CN104825402B - A kind of medicinal composition for injections containing gemcitabine - Google Patents
A kind of medicinal composition for injections containing gemcitabine Download PDFInfo
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Abstract
The present invention is directed to the defects of gemcitabine bulk pharmaceutical chemicals are to moisture and unstable oxidizing condition, devises a kind of medicinal composition for injections containing gemcitabine.By adding in the polyphenol kind antioxidant of specific dosage in combination and controlling the technical method of water content in final freeze-drying prods, a kind of stability more preferably gemcitabine freeze-drying preparation for injection has been obtained.Gemcitabine freeze-drying preparation for injection preparation method of the present invention is simple, customary preparation methods production can be used, without special installation, there is easy industrialization, production efficiency is high, stability is good, the remarkable advantages such as quality controllable, there is prominent substantive distinguishing features and significant progress.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of medicinal composition for injections containing gemcitabine and its
Preparation method and purposes.
Background technology
Gemcitabine hydrochloride (Gemcitabine hydrochloride) is that one kind that nineteen eighty-three Li Lai company develops is new
Difluoronucleosides class antimetabolic tumour medicine, English name Gemcitabine, the entitled 2 '-deoxidation -2 ' of chemistry, 2 '-bis- fluorine adenosines
(β-isomers), molecular formula C9H11F2N3O4, molecular weight 263.1.Preparation compound used therefor is gemcitabine hydrochloride, point
Minor is C9H11F2N3O4HCl, and molecular weight 299.66, structural formula is as follows：
Gemcitabine mainly kills DNA synthesis (S) phase cells, and cell can also be blocked to be in progress from G1 to the S phases.It is in cell
It is interior that active diphosphate (dFdCDP) and triphosphate (dFdCTP) are converted by nucleoside kinase, inhibit the synthesis of DNA.
On the one hand, dFdCDP inhibit ribonucleotide reductase, make deoxynucleotide triphosphates necessary to synthetic DNA (including
Including dCTP) generation reduction.On the other hand, in dFdCDP and dCTP competitions incorporation DNA molecular, and the drop of intracellular dCTP concentration
It is low more to promote incorporations of the dFdCTP to DNA.After dFdCTP incorporations DNA, since archaeal dna polymerase cannot remove the dFdCTP of incorporation
And DNA chain in extension is repaired, the dFdCTP mixed in extended chain can further inhibit DNA synthesis.In addition, its can make it is chronic red
Be myelosis disease T lymphoblast like cells nuclear dna in fragment sample change, so as to cause Apoptosis.
Nineteen ninety-five South Africa, Sweden, Holland, the state approvals hydrochloride for injection gemcitabine listing such as Australia, 1996
FDA approvals are clinically used for treatment non-small cell lung cancer and the first-line treatment of cancer of pancreas, approval of import Lilly companies of China in 1999
Hydrochloride for injection gemcitabine.
Gemcitabine is treatment one of most effective first-line drug of non-small cell lung cancer, has that mechanism of action is unique, anti-knurl
It composes wide, high remission rate, extend life cycle and the advantages such as toxic reaction is low, with other chemotherapeutics without crossing drug resistant and toxic reaction
The features such as without superposition, particularly it can effectively extend the life of patient, improve quality of life of patients.At present, hydrochloride for injection is lucky
His western shore obtains extensive clinical practice in more than 100 a countries.
1998, Li Lai companies disclosed the product of its commercialized product hydrochloride for injection gemcitabine in FDA websites for the first time
Specification, and disclose the formula of product：Every bottle of gemcitabine hydrochloride containing 200mg (being represented with free alkali), 200mg mannitol and
12.5mg sodium acetates, are prepared into sterile lyophilized powder.
But gemcitabine bulk pharmaceutical chemicals and unstable, especially degrading under oxidation and alkaline condition, it is miscellaneous to generate the following two kinds
Matter, impurity A, chemical entitled, 2 '-deoxidation -2 ', 2 '-two fluorouracils, structure are as follows：
Impurity B, chemistry is entitled, and 4- amino -1- (bis- fluoro-alpha-D- erythro forms ribofuranose of 2- deoxidations -2,2-) pyrimidine -2 (1H) -
Ketone, structural formula are as follows：
Can especially degrade production impurity A under hydrolysis and acid condition.
In this regard, researcher proposes different solution methods.
Chinese patent CN102302462B discloses a kind of gemcitabine hydrochloride lyophilized formulations, by gemcitabine hydrochloride, freezes
Dry protective agent and antioxidant composition, wherein：Gemcitabine hydrochloride accounts for 20-70 parts by weight, and freeze drying protectant accounts for 15-60 weight
Part, antioxidant accounts for 0.005-0.5 parts by weight.The purpose for adding in antioxidant is the stability for further improving drug, this is specially
Antioxidant selected in profit is any one in pyrosulfurous acid hydrogen sodium, citric acid, vitamin C, L-cysteine.Burnt sulfurous
Sour hydrogen sodium is harmful to human body, has clinically reported many adverse reactions at present, is most commonly that sulphite allergy (especially
It is asthma patient), symptom is bronchial spasm, stridulates, has difficulty in breathing, pernicious laryngeal edema, and low blood pressure, shock are even dead.
In addition, there is some research reports, sulphite may chromosome and DNA be caused to damage and protein in cystine linkage
Irreversible reaction etc..
Chinese patent CN102144981A discloses a kind of gemcitabine hydrochloride lyophilized powder injection and preparation method thereof.The powder
Injection includes 20-30 parts of gemcitabine hydrochloride, 5-9 parts of mannitol, 3-10 parts of sodium acetate, 5-9 parts of lactose.Though the freeze drying powder injection
So there is the advantages of process route is simple, and freeze-drying time is short, easy to operate, it is newborn yet with adding lactose as additives
Sugar easily causes " lactose intolerance ", is especially mainly in Asia.Furthermore, it is also possible to introducing residual protein and miscellaneous sugar etc. has
The anaphylactogen that substance is brought is closed, there may be certain risks for clinical practice.
Chinese patent CN101564381A discloses a kind of gemcitabine hydrochloride lyophilized powder injection, by gemcitabine hydrochloride,
Mannitol and sodium acetate composition, wherein gemcitabine hydrochloride and mannitol weight proportion are 1: 0.5-5, gemcitabine hydrochloride and vinegar
Sour sodium weight proportion is 1: 0.01-0.1.
To sum up, the prior art is not fully solved the stability problem of gemcitabine preparation.
The content of the invention
As described above, in order to solve the stability problem of gemcitabine preparation, a kind of better Ji Xita of stability is obtained
Shore preparation.Inventor obtains a kind of composition for injection containing gemcitabine, said composition is with Ji Xita by further investigation
Shore is main ingredient ingredient, including antioxidant, frozen-dried supporting agent, cosolvent, pH adjusting agent.
Said composition can be further prepared into freeze-drying preparation for injection as follows：
1) gemcitabine hydrochloride bulk pharmaceutical chemicals is taken to crush, it is spare；
2) take the water for injection of full dose 80%, sequentially add cosolvent sodium acetate, antioxidant, frozen-dried supporting agent mannitol and
Bulk pharmaceutical chemicals gemcitabine hydrochloride, stirring, makes dissolving；
3) using 0.1M hydrochloric acid and sodium hydroxide as pH adjusting agent, pH value of solution is adjusted to 2.5-3.5, and is settled to full dose；
4) 0.2% needle-use activated carbon, insulated and stirred 30 minutes are added in into step 3) acquired solution；
5) step 4) acquired solution is taken, with 0.45um filters, is filtered, twice；
6) step 5) acquired solution is taken, pours into appropriate volumetric control bottle, partly jumps a queue, for lyophilized preceding preparation；
7) preparation before step 6) obtained freeze-drying is taken, is inserted in freeze dryer, is freezed, removes moisture；
8) step 7) freeze-drying process terminates, and inflated with nitrogen is jumped a queue entirely, rolls lid to get gemcitabine freeze-drying preparation for injection；
It is characterized in that, the antioxidant is polyphenol compound, the gemcitabine freezes small with injection water content
In 1.0%.
Polyphenol compound refers in aromatic hydrocarbon one or more hydrogen atoms on phenyl ring and is optionally substituted by a hydroxyl group generated compound,
It is the important secondary metabolite of plant, natural polyphenol component has various biological activity, such as anti-oxidant, anti-spoke
It penetrates, anticancer, blood pressure lowering etc., very important effect is played to the health of the mankind.
Tea polyphenols also known as tea tannin, tea tannin are the general names of the polyhydroxyl phenolic compound contained in tealeaves.Wherein
Catechin compounds are the bulk composition of tea polyphenols, account for the 65%~80% of tea polyphenols total amount.Catechin compounds master
To include four kinds of epicatechin, epigallocatechin, L-Epicatechin gallate and nutgall catechin gallic acid ester
Substance.
In tea polyphenols structure there is active phenolic hydroxyl group, hydrogen donor can be used as, singlet oxygen is reduced Viability relatively low
Triplet oxygen, so as to reduce the generation of oxygen radical, and the chain reaction of free radical can be terminated, capture excessive free radical,
Therefore frequently as a kind of preferable antioxidant.Secondly, under neutral, acid condition, the phenolic hydroxyl groups of tea polyphenols easily with metal
Ion chelating, so as to prevent catalytic action of the metal ion to free radical chain reactions.Tea polyphenols and radical reaction generate compared with
For stable Phenoxy radical, so as to achieve the purpose that directly to remove free radical.
Nutgall catechin gallic acid ester (EGCG) is a kind of composition extracted from Chinese green tea, it is that green tea is main
Activity and water-soluble components, be the highest component of content in catechin, account for the 9%-13% of green tea gross weight, because with special
Stereochemical structure, EGCG has very strong antioxidation activity, and antioxidation activity is at least ascorbic more than 100 times, is
25 times of vitamin E.Structural formula is as follows：
After further research, antioxidant used in the composition for injection containing gemcitabine is confirmed not eat
Sub- catechin and gallate, and its in the composition shared mass percent be 0.3%-0.5%.
Contain gemcitabine 200mg or 1000mg in the unit-dose composition.
The composition prescription is as follows：
| Supplementary material | Specification 1 | Specification 2 |
| Gemcitabine hydrochloride (in terms of gemcitabine) | 200g | 1000g |
| Mannitol | 200g | 1000g |
| Sodium acetate | 12.5g | 62.5g |
| Nutgall catechin gallic acid ester | 2.0g | 10.0g |
| 0.1M hydrochloric acid or sodium hydroxide | In right amount | In right amount |
| It injects water to | 10000ml | 50000ml |
| pH | 2.5-3.5 | 2.5-3.5 |
| It is made altogether | 1000 | 1000 |
。
Preparation process is as follows：
1) gemcitabine hydrochloride bulk pharmaceutical chemicals is taken to crush, it is spare；
2) take the water for injection of full dose 80%, sequentially add sodium acetate, nutgall catechin gallic acid ester, mannitol and
Gemcitabine hydrochloride, stirring, makes dissolving；
3) using 0.1M hydrochloric acid and sodium hydroxide as pH adjusting agent, pH value of solution is adjusted to 2.5-3.5, and is settled to full dose；
4) 0.2% needle-use activated carbon, insulated and stirred 30 minutes are added in into step 3) acquired solution；
5) step 4) acquired solution is taken, with 0.45um filters, is filtered, twice；
6) step 5) acquired solution is taken, pours into appropriate volumetric control bottle, partly jumps a queue, for lyophilized preceding preparation；
7) preparation before step 6) obtained freeze-drying is taken, is inserted in freeze dryer, is freezed, removes moisture；
8) step 7) freeze-drying process terminates, and inflated with nitrogen is jumped a queue entirely, rolls lid to get gemcitabine freeze-drying preparation for injection, whole
Product moisture is less than 1.0%.
The advantageous effect further illustrated the present invention is tested by following.
It tests antioxidant selection and dosage determines to test
Known gemcitabine hydrochloride bulk pharmaceutical chemicals are to (60 DEG C, 10 days) stabilizations of illumination and high temperature.By gemcitabine hydrochloride raw material
Medicine；Gemcitabine hydrochloride respectively with vitamin C, sodium pyrosulfite, nutgall catechin gallic acid ester mixing, three kinds of antioxidant
Each respectively by weight percent 0.1%, 0.3%, 1.0% adds in, and first part of sample be dissolved in water for injection, latter 9 parts
Sample is dissolved separately in 0.3% hydrogen peroxide solution.Number consecutively A, B, C, D, E, F, G, H, I, J.Dissolve 1 it is small when after, respectively
It is measured by sampling, the degradation percentage of gemcitabine hydrochloride is as shown in the table：
| Sample number into spectrum | Degrading quality percentage (%) | Sample number into spectrum | Degrading quality percentage (%) |
| A(API) | 1.14 | F (0.3% is burnt sub-) | 2.81 |
| B (0.1%Vc) | 4.86 | G (1.0% is burnt sub-) | 2.20 |
| C (0.3%Vc) | 3.36 | H (0.1% does not have) | 1.56 |
| D (1.0%Vc) | 2.49 | I (0.3% does not have) | 1.21 |
| E (0.1% is burnt sub-) | 3.28 | J (1.0% does not have) | 1.08 |
。
Three kinds of antioxidant are can be seen that under the conditions of identical mass percent from more than experimental result, nutgall catechin
Gallate oxidation resistance is most strong, is embodied in H, I, other two kinds of J groups sample mass percent identical with addition resists
The sample of oxygen agent, degrading quality percentage are lower.
In H, tri- groups of samples of I, J, with the raising of antioxidant mass percent, bulk pharmaceutical chemicals degradation gradually decreases, sample I
It is almost identical with sample A with J degradation percentages, illustrate under the conditions of this two kinds of mass percent antioxidant, free oxygen is complete
It offsets, bulk pharmaceutical chemicals are unaffected.Why degrading quality percentage is higher, is because bulk pharmaceutical chemicals are unstable to aqueous solution in itself
Fixed, degradable, water content cannot be excessively high in product lyophilized formulations from another side illustration.
Therefore with this result of the test, nutgall catechin gallic acid of the mass percent for 0.3%-1.0% can be selected
Ester is added in the preparation of gemcitabine, as antioxidant to enhance its stability.For the ease of operation, about 0.5% is selected to add
Enter.
Experiment two：Freeze-drying preparation for injection prepares and detection.
Eutectic point determines；
Gemcitabine hydrochloride contains drug solns before 1 obtained freeze-drying of Example, is measured through electric-resistivity method, and eutectic point is -17.5
DEG C, due to 2 two specification pieces of embodiment 1 and embodiment, it the difference is that only that packaging material volume used is different, composition
It is identical, therefore gemcitabine hydrochloride contains drug solns before 2 obtained freeze-drying of embodiment, eutectic point is similarly -17.5 DEG C.
Lyophilized technique confirms：
This product need to below eutectic point 10 DEG C or so progress pre-freezes so that sample fully charge, carries out primary drying afterwards,
It is preliminary to remove moisture, redrying is finally carried out further to remove moisture, the final water content of this product need to reach less than 1.0%,
Therefore only need to be after identical pre-freeze and primary drying process, the appropriate time for adjusting redrying, you can sample needed for acquisition.
Lyophilized technique is as follows：
1) inlet:By gemcitabine hydrochloride drug containing solution bottle before 2 obtained freeze-drying of canned embodiment 1 and embodiment
Son is sent into freeze drying box；
2) pre-freeze：Flaggy temperature is set as -40 DEG C, treats that sample temperature drops to -35 DEG C or so, when holding 4 is small, starts true
Sky pump, drying box vacuum degree reach 20Pa, start to warm up drying；
3) it is dry for the first time：Controlling vacuum degree, flaggy temperature is set as -10 DEG C in 15-30Pa -- it 15 DEG C, slowly heats up,
When being warming up to that heat preservation 15 is small after design temperature；
4) second of drying：Flaggy temperature is set as 20 DEG C, after being slowly increased to design temperature, when maintenance 2 is small respectively, 5
Hour, 10 it is small when, 15 it is small when；
5) freeze and terminate, nitrogen, and tamponade are poured into freeze drying box.
The sample of two specification different secondary drying times obtained by above-mentioned experiment is taken, with Karl_Fischer method determination sample water
Point, it is as shown in the table：
| Specification | 2 it is small when | 5 it is small when | 10 it is small when | 15 it is small when |
| 200mg | 1.3% | 0.8% | 0.75% | 0.7% |
| 1.0g | 1.5% | 1.2% | 0.9% | 0.85% |
。
Learn that final sample water content can be controlled below 1.0% completely by this experiment.
Experiment three：Injection gemcitabine freeze-dried powder and commercially available freeze-dried powder accelerated stability contrast test
Two gauge hypodermics gemcitabine freeze-dried powder (containing packing) and commercially available Ji Xi in Example 1 and embodiment 2
His shore freeze-dried powder stores 12 months under the conditions of putting 40 DEG C ± 2 DEG C respectively (containing packaging), respectively at 0 month, January, and March, June, December,
Relevant nature is measured by sampling, obtains corresponding data, it is as shown in the table：
It can be seen from upper table data according to embodiment 1 of the present invention and 2 prescription of embodiment and technique prepared by hydrochloric acid
Gemcitabine freeze-drying preparation for injection, under acceleration conditions, after storage in 12 months, content, related substance is varied from, but
Be content more than 97%, the generation of impurity A % and impurity B % are effectively suppressed, maximum only 0.343% and 0.336%,
It corresponds, then maximum is respectively 0.670% and 0.591% for impurity A and impurity B content in commercially available product.Make us unexpected
Be 12 months when, gemcitabine content substantially lists sample beyond corresponding specification gemcitabine in sample, more than 97%, and
Corresponding commercially available product content is then less than 95%, and other maximum single miscellaneous and other total impurities contents decrease.
Gemcitabine freeze-drying preparation for injection as described above, as the ejection preparation of gemcitabine, suitable for treating not
The late period that can be performed the operation or metastatic cancer of pancreas and treatment Local advancement or Metastatic Nsclc, treatment middle and advanced stage are non-
Small Cell Lung Cancer, cancer of pancreas, carcinoma of urinary bladder, breast cancer and other entity tumors.
I.e. by the present invention prescription and technique make gemcitabine freeze-drying preparation for injection in storing process, impurity A and
The generation of impurity B is effectively suppressed, so as to the drug quality improved.So that the present invention has prominent substantive distinguishing features
And marked improvement, and with practicability.
Specific embodiment
The advantageous effect further illustrated the present invention is tested by following.But it is not limited to following embodiments, this field
Technical staff made on the basis of the present invention, equivalent substitute or the conversion of substantive content of the present invention are not departed from, also at this
Within the protection domain of invention.
The preparation of 1 200mg specification gemcitabine freeze-drying preparation for injection of embodiment
| Supplementary material | Dosage |
| Gemcitabine hydrochloride (in terms of gemcitabine) | 200g |
| Mannitol | 200g |
| Sodium acetate | 12.5g |
| Nutgall catechin gallic acid ester | 2.0g |
| 0.1M hydrochloric acid or sodium hydroxide | In right amount |
| It injects water to | 10000ml |
| pH | 2.5-3.5 |
| It is made altogether | 1000 |
。
Preparation process is as follows：
1) gemcitabine hydrochloride bulk pharmaceutical chemicals is taken to crush, it is spare；
2) take the water for injection of full dose 80%, sequentially add sodium acetate, nutgall catechin gallic acid ester, mannitol and
Gemcitabine hydrochloride, stirring, makes dissolving；
3) using 0.1M hydrochloric acid and sodium hydroxide as pH adjusting agent, pH value of solution is adjusted to 2.5-3.5, and is settled to full dose；
4) 0.2% needle-use activated carbon, insulated and stirred 30 minutes are added in into step 3) acquired solution；
5) step 4) acquired solution is taken, with 0.45um filters, is filtered, twice；
6) step 5) acquired solution is taken, pours into appropriate volumetric control bottle, partly jumps a queue, for lyophilized preceding preparation；
9) inlet：Gemcitabine hydrochloride drug containing solution bottle obtained by canned step 6) is sent into freeze drying box；
10) pre-freeze：Flaggy temperature is set as -40 DEG C, treats that sample temperature drops to -35 DEG C or so, when holding 4 is small, starts
Vacuum pump, drying box vacuum degree reach 20Pa, start to warm up drying；
11) it is dry for the first time：Controlling vacuum degree, flaggy temperature is set as -10 DEG C -15 DEG C in 15-30Pa, slowly heats up,
When being warming up to that heat preservation 15 is small after design temperature；
12) second of drying：Flaggy temperature is set as 20 DEG C, after being slowly increased to design temperature, when maintenance 5 is small；
13) freeze and terminate, nitrogen, and tamponade are poured into freeze drying box, prick aluminium lid.
The preparation of embodiment 21000mg specification gemcitabine freeze-drying preparation for injection
| Supplementary material | Dosage |
| Gemcitabine hydrochloride (in terms of gemcitabine) | 1000g |
| Mannitol | 1000g |
| Sodium acetate | 62.5g |
| Nutgall catechin gallic acid ester | 10.0g |
| 0.1M hydrochloric acid or sodium hydroxide | In right amount |
| It injects water to | 50000ml |
| pH | 2.5-3.5 |
| It is made altogether | 1000 |
。
Preparation process is as follows：
1) gemcitabine hydrochloride bulk pharmaceutical chemicals is taken to crush, it is spare；
2) take the water for injection of full dose 80%, sequentially add sodium acetate, nutgall catechin gallic acid ester, mannitol and
Gemcitabine hydrochloride, stirring, makes dissolving；
3) using 0.1M hydrochloric acid and sodium hydroxide as pH adjusting agent, pH value of solution is adjusted to 2.5-3.5, and is settled to full dose；
4) 0.2% needle-use activated carbon, insulated and stirred 30 minutes are added in into step 3) acquired solution；
5) step 4) acquired solution is taken, with 0.45um filters, is filtered, twice；
6) step 5) acquired solution is taken, pours into appropriate volumetric control bottle, partly jumps a queue, for lyophilized preceding preparation；
9) inlet：Gemcitabine hydrochloride drug containing solution bottle obtained by canned step 6) is sent into freeze drying box；
10) pre-freeze：Flaggy temperature is set as -40 DEG C, treats that sample temperature drops to -35 DEG C or so, when holding 4 is small, starts
Vacuum pump, drying box vacuum degree reach 20Pa, start to warm up drying；
11) it is dry for the first time：Controlling vacuum degree, flaggy temperature is set as -10 DEG C in 15-30Pa -- it 15 DEG C, slowly heats up,
When being warming up to that heat preservation 15 is small after design temperature；
12) second of drying：Flaggy temperature is set as 20 DEG C, after being slowly increased to design temperature, when maintenance 10 is small；
13) freeze and terminate, nitrogen, and tamponade are poured into freeze drying box, prick aluminium lid.
Claims (4)
1. a kind of medicinal composition for injections containing gemcitabine, said composition is frozen by main ingredient ingredient gemcitabine, antioxidant
Dry supporting agent mannitol, cosolvent sodium acetate, pH adjusting agent composition are further prepared into injection and freeze system as follows
Agent：
1) gemcitabine hydrochloride bulk pharmaceutical chemicals is taken to crush, it is spare；
2) water for injection of full dose 80% is taken, sequentially adds cosolvent sodium acetate, antioxidant, frozen-dried supporting agent mannitol and raw material
Medicine gemcitabine hydrochloride, stirring, makes dissolving；
3) using 0.1M hydrochloric acid and sodium hydroxide as pH adjusting agent, pH value of solution is adjusted to 2.5-3.5, and is settled to full dose；
4) 0.2% needle-use activated carbon, insulated and stirred 30 minutes are added in into step 3) acquired solution；
5) step 4) acquired solution is taken, with 0.45 μm of filter, is filtered, twice；
6) step 5) acquired solution is taken, pours into appropriate volumetric control bottle, partly jumps a queue, for lyophilized preceding preparation；
7) preparation before step 6) obtained freeze-drying is taken, is inserted in freeze dryer, is freezed, removes moisture；
8) step 7) freeze-drying process terminates, and inflated with nitrogen is jumped a queue entirely, rolls lid to get gemcitabine freeze-drying preparation for injection；
It is characterized in that, the antioxidant is nutgall catechin gallic acid ester, shared mass percent is in the composition
0.3%-0.5%, the gemcitabine is freezed is less than 1.0% with injection water content.
2. the medicinal composition for injections containing gemcitabine as described in claim 1, it is characterised in that pass through following prescription
It is prepared into freeze-drying composition for injection：
3. the medicinal composition for injections containing gemcitabine as described in claim 1-2 is any, it is characterised in that by such as
Lower step is prepared into freeze-drying composition for injection：
1) gemcitabine hydrochloride bulk pharmaceutical chemicals is taken to crush, it is spare；
2) water for injection of full dose 80% is taken, sequentially adds sodium acetate, nutgall catechin gallic acid ester, mannitol and hydrochloric acid
Gemcitabine, stirring, makes dissolving；
3) using 0.1M hydrochloric acid and sodium hydroxide as pH adjusting agent, pH value of solution is adjusted to 2.5-3.5, and is settled to full dose；
4) 0.2% needle-use activated carbon, insulated and stirred 30 minutes are added in into step 3) acquired solution；
5) step 4) acquired solution is taken, with 0.45 μm of filter, is filtered, twice；
6) step 5) acquired solution is taken, pours into appropriate volumetric control bottle, partly jumps a queue, for lyophilized preceding preparation；
7) preparation before step 6) obtained freeze-drying is taken, is inserted in freeze dryer, is freezed, removes moisture；
8) step 7) freeze-drying process terminates, and inflated with nitrogen is jumped a queue entirely, rolls lid to get gemcitabine freeze-drying preparation for injection, finished product
Moisture is less than 1.0%.
4. the medicinal composition for injections containing gemcitabine as described in claim 1-2 is any, it is characterised in that by such as
Lower step is prepared into freeze-drying composition for injection：
1) gemcitabine hydrochloride bulk pharmaceutical chemicals is taken to crush, it is spare；
2) water for injection of full dose 80% is taken, sequentially adds sodium acetate, nutgall catechin gallic acid ester, mannitol and hydrochloric acid
Gemcitabine, stirring, makes dissolving；
3) using 0.1M hydrochloric acid and sodium hydroxide as pH adjusting agent, pH value of solution is adjusted to 2.5-3.5, and is settled to full dose；
4) 0.2% needle-use activated carbon, insulated and stirred 30 minutes are added in into step 3) acquired solution；
5) step 4) acquired solution is taken, with 0.45 μm of filter, is filtered, twice；
6) step 5) acquired solution is taken, pours into appropriate volumetric control bottle, partly jumps a queue, for lyophilized preceding preparation；
7) inlet：Gemcitabine hydrochloride drug containing solution bottle obtained by canned step 6) is sent into freeze drying box；
8) pre-freeze：Flaggy temperature is set as -40 DEG C, treats that sample temperature drops to -35 DEG C or so, when holding 4 is small, starts vacuum
Pump, drying box vacuum degree reach 20Pa, start to warm up drying；
9) it is dry for the first time：Controlling vacuum degree, flaggy temperature is set as -10 DEG C -15 DEG C in 15-30Pa, slowly heats up, is warming up to
When heat preservation 15 is small after design temperature；
10) second of drying：Flaggy temperature is set as 20 DEG C, after being slowly increased to design temperature, when maintenance 5 is small；
11) freeze and terminate, nitrogen, and tamponade are poured into freeze drying box, prick aluminium lid.
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| CN201810050733.4A CN108066291A (en) | 2015-04-23 | 2015-04-23 | Gemcitabine pharmaceutical composition |
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| CN108440625A (en) * | 2018-04-18 | 2018-08-24 | 日照市普达医药科技有限公司 | A kind of Difluoronucleosides class antimetabolite anticarcinogen destroying cellular replication |
| CN109464403A (en) * | 2018-12-07 | 2019-03-15 | 江苏瑾辉生物科技有限公司 | Theaflavih digallate (TFDG) monomer freeze drying powder injection and preparation method thereof |
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| CN102144981B (en) * | 2011-04-07 | 2013-02-27 | 海南锦瑞制药股份有限公司 | Gemcitabine hydrochloride lyophilized powder injection and preparation method thereof |
| TW201532621A (en) * | 2013-04-22 | 2015-09-01 | Neocutis Sa | Antioxidant compositions and methods of using the same |
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| CN1714792A (en) * | 2004-06-28 | 2006-01-04 | 萧树东 | Composition of epigallocatechin, gallate and folic acid and its use |
| CN101669920A (en) * | 2008-09-10 | 2010-03-17 | 阜宁怀仁生物有限公司 | Strong anti-oxidation DHA microcapsule and preparation method thereof |
| CN101564381A (en) * | 2009-06-05 | 2009-10-28 | 江苏奥赛康药业有限公司 | Gemcitabine hydrochloride lyophilized powder injection |
| CN102793677A (en) * | 2011-05-27 | 2012-11-28 | 重庆莱美药业股份有限公司 | Method for preparing gemcitabine hydrochloride lyophilized powder |
| CN102302462A (en) * | 2011-09-08 | 2012-01-04 | 上海希迪制药有限公司 | Gemcitabine hydrochloride lyophilized preparation |
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| CN108066291A (en) | 2018-05-25 |
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