusing.
Embodiment six
Method for preparing: under inert gas shielding, injection soybean oil 225g and oleic acid 6g are mixed into oil phase, are preheated to 60 ℃; Soybean phospholipid 125g, sodium sulfite 4g are joined in the 600ml water for injection, be stirred into water, be preheated to 60 ℃; Under high-speed stirred that oil phase is mixed with water evenly; And process colostrum through the homogenize of high pressure homogenization machine, and add gemcitabine hydrochloride 10g, regulate pH value to 6.0; Add water and be settled to 1000ml, it is transferred to continue emulsifying to mean diameter in the high pressure homogenization machine about 15nm; Fill, the inflated with nitrogen sealing by fusing.
Embodiment seven
Method for preparing: under inert gas shielding, injection soybean oil 300g and oleic acid 5g are mixed into oil phase, are preheated to 60 ℃; Soybean phospholipid 200g, sodium sulfite 5g are joined in the 650ml water for injection, be stirred into water, be preheated to 60 ℃; Under high-speed stirred that oil phase is mixed with water evenly; And process colostrum through the homogenize of high pressure homogenization machine, and add gemcitabine hydrochloride 10g, regulate pH value to 5.0; Add water and be settled to 1000ml, it is transferred to continue emulsifying to mean diameter in the high pressure homogenization machine about 15nm; Fill, the inflated with nitrogen sealing by fusing.
Embodiment eight
Method for preparing: under inert gas shielding, injection soybean oil 450g and oleic acid 12g are mixed into oil phase, are preheated to 60 ℃; Soybean phospholipid 150g, sodium sulfite 8g are joined in the 650ml water for injection, be stirred into water, be preheated to 60 ℃; Under high-speed stirred that oil phase is mixed with water evenly; And process colostrum through the homogenize of high pressure homogenization machine, and add gemcitabine hydrochloride 10g, regulate pH value to 5.0; Add water and be settled to 1000ml, it is transferred to continue emulsifying to mean diameter in the high pressure homogenization machine about 15nm; Fill, the inflated with nitrogen sealing by fusing.
Embodiment nine
Method for preparing: under inert gas shielding, injection soybean oil 300g and oleic acid 10g are mixed into oil phase, are preheated to 60 ℃; Tween 80 135g, sodium ascorbate 5g are joined in the 600ml water for injection, be stirred into water, be preheated to 60 ℃; Under high-speed stirred that oil phase is mixed with water evenly; And process colostrum through the homogenize of high pressure homogenization machine, and add gemcitabine hydrochloride 10g, regulate pH value to 5.0; Add water and be settled to 1000ml, it is transferred to continue emulsifying to mean diameter in the high pressure homogenization machine about 20nm; Fill, the inflated with nitrogen sealing by fusing.
Embodiment ten
Method for preparing: under inert gas shielding, injection soybean oil 300g and oleic acid 10g are mixed into oil phase, are preheated to 60 ℃; Tween 80 135g, sodium ascorbate 5g are joined in the 600ml water for injection, be stirred into water, be preheated to 60 ℃; Under high-speed stirred that oil phase is mixed with water evenly; And process colostrum through the homogenize of high pressure homogenization machine, and add gemcitabine hydrochloride 10g, regulate pH value to 5.0; Add water and be settled to 1000ml, it is transferred to continue emulsifying to mean diameter in the high pressure homogenization machine about 50nm; Fill, the inflated with nitrogen sealing by fusing.
Embodiment 11
Method for preparing: under inert gas shielding, 300g is mixed into oil phase with the injection soybean oil, is preheated to 60 ℃; Tween 80 135g, sodium ascorbate 5g and enuatrol 10g are joined in the 600ml water for injection, be stirred into water, be preheated to 60 ℃; Under high-speed stirred that oil phase is mixed with water evenly; And process colostrum through the homogenize of high pressure homogenization machine, and add gemcitabine hydrochloride 10g, regulate pH value to 5.7; Add water and be settled to 1000ml, it is transferred to continue emulsifying to mean diameter in the high pressure homogenization machine about 50nm; Fill, the inflated with nitrogen sealing by fusing.
Embodiment 12
Method for preparing: under inert gas shielding, 250g is mixed into oil phase with the medium-chain fatty acid triglyceride, is preheated to 70 ℃; Tween 80 150g, sodium ascorbate 7g and enuatrol 13g are joined in the 650ml water for injection, be stirred into water, be preheated to 70 ℃; Under high-speed stirred that oil phase is mixed with water evenly; And process colostrum through the homogenize of high pressure homogenization machine, and add gemcitabine hydrochloride 10g, regulate pH value to 6.0; Add water and be settled to 1000ml, it is transferred to continue emulsifying to mean diameter in the high pressure homogenization machine about 20nm; Fill, the inflated with nitrogen sealing by fusing.
Embodiment 13
Method for preparing: under inert gas shielding, injection soybean oil 300g and ascorbyl palmitate 5g are mixed into oil phase, are preheated to 60 ℃; Tween 80 135g and enuatrol 10g are joined in the 600ml water for injection, be stirred into water, be preheated to 60 ℃; Under high-speed stirred that oil phase is mixed with water evenly; And process colostrum through the homogenize of high pressure homogenization machine, and add gemcitabine hydrochloride 10g, regulate pH value to 5.7; Add water and be settled to 1000ml, it is transferred to continue emulsifying to mean diameter in the high pressure homogenization machine about 20nm; Fill, the inflated with nitrogen sealing by fusing.
Experimental example one entrapment efficiency determination
Medicine assay method: chromatographic column: Diamonsil
TMC
18(4.6mm*250mm, 5 μ m); Mobile phase: with 0.05mol/L ammonium acetate buffer (get ammonium acetate 3.85g, add water 800ml dissolving, transfer pH to 5.7, add water to 1000ml)-methanol (90: 10) with glacial acetic acid; Detect wavelength: 268nm; Flow velocity: 1.0ml/min; 40 ℃ of column temperatures, sample size: 20 μ L.
The entrapment efficiency determination method: 1 of sample thief, the accurate 2.0ml that draws places the 10ml measuring bottle, and thin up with 8010 type ultrafilters (MILLIPORE company) ultrafiltration, discards filtrating just to scale, and getting subsequent filtrate is need testing solution.Draw need testing solution respectively, reference substance solution 20 μ L inject chromatograph of liquid, the record chromatogram calculates preparation aqueous phase medicament contg with external standard method, is designated as W; Press the medicine total content of these article of method calculating under the assay item in addition, be designated as W
0Be calculated as follows the envelop rate of sample.
Envelop rate En=(W
0-W)/W
0* 100%
Measuring as stated above averages behind the envelop rate of three lot sample article is E, and it is as shown in table 1 to measure the result:
Table 1 gemcitabine hydrochloride injection is sealed rate and is measured
| The embodiment title | E(％) |
| Embodiment one | 95.8 |
| Embodiment two | 93.5 |
| Embodiment three | 94.6 |
| Embodiment four | 96.9 |
| Embodiment five | 97.7 |
| Embodiment six | 99.3 |
| Embodiment seven | 99.1 |
| Embodiment eight | 98.9 |
| Embodiment nine | 99.5 |
| Embodiment ten | 98.7 |
| Embodiment 11 | 99.1 |
| Embodiment 12 | 99.6 |
| Embodiment 13 | 99.8 |
Conclusion: the injection entrapment efficiency effect that can find out this invention from The above results is fine, meets the national drug prescription, has good clinical value.
Experimental example two stability tests
Measure the stability data of injection of the present invention as follows.
Assay method: the sample of getting each embodiment of 1ml respectively places special centrifuge tube, and it is centrifugal with the 2000rpm rotating speed to put into table model high speed centrifuge, after centrifugal 15 minutes, takes out centrifuge tube.It is an amount of by the bottom sample to be splashed into small beaker, draws 50.0 μ L with microscale sampler and is added in the 25ml measuring bottle, is diluted to scale with water for injection, mixing.Under the 500nm wavelength, detect its trap value (A) with the water level blank.Get 50.0 μ L raw samples again and place the 25ml measuring bottle, use the water for injection standardize solution, detect its absorption value (A in same wavelength
0).Press mathematical formulae K
E=(| A
0-A|/A
0) * 100%, calculate the stability parameter K of this Emulsion
EK
EMore little Emulsion is stable more.Experimental result is as shown in table 2:
Table 2 gemcitabine hydrochloride injection stability is measured
| The embodiment title | K EValue | Sample appearance |
| Embodiment one | 0.451 | Do not see oil droplet |
| Embodiment two | 0.469 | Do not see oil droplet |
| Embodiment three | 0.416 | Do not see oil droplet |
| Embodiment four | 0.446 | Do not see oil droplet |
| Embodiment five | 0.421 | Do not see oil droplet |
| Embodiment six | 0.403 | Do not see oil droplet |
| Embodiment seven | 0.412 | Do not see oil droplet |
| Embodiment eight | 0.432 | Do not see oil droplet |
| Embodiment nine | 0.451 | Do not see oil droplet |
| Embodiment ten | 0.415 | Do not see oil droplet |
| Embodiment 11 | 0.406 | Do not see oil droplet |
| Embodiment 12 | 0.408 | Do not see oil droplet |
| Embodiment 13 | 0.408 | Do not see oil droplet |
In addition, through conventional method working sample long-time stability, after sample stores 6 months at ambient temperature, measure Emulsion percentage of head rice among all embodiment, the result shows that the Emulsion percentage of head rice of each embodiment sample all reaches more than 92%.
Conclusion: through measuring, sample stability is better, is suitable for clinical practice, but the longer-term storage.
Claims (12)
1. a gemcitabine or its salt nano-emulsion injection; It is characterized in that said injection contains gemcitabine or its salt, oil for injection, surfactant and water for injection; Wherein the weight ratio of gemcitabine or its salt, oil for injection, surfactant is 1: 10～100: 10～100, and the mean diameter of emulsion droplet is 1～100nm in the Emulsion.
2. gemcitabine according to claim 1 or its salt nano-emulsion injection is characterized in that said injection is an oil-in-water type, and wherein the weight ratio of gemcitabine or its salt, oil for injection, surfactant is 1: 20～50: 10～20.
3. gemcitabine according to claim 1 or its salt nano-emulsion injection is characterized in that the salt of said gemcitabine is hydrochlorate.
4. gemcitabine according to claim 1 or its salt nano-emulsion injection is characterized in that said oil for injection is selected from one or more in mineral oil, vegetable oil, animal oil or the artificial oil; Said vegetable oil is selected from one or more in soybean oil, Oleum Arachidis hypogaeae semen, Semen Maydis oil, Oleum sesami, safflower oil, Oleum Ricini, Petiolus Trachycarpi oil, Oleum Gossypii semen, Oleum Cocois, the medium-chain fatty acid triglyceride, one or more in preferred soybean oil, Oleum Arachidis hypogaeae semen, Oleum sesami or the medium-chain fatty acid triglyceride; Said animal oil is selected from fish oil, sperm oil or its mixture.
5. gemcitabine according to claim 1 or its salt nano-emulsion injection is characterized in that said surfactant is selected from phospholipid, nonionic surfactant or its mixture.
6. gemcitabine according to claim 5 or its salt nano-emulsion injection is characterized in that said phospholipid is selected from lecithin, fabaceous lecithin or its mixture, preferably lecithin or fabaceous lecithin; Said non-ionic surface active agent is selected from polyoxyethylene and polyethylene glycols non-ionic surface active agent; Said polyoxyethylene non-ionic surface active agent is selected from polysorbas20, polysorbate40, polysorbate60, Tween 80, polysorbate85, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, poloxamer 188 or its mixture; Preferred Tween 80 or poloxamer 188, said polyethylene glycols non-ionic surface active agent is selected from Pegylation and gathers hexadecane cyanoacrylate, Polyethylene Glycol stearic acid, Polyethylene Glycol vitamin e succinate or its mixture.
7. according to any described gemcitabine of claim 1-6 or its salt nano-emulsion injection, it is characterized in that the mean diameter of emulsion droplet is 1～70nm in the said Emulsion, preferred 1～50nm, more preferably 1～20nm.
8. according to any described gemcitabine of claim 1-5 or its salt nano-emulsion injection, it is characterized in that, also comprise in antioxidant or the stabilizing agent one or more.
9. gemcitabine according to claim 8 or its salt nano-emulsion injection; It is characterized in that; Said antioxidant is selected from water solublity antioxidant or oil-soluble antioxidant, and wherein water solublity antioxidant is selected from sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium ascorbate, L-cysteine or its mixture; Oil-soluble antioxidant is selected from BHA, BHT, vitamin E, ascorbyl palmitate or its mixture, and wherein said antioxidant accounts for 0%～1w/v% of injection.
10. gemcitabine according to claim 8 or its salt nano-emulsion injection; It is characterized in that; Said stabilizing agent is selected from oleic acid, enuatrol, cholic acid, sodium cholate, dextran-70, deoxycholic acid, sodium deoxycholate or its mixture, 0%～1.5w/v% of wherein said stabilizer comprises injection.
11. a method for preparing the described gemcitabine of above-mentioned any claim or its salt nano-emulsion injection comprises the steps:
Under inert gas shielding, oil for injection is stirred into oil phase;
Surfactant is added proper amount of water for injection, be stirred into water;
Under the high-speed stirred, oil phase is mixed with water evenly, and process colostrum through the high pressure homogenizer homogenize;
Add gemcitabine or its salt to first Ruzhong;
Regulating pH value is 4～9, continues to add water and is settled to full dose, fully stirs or makes the emulsion droplet mean diameter meet the requirements of nanorize through the high pressure homogenizer homogenize.
12. a method for preparing the described gemcitabine of above-mentioned any claim or its salt nano-emulsion injection comprises the steps:
Under inert gas shielding, oil for injection, oil-soluble antioxidant are stirred into oil phase;
Water solublity antioxidant stabilizers and surfactant are added in the proper amount of water for injection, be stirred into water;
Under high-speed stirred, oil phase is mixed with water evenly, and process colostrum through the high pressure homogenizer homogenize;
Add gemcitabine or its salt to first Ruzhong;
Regulate pH value 4～9. continue to add water to be settled to full dose, fully stir or meet the requirements of nanorize through high pressure homogenization machine homogenize to emulsion droplet mean diameter.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201210088549 CN102600077B (en) | 2012-03-29 | 2012-03-29 | Gemcitabine or gemcitabine salt nano-emulsion injecta and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201210088549 CN102600077B (en) | 2012-03-29 | 2012-03-29 | Gemcitabine or gemcitabine salt nano-emulsion injecta and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102600077A true CN102600077A (en) | 2012-07-25 |
| CN102600077B CN102600077B (en) | 2013-06-05 |
Family
ID=46518108
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201210088549 Active CN102600077B (en) | 2012-03-29 | 2012-03-29 | Gemcitabine or gemcitabine salt nano-emulsion injecta and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102600077B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103830177A (en) * | 2014-03-05 | 2014-06-04 | 王栾秋 | Gemcitabine hydrochloride injection and preparation method thereof |
| CN104208087A (en) * | 2014-09-17 | 2014-12-17 | 句容亿格纳米材料厂 | Paclitaxel composite nano-emulsion and preparation method thereof |
| CN105030682A (en) * | 2015-06-24 | 2015-11-11 | 广州复大医疗股份有限公司复大肿瘤医院 | Nanometer particle colloid, method for preparing same and application of nanometer particle colloid |
| WO2016062288A1 (en) * | 2014-10-24 | 2016-04-28 | 朗齐生物医学股份有限公司 | Uses of metabolic disease medicament for preparing cancer-inhibiting pharmaceutical composition |
| CN107260752A (en) * | 2017-05-25 | 2017-10-20 | 广东工业大学 | A kind of pharmaceutical composition of collaboration anti-pancreatic cancer |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1650883A (en) * | 2005-01-17 | 2005-08-10 | 黄家章 | Jixitabing hydrochloride solution type injection agent |
| CN101244036A (en) * | 2008-03-28 | 2008-08-20 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | High dispersion does type containing cholesterol group phosphoryl nucleoside analogue |
| WO2010045292A2 (en) * | 2008-10-15 | 2010-04-22 | The University Of North Carolina At Chapel Hill | Nanoparticle compositions comprising liquid oil cores |
| CN101904814A (en) * | 2009-06-04 | 2010-12-08 | 上海恒瑞医药有限公司 | Preparation method of drug loaded emulsion |
| WO2011062503A1 (en) * | 2009-11-20 | 2011-05-26 | Clavis Pharma As | Parenteral formulations of gemcitabine derivatives |
-
2012
- 2012-03-29 CN CN 201210088549 patent/CN102600077B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1650883A (en) * | 2005-01-17 | 2005-08-10 | 黄家章 | Jixitabing hydrochloride solution type injection agent |
| CN101244036A (en) * | 2008-03-28 | 2008-08-20 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | High dispersion does type containing cholesterol group phosphoryl nucleoside analogue |
| WO2010045292A2 (en) * | 2008-10-15 | 2010-04-22 | The University Of North Carolina At Chapel Hill | Nanoparticle compositions comprising liquid oil cores |
| CN101904814A (en) * | 2009-06-04 | 2010-12-08 | 上海恒瑞医药有限公司 | Preparation method of drug loaded emulsion |
| WO2011062503A1 (en) * | 2009-11-20 | 2011-05-26 | Clavis Pharma As | Parenteral formulations of gemcitabine derivatives |
Non-Patent Citations (2)
| Title |
|---|
| NICOLAS ANTON，等: "Reverse micelle-loaded lipid nano-emulsions: New technology fornano-encapsulation of hydrophilic materials", 《INTERNATIONAL JOURNAL OF PHARMACEUTICS》, vol. 398, 31 December 2010 (2010-12-31), pages 204 - 209 * |
| 李津明: "《现代制药技术》", 30 April 2005, article "亚微乳剂", pages: 277-280 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103830177A (en) * | 2014-03-05 | 2014-06-04 | 王栾秋 | Gemcitabine hydrochloride injection and preparation method thereof |
| CN104208087A (en) * | 2014-09-17 | 2014-12-17 | 句容亿格纳米材料厂 | Paclitaxel composite nano-emulsion and preparation method thereof |
| WO2016062288A1 (en) * | 2014-10-24 | 2016-04-28 | 朗齐生物医学股份有限公司 | Uses of metabolic disease medicament for preparing cancer-inhibiting pharmaceutical composition |
| CN105030682A (en) * | 2015-06-24 | 2015-11-11 | 广州复大医疗股份有限公司复大肿瘤医院 | Nanometer particle colloid, method for preparing same and application of nanometer particle colloid |
| CN105030682B (en) * | 2015-06-24 | 2018-02-09 | 广州复大医疗股份有限公司 | A kind of nanoparticle colloid and preparation method thereof and purposes |
| CN107260752A (en) * | 2017-05-25 | 2017-10-20 | 广东工业大学 | A kind of pharmaceutical composition of collaboration anti-pancreatic cancer |
| CN107260752B (en) * | 2017-05-25 | 2020-07-21 | 广东工业大学 | Synergistic anti-pancreatic cancer pharmaceutical composition |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102600077B (en) | 2013-06-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Guorgui et al. | Curcumin formulated in solid lipid nanoparticles has enhanced efficacy in Hodgkin's lymphoma in mice | |
| Lasa-Saracibar et al. | Lipid nanoparticles for cancer therapy: state of the art and future prospects | |
| Chu et al. | Plasma, tumor and tissue pharmacokinetics of Docetaxel delivered via nanoparticles of different sizes and shapes in mice bearing SKOV-3 human ovarian carcinoma xenograft | |
| JP6861682B2 (en) | Coenzyme Q10 (CoQ10) for intravenous administration and how to use it | |
| CN102600077B (en) | Gemcitabine or gemcitabine salt nano-emulsion injecta and preparation method thereof | |
| Galagudza et al. | Targeted drug delivery into reversibly injured myocardium with silica nanoparticles: surface functionalization, natural biodistribution, and acute toxicity | |
| JP6529527B2 (en) | Azole pharmaceutical formulations for parenteral administration and methods for their preparation and their use as treatments for diseases susceptible to azole compounds | |
| Talekar et al. | Development of PIK-75 nanosuspension formulation with enhanced delivery efficiency and cytotoxicity for targeted anti-cancer therapy | |
| Battaglia et al. | Methotrexate-loaded SLNs prepared by coacervation technique: in vitro cytotoxicity and in vivo pharmacokinetics and biodistribution | |
| Paolino et al. | Gemcitabine-loaded biocompatible nanocapsules for the effective treatment of human cancer | |
| Mukthavaram et al. | High-efficiency liposomal encapsulation of a tyrosine kinase inhibitor leads to improved in vivo toxicity and tumor response profile | |
| Hafez et al. | Nanomedicine-based approaches for improved delivery of phyto-therapeutics for cancer therapy | |
| Li et al. | Anti-tumor efficacy of folate modified PLGA-based nanoparticles for the co-delivery of drugs in ovarian cancer | |
| EP1954265A2 (en) | Compositions containing ansamycin | |
| CN102784107B (en) | Gemcitabine or salt liposome thereof, and preparation method and application thereof | |
| Sethuraman et al. | In vivo synergistic anti-tumor effect of lumefantrine combined with pH responsive behavior of nano calcium phosphate based lipid nanoparticles on lung cancer | |
| CN103976950A (en) | Adriamycin nano drug delivery system as well as preparation method and application thereof | |
| WO2012097049A2 (en) | Dna repair enzyme inhibitor nanoparticles and uses thereof | |
| Liu et al. | Intracellular target delivery of 10-hydroxycamptothecin with solid lipid nanoparticles against multidrug resistance | |
| Kuehl et al. | Inhalation delivery of topotecan is superior to intravenous exposure for suppressing lung cancer in a preclinical model | |
| Qi et al. | Berberine-10-hydroxy camptothecine-loaded lipid microsphere for the synergistic treatment of liver cancer by inhibiting topoisomerase and HIF-1α | |
| Liu et al. | Preparation and in vivo safety evaluations of antileukemic homoharringtonine-loaded PEGylated liposomes | |
| Pan et al. | Recent advances in boosting EGFR tyrosine kinase inhibitors-based cancer therapy | |
| WO2013085998A1 (en) | Therapeutic compositions and related methods of use | |
| CN102846547B (en) | Gemcitabine or its salt liposome and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee | ||
| CP01 | Change in the name or title of a patent holder |
Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Patentee after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Patentee before: Jiangsu best Pharmaceutical Co.,Ltd. Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Patentee after: Jiangsu best Pharmaceutical Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Patentee before: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. |