CN102166186A - More stable nitrogen heterocyclic peptide preparation - Google Patents
More stable nitrogen heterocyclic peptide preparation Download PDFInfo
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- CN102166186A CN102166186A CN2011100969971A CN201110096997A CN102166186A CN 102166186 A CN102166186 A CN 102166186A CN 2011100969971 A CN2011100969971 A CN 2011100969971A CN 201110096997 A CN201110096997 A CN 201110096997A CN 102166186 A CN102166186 A CN 102166186A
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- Prior art keywords
- caspofungin
- sodium
- injection
- mixture
- preparation compositions
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- 238000002360 preparation method Methods 0.000 title claims abstract description 45
- 229910052757 nitrogen Inorganic materials 0.000 title 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 title 1
- 108090000765 processed proteins & peptides Proteins 0.000 title 1
- 108010020326 Caspofungin Proteins 0.000 claims abstract description 42
- 239000000203 mixture Substances 0.000 claims abstract description 39
- 229960003034 caspofungin Drugs 0.000 claims abstract description 37
- JYIKNQVWKBUSNH-WVDDFWQHSA-N caspofungin Chemical compound C1([C@H](O)[C@@H](O)[C@H]2C(=O)N[C@H](C(=O)N3CC[C@H](O)[C@H]3C(=O)N[C@H](NCCN)[C@H](O)C[C@@H](C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCC[C@@H](C)C[C@@H](C)CC)[C@H](O)CCN)=CC=C(O)C=C1 JYIKNQVWKBUSNH-WVDDFWQHSA-N 0.000 claims abstract description 37
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims abstract description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims abstract description 4
- 229910019142 PO4 Inorganic materials 0.000 claims abstract description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims abstract description 4
- 239000010452 phosphate Substances 0.000 claims abstract description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- 230000001105 regulatory effect Effects 0.000 claims abstract description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 11
- 239000000872 buffer Substances 0.000 claims description 11
- 239000000600 sorbitol Substances 0.000 claims description 11
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 7
- 229930195725 Mannitol Natural products 0.000 claims description 7
- 239000000594 mannitol Substances 0.000 claims description 7
- 235000010355 mannitol Nutrition 0.000 claims description 7
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical group OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 6
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 6
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 6
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 4
- 229930006000 Sucrose Natural products 0.000 claims description 4
- 239000005720 sucrose Substances 0.000 claims description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 239000003963 antioxidant agent Substances 0.000 claims description 2
- 230000003078 antioxidant effect Effects 0.000 claims description 2
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 claims 4
- 229910052739 hydrogen Inorganic materials 0.000 claims 4
- 239000001257 hydrogen Substances 0.000 claims 4
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical group [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 claims 4
- 229910000342 sodium bisulfate Inorganic materials 0.000 claims 4
- 239000001509 sodium citrate Substances 0.000 claims 4
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims 4
- 239000001540 sodium lactate Substances 0.000 claims 4
- 229940005581 sodium lactate Drugs 0.000 claims 4
- 235000011088 sodium lactate Nutrition 0.000 claims 4
- 239000001488 sodium phosphate Substances 0.000 claims 4
- 229910000162 sodium phosphate Inorganic materials 0.000 claims 4
- 235000011008 sodium phosphates Nutrition 0.000 claims 4
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims 2
- 229940001447 lactate Drugs 0.000 claims 1
- 229940107285 caspofungin injection Drugs 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 5
- 239000007853 buffer solution Substances 0.000 abstract 2
- 229910021653 sulphate ion Inorganic materials 0.000 abstract 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract 1
- 239000007924 injection Substances 0.000 description 54
- 238000002347 injection Methods 0.000 description 54
- 229940090044 injection Drugs 0.000 description 53
- 238000012360 testing method Methods 0.000 description 30
- 238000002474 experimental method Methods 0.000 description 24
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- 230000036783 anaphylactic response Effects 0.000 description 8
- 208000003455 anaphylaxis Diseases 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- 230000002949 hemolytic effect Effects 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 230000008588 hemolysis Effects 0.000 description 7
- 239000003978 infusion fluid Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
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- 238000000034 method Methods 0.000 description 6
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- 229960000730 caspofungin acetate Drugs 0.000 description 5
- 229940093181 glucose injection Drugs 0.000 description 5
- 239000013558 reference substance Substances 0.000 description 5
- 210000003462 vein Anatomy 0.000 description 5
- OGUJBRYAAJYXQP-IJFZAWIJSA-N vuw370o5qe Chemical compound CC(O)=O.CC(O)=O.C1([C@H](O)[C@@H](O)[C@H]2C(=O)N[C@H](C(=O)N3CC[C@H](O)[C@H]3C(=O)N[C@H](NCCN)[C@H](O)C[C@@H](C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCC[C@@H](C)C[C@@H](C)CC)[C@H](O)CCN)=CC=C(O)C=C1 OGUJBRYAAJYXQP-IJFZAWIJSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 206010020565 Hyperaemia Diseases 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 230000004520 agglutination Effects 0.000 description 4
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- 238000001914 filtration Methods 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
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- 239000008354 sodium chloride injection Substances 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 206010015719 Exsanguination Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 206010070834 Sensitisation Diseases 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 230000000843 anti-fungal effect Effects 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
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- 238000010253 intravenous injection Methods 0.000 description 2
- 239000002932 luster Substances 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
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- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 240000006409 Acacia auriculiformis Species 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- PNRCPRFZQWTNMZ-LBMXXOTESA-N CCC(C)CC(C)CCCCCCCCC(N[C@@H](C[C@H]([C@@H](NCCN)NC([C@H]([C@H](CC1)O)N1C(C[C@@H](CCN)O)=O)=O)O)C(N[C@@H]([C@@H](C)O)C(N(C[C@@H](C1)O)[C@@]1(C(N[C@@H]([C@@H]([C@H](c(cc1)ccc1O)O)O)C(N)=O)=O)N)=O)=O)=O Chemical compound CCC(C)CC(C)CCCCCCCCC(N[C@@H](C[C@H]([C@@H](NCCN)NC([C@H]([C@H](CC1)O)N1C(C[C@@H](CCN)O)=O)=O)O)C(N[C@@H]([C@@H](C)O)C(N(C[C@@H](C1)O)[C@@]1(C(N[C@@H]([C@@H]([C@H](c(cc1)ccc1O)O)O)C(N)=O)=O)N)=O)=O)=O PNRCPRFZQWTNMZ-LBMXXOTESA-N 0.000 description 1
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- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- HCBIBCJNVBAKAB-UHFFFAOYSA-N Procaine hydrochloride Chemical compound Cl.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 HCBIBCJNVBAKAB-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
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- 239000008103 glucose Substances 0.000 description 1
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 1
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Abstract
The invention belongs to the technical field of pharmaceutical preparations and provides a caspofungin injection preparation composition. The caspofungin injection preparation composition comprises 5 to 250 mg/ml of caspofungin or pharmaceutically available salt of the caspofungin, 5 to 150 mg/ml of excipient, 10 to 250 mM of buffer solution and an appropriate amount of sodium hydroxide or hydrochloric acid of which the pH value is regulated to be between 3.0 and 8.0, wherein the buffer solution is sulphate, citrate, phosphate, lactate or a mixture of the sulphate, the citrate, the phosphate and the lactate. The caspofungin injection preparation can be stored at room temperature, so that the stability is obviously improved, and the circulation and use of medicaments are facilitated.
Description
Technical field
The present invention relates to antifungal preparation, relate in particular to a kind of more stable azepine Cyclohexapeptides class preparation.
Background technology
Caspofungin (Caspofungin), structural formula have been widely used as preparation treatment or prevention antifungal preparation shown in (I).U.S. Pat 5552521 discloses its preparation method.This chemical compound itself is very unstable, and hydrolysis, dimerization or oxidation etc. take place easily.
Before, once with tartaric acid do buffer agent with Caspofungin make lyophilized preparation keep stability, yet Caspofungin therein easily the degraded.
Granted publication number is a kind of for the Chinese patent of CN1132624C discloses makes the Caspofungin ejection preparation compositions of buffer agent with acetate, and its stability is made height of buffer agent relatively with tartaric acid, and degradation product is also less.According to the commercially available injection caspofungin acetate preparation of this patent, airtight bottled freeze-dried powder should be stored in 2 to 8 ℃; Before preparation patient's transfusion, lysate can be stored in to be kept below 25 ℃ or 25 ℃ 24 hours; The transfusion that finally is used for patient in quiet notes bag or bottle can be stored in to be kept below 25 ℃ or 25 ℃ 24 hours.And in 2 to 8 ℃ refrigerator, can keep 48 hours.Because its unstability causes the condition of storage harshness, bring hidden danger to medicine circulation, patient safety.
Summary of the invention
The objective of the invention is to overcome the deficiencies in the prior art, a kind of more stable Caspofungin ejection preparation compositions is provided.
For achieving the above object, the technical solution used in the present invention is:
A kind of Caspofungin ejection preparation compositions, comprise that it is 3.0-8.0 that the pharmaceutically available salt 5-250mg/ml of Caspofungin or its, excipient 5-150mg/ml, buffer 10-250mM and an amount of sodium hydroxide or hydrochloric acid are regulated pH value, wherein buffer agent is sulfate, citrate, phosphate, lactate or its mixture.
Beneficial effect of the present invention: can preserve under room temperature, stability significantly increases, and is beneficial to the circulation and the use of medicine.
Description of drawings
Fig. 1 influences graph of a relation for excipient content in the Caspofungin ejection preparation compositions of the present invention to the accelerated test content of material.
Fig. 2 influences graph of a relation for Caspofungin ejection preparation compositions pH value of the present invention to the accelerated test content of material.
The specific embodiment
The present invention has carried out lot of experiments for the amount of investigating excipient, pH value, the buffer salt radical ion stability influence to the injection caspofungin formulations.Verified, to fill sugar composite for two kinds and be better than a kind of filling sugar, concrete outcome is as follows: sorbitol+mannitol＞sorbitol+lactose＞sorbitol+sucrose＞sorbitol＞mannitol＞sucrose.And discover that formulation excipients is selected the mixture of sorbitol or sorbitol and other excipient for use, stability is better than former patent.The consumption experimental result of excipient is seen Fig. 1, and its optimum consumption is 40-60mg/ml.Simultaneously, the pH value scope of preparation has also been done big quantity research, the result shows that best pH scope is 5.0-7.5, and concrete experimental data is seen accompanying drawing 2.And this patent has also been done big quantity research to buffer salt radical ion kind, and the result proves that the stability order is: Na
+＞K
+＞Mg
2+＞Ca
2+
Experimentation shows that the concentration of the pharmaceutically available salt of Caspofungin or its in preparation compositions can be 5-250mg/ml, and following examples contrast with the commercially available prod for convenient, use the concentration identical with commercially available reference substance.
Below with embodiment the present invention is specifically described.
Embodiment 1
Table 1-1 embodiment 1 composite formula
| Component | Consumption |
| Caspofungin | 42mg/ml |
| Sorbitol | 30mg/ml |
| Mannitol | 20mg/ml |
| Sodium dihydrogen phosphate | 20mM |
| Sodium hydroxide | In right amount, transfer to pH to 6.6 |
Its preparation process is as follows: add 75g sorbitol, 50g mannitol, 1750ml water in the 2500ml beaker, add Caspofungin, to its final standardize solution concentration be 42mg/ml, adding sodium dihydrogen phosphate to its concentration is 20mM, and with 1NNaOH with pH regulator to 6.6.Add injection water standardize solution.Before filtration, add the 12.5g activated carbon in the injection, under agitation adsorbed pyrogen 30 minutes, decarburization is filtered.Filtrate is filtered through 0.22 μ m titanium rod filter, again through 0.22 μ m microporous filter membrane aseptic filtration.Every bottle of amount with 1.25ml is packed into the 10ml vial, lyophilization, and tamponade, Zha Gai obtains the injection caspofungin formulations.
Make 1000 of injection caspofungin formulations by embodiment 1, logical accelerated test is investigated its stability.By animal blood vessels zest, muscle irritation, haemolysis and anaphylaxis experiment, local irritation is investigated.By with the common infusion fluid compatibility, observe its outward appearance, related substance and changes of contents and investigated its stability in common infusion fluid.
Accelerated test:
Listing reference substance and the contrast of embodiment 1 sample
Respectively the batch sample of commercially available injection caspofungin acetate preparation reference substance and embodiment one being put into temperature and be 40 ± 2 ℃, relative humidity and be 75% ± 5% climatic chamber investigates, 0,1,2,3 and sampling and measuring 6 months the time, the results are shown in Table 1-2 and table 1-3 respectively.
The commercially available reference substance accelerated test of table 1-2 result
Table 1-3 tests a sample accelerated test result
By showing 1-2 and table 1-3 as can be seen, investigate 6 months through accelerated test, the injection caspofungin formulations of embodiment 1 preparation compares with the injection caspofungin acetate preparation that has gone on the market, appearance luster, pH, clarity of solution index are suitable, the impurity of the test sample of listing increases, content descends obviously, show that the Caspofungin injection that the present invention prepares can preserve under room temperature, stability increases.
Blood vessel irritation, muscle irritation, anaphylaxis and hemolytic experiment:
Blood vessel irritation:
Choose 6 of the undamaged healthy rabbits of ears, left side auricular vein injection embodiment 1 injection 1ml, capacity 5% glucose injections such as auris dextra injection, were injected 7 days continuously at every day 1 time.
During the injection, regularly observe the irritative response of auricular vein every day.Put to death rabbit on the 8th day, and got bilateral auricular vein and surrounding tissue, use formaldehyde fixed, do the conventional organization section at the injection site proximal part, light microscopic is observed down and is had or not pathological change.Observation index and criterion see Table 1-4.
Table 1-4 blood vessel irritation scoring and criterion
The result shows that the zest of rabbit auricular vein injection embodiment 1 injection compares no significant difference with 5% glucose injection.Inflammatory reactions such as the congestion of blood vessel, surrounding tissue edema are not seen in perusal.Tissue slice checks, do not see that blood vessel structure is unusual, endothelial injury, thrombosis and other pathological change.The blood vessel of its naked eyes and om observation, the cumulative score of surrounding tissue show nonirritant all less than 0.5.
Muscle irritation:
Get 6 of healthy rabbits, injection embodiment 1 injection 1ml in every rabbit left side quadriceps femoris, inject with the volume normal saline on the right side.The injection back is observed injection site muscle and is had or not reactions such as hyperemia, edema, and (the 3rd day) sacrificed by exsanguination behind the half animal 48h is vertically cut skin, and injection site, perusal both sides has or not reactions such as hyperemia, edema, and gets its tissue and do pathologic finding.Then by the irritant reaction of showing this medicine of standard evaluation among the 1-5.Remaining animal continues to observe 14d,
Repeated aforesaid operations in the 18th day after the sacrificed by exsanguination, evaluation criterion sees Table 1-5.
Table 1-5 muscular irritation reaction evaluating standard
The result shows, after injecting embodiment 1 injection in the quadriceps femoris of rabbit left side, perusal injection site muscle does not have reactions such as hyperemia, edema, and explicitly irritant reaction such as tissue degeneratiaon or necrosis are not also seen in the pathological tissue inspection, compare no significant difference with the normal saline side.
Sensitization to Cavia porcellus:
Choose 6 of healthy guinea pigs, every lumbar injection embodiment 1 injection 0.5ml, the next day, inject 1 time, injects altogether 3 times.Be divided into 2 groups then at random, after the 1st administration 14 or 21 days respectively, intravenous injection embodiment 1 injection 1ml.Observe Cavia porcellus and have or not allergic symptoms such as excited uneasiness, dyspnea.
Two groups of Cavia porcelluss of result are all movable normal, do not see adnormal respiration etc.
External hemolytic test:
Prepare 2% rabbit red cell suspension.Get 7 in test tube, 1-6 adds various liquid by table.Each test tube is shaken up gently, put in 37 ℃ of waters bath with thermostatic control and hatch, observe 0.5,1,2,3,6 hour result.Erythrocyte agglutination in vitro and hemolytic criterion see Table 1-7.
The external hemolytic test application of sample of table 1-6 sample table
Outer haemolysis of table 1-7 red cell body and agglutination test criterion
As a result, the distilled water control tube was complete hemolysis in 0.5 hour.Normal saline and each concentration of embodiment 1 sample did not all have haemolysis in 6 hours.Jolting gently, the erythrocyte of normal saline and each concentration embodiment 1 sample cell bottom sediments all can disperse fully, shows that the Caspofungin injection does not have red cell agglutination.
Blood vessel irritation, muscle irritation, external hemolytic and anaphylaxis experiment show that embodiment 1 injection does not have tangible zest, anaphylaxis, can not cause hemolytic reaction yet.
Stability experiment in the transfusion:
Injection Caspofungin with 10.5ml purified water dilution embodiment 1 preparation, draw 10ml respectively, use common infusion fluid respectively: 0.9% sodium chloride injection (0.9%NS), 5% glucose injection (5%GS), be diluted to 200ml, making Caspofungin concentration is 0.25mg/ml.Respectively at 25 ℃, minute is observed its outward appearance, impurity, changes of contents, the results are shown in Table 1-8.
Table 1-8 injection stability experiment
The result shows, the caspofungin formulations and the common infusion fluid of embodiment 1 preparation, 0.9% sodium chloride injection (0.9%NS), 5% glucose injection (5%GS) compatibility use, and stability is all better, therefore, this embodiment makes sample and can use with these compatibilities of infusing.
Embodiment 2-embodiment 10
Embodiment 2-embodiment 10 prescriptions are as following table
The preparation process of embodiment 2-embodiment 10 and embodiment's 1 is basic identical, all be in the 2500ml beaker, to add all excipient earlier, 1750ml water, adding Caspofungin to its final standardize solution concentration is 42mg/ml, add buffer salt to its concentration, and with pH regulator to 6.6, add injection water standardize solution with 1NNaOH.Wherein among the embodiment 10, benzyl alcohol and sodium thiosulfate add after adding excipient.Before filtration, add the 12.5g activated carbon in the injection, under agitation adsorbed pyrogen 30 minutes, decarburization is filtered.Filtrate is filtered through 0.22 μ m titanium rod filter, again through 0.22 μ m microporous filter membrane aseptic filtration.Every bottle of amount with 1.75ml is packed into the 10ml vial, lyophilization, and tamponade, Zha Gai obtains the injection Caspofungin.With 10.5ml purified water dilution lyophilized products, analyze experiment.
Make 1000 of injection Caspofungins by embodiment 2-embodiment 10, its stability is investigated by accelerated test.By animal blood vessels zest, muscle irritation, haemolysis and anaphylaxis experiment, local irritation is investigated.By with the common infusion fluid compatibility, observe its outward appearance, related substance and changes of contents and investigated its stability in common infusion fluid.Accelerated test:
Method by embodiment 1 is carried out accelerated test to embodiment 2-embodiment 10 gained preparation compositions respectively, the results are shown in Table 2-3～10-3.
Table 2-3 sample accelerated test result
Table 3-3 sample accelerated test result
Table 4-3 sample accelerated test result
Table 5-3 sample accelerated test result
Table 6-3 sample accelerated test result
Table 7-3 sample accelerated test result
Table 8-3 sample accelerated test result
Table 9-3 sample accelerated test result
Table 10-3 sample accelerated test result
Contrast as can be seen by table 1-2 and table 2-3～table 10-3, investigate 6 months through accelerated test, the injection caspofungin formulations of embodiment 2-embodiment 10 preparations compares with the injection caspofungin acetate preparation that has gone on the market, appearance luster, pH, clarity of solution index are suitable, the impurity of the test sample of listing increases, content descends obviously, show that the Caspofungin injection that the present invention prepares can preserve under room temperature, stability increases.Blood vessel irritation, muscle irritation, anaphylaxis and hemolytic experiment:
Blood vessel irritation:
Adopt the method identical with embodiment 1, the result shows that the zest of rabbit auricular vein injection embodiment 2～embodiment 10 injection is with 5% glucose injection comparison no significant difference.Inflammatory reactions such as the congestion of blood vessel, surrounding tissue edema are not seen in perusal.Tissue slice checks, do not see that blood vessel structure is unusual, endothelial injury, thrombosis and other pathological change.The blood vessel of its naked eyes and om observation, the cumulative score of surrounding tissue show nonirritant all less than 0.5.
Muscle irritation:
Adopt the method identical with embodiment 1, the result shows, after injecting real embodiment 2～embodiment 10 injection in the quadriceps femoris of rabbit left side, perusal injection site muscle does not have reactions such as hyperemia, edema, explicitly irritant reaction such as tissue degeneratiaon or necrosis are not also seen in the pathological tissue inspection, compare no significant difference with the normal saline side.
Sensitization to Cavia porcellus:
Adopt the method identical with embodiment 1, the result shows that behind intravenous injection embodiment 2～embodiment 10 injection, two groups of Cavia porcelluss of result are all normally movable, do not see adnormal respiration etc.
External hemolytic test:
Adopt the method identical with embodiment 1, the result, the distilled water control tube was complete hemolysis in 0.5 hour.Normal saline and each concentration of embodiment 2～embodiment 10 samples did not all have haemolysis in 6 hours.Jolting gently, the erythrocyte of normal saline and each concentration embodiment 1 sample cell bottom sediments all can disperse fully, shows that the Caspofungin injection does not have red cell agglutination.
Blood vessel irritation, muscle irritation, external hemolytic and anaphylaxis experiment show that embodiment 2～embodiment 10 injection do not have tangible zest, anaphylaxis, can not cause hemolytic reaction yet.
Stability experiment in the transfusion:
Stability experiment in respectively embodiment 2-embodiment 10 gained preparation compositions being infused by the method for embodiment 1 the results are shown in Table 2-8～10-8.
Table 1-8 injection stability experiment
Table 2-8 injection stability experiment
Table 3-8 injection stability experiment
Table 4-8 injection stability experiment
Table 5-8 injection stability experiment
Table 6-8 injection stability experiment
Table 7-8 injection stability experiment
Table 8-8 injection stability experiment
Table 9-8 injection stability experiment
Table 10-8 injection stability experiment
The above results shows, the caspofungin formulations and the common infusion fluid of embodiment 2～embodiment 10 preparations, 0.9% sodium chloride injection (0.9%NS), 5% glucose injection (5%GS) compatibility use, and stability is all better, therefore, this embodiment makes sample and can use with these compatibilities of infusing.
Commercially available injection caspofungin acetate preparation, airtight bottled freeze-dried powder should be stored in 2 to 8 ℃; Before preparation patient's transfusion, lysate can be stored in to be kept below 25 ℃ or 25 ℃ 24 hours; The transfusion that finally is used for patient in quiet notes bag or bottle can be stored in to be kept below 25 ℃ or 25 ℃ 24 hours.And in 2 to 8 ℃ refrigerator, can keep 48 hours.Because its unstability causes the condition of storage harshness, bring hidden danger to medicine circulation, patient safety.Sample stability by the above embodiment of experiment showed, 2-embodiment 10 preparations is better than commercially available reference substance, and safety is good, therefore can use for clinical injection.
Above content be in conjunction with concrete preferred implementation to further describing that the present invention did, can not assert that concrete enforcement of the present invention is confined to these explanations.For the general technical staff of the technical field of the invention, without departing from the inventive concept of the premise, make concrete change or change and all belong to protection scope of the present invention.
Claims (10)
1. Caspofungin ejection preparation compositions, it is characterized in that: comprise that it is 3.0-8.0 that the pharmaceutically available salt 5-250mg/ml of Caspofungin or its, excipient 5-150mg/ml, buffer 10-250mM and an amount of sodium hydroxide or hydrochloric acid are regulated pH value, wherein buffer agent is sulfate, citrate, phosphate, lactate or its mixture.
2. Caspofungin ejection preparation compositions according to claim 1 is characterized in that: described excipient is sorbitol, mannitol, lactose, sucrose or its mixture, and content is 40-60mg/ml.
3. Caspofungin ejection preparation compositions according to claim 2 is characterized in that: described excipient is the mixture of sorbitol or sorbitol and one of mannitol, lactose and sucrose.
4. Caspofungin ejection preparation compositions according to claim 3 is characterized in that: described excipient is the mixture of sorbitol and mannitol.
5. Caspofungin ejection preparation compositions according to claim 1 and 2 is characterized in that: described buffer agent is sodium bisulfate, sodium citrate, sodium phosphate, disodium-hydrogen, sodium dihydrogen phosphate, sodium lactate or its mixture.
6. Caspofungin ejection preparation compositions according to claim 3 is characterized in that: described buffer agent is sodium bisulfate, sodium citrate, sodium phosphate, disodium-hydrogen, sodium dihydrogen phosphate, sodium lactate or its mixture.
7. Caspofungin ejection preparation compositions according to claim 4 is characterized in that: described buffer agent is sodium bisulfate, sodium citrate, sodium phosphate, disodium-hydrogen, sodium dihydrogen phosphate, sodium lactate or its mixture.
8. Caspofungin ejection preparation compositions according to claim 1 and 2 is characterized in that: pH value is 5.0-7.5.
9. Caspofungin ejection preparation compositions according to claim 8 is characterized in that: described buffer agent is sodium bisulfate, sodium citrate, sodium phosphate, disodium-hydrogen, sodium dihydrogen phosphate, sodium lactate or its mixture.
10. Caspofungin ejection preparation compositions according to claim 1 and 2 is characterized in that: also further comprise the agent that relieves the pain of pharmaceutically available antioxidant and part.
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103212059A (en) * | 2012-01-18 | 2013-07-24 | 江苏恒瑞医药股份有限公司 | Composition containing antifungal drug and lactate buffering liquid |
| CN103212058A (en) * | 2012-01-18 | 2013-07-24 | 江苏恒瑞医药股份有限公司 | Composition containing antifungal drug and lactate buffering agent |
| CN103845725A (en) * | 2012-11-30 | 2014-06-11 | 上海医药工业研究院 | Relatively stable caspofungin composition |
| CN103911422A (en) * | 2014-04-21 | 2014-07-09 | 北京市药品检验所 | Sterility testing method of antifungal pharmaceutical preparation |
| WO2014171687A1 (en) * | 2013-04-15 | 2014-10-23 | 에스케이케미칼주식회사 | Pharmaceutical composition with improved stability comprising caspofungin and buffer agent |
| CN104116716A (en) * | 2013-04-25 | 2014-10-29 | 四川海思科制药有限公司 | Pharmaceutical composition of freeze-dried powder injection containing caspofungin |
| CN105434343A (en) * | 2016-01-06 | 2016-03-30 | 青岛辰达生物科技有限公司 | Irinotecan hydrochloride injection and preparation method thereof |
| US9636407B2 (en) | 2012-11-20 | 2017-05-02 | Fresenius Kabi Usa, Llc | Caspofungin acetate formulations |
| CN107158359A (en) * | 2017-05-26 | 2017-09-15 | 江苏恒瑞医药股份有限公司 | A kind of Caspofungin freeze-dried composition of stabilization and preparation method thereof |
| CN113368038A (en) * | 2020-03-10 | 2021-09-10 | 鲁南制药集团股份有限公司 | Caspofungin acetate injection and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103212058A (en) * | 2012-01-18 | 2013-07-24 | 江苏恒瑞医药股份有限公司 | Composition containing antifungal drug and lactate buffering agent |
| CN103212059A (en) * | 2012-01-18 | 2013-07-24 | 江苏恒瑞医药股份有限公司 | Composition containing antifungal drug and lactate buffering liquid |
| WO2014071743A1 (en) * | 2012-11-09 | 2014-05-15 | 江苏恒瑞医药股份有限公司 | Composition containing antifungal drug and lactate buffer |
| US9636407B2 (en) | 2012-11-20 | 2017-05-02 | Fresenius Kabi Usa, Llc | Caspofungin acetate formulations |
| CN103845725A (en) * | 2012-11-30 | 2014-06-11 | 上海医药工业研究院 | Relatively stable caspofungin composition |
| WO2014171687A1 (en) * | 2013-04-15 | 2014-10-23 | 에스케이케미칼주식회사 | Pharmaceutical composition with improved stability comprising caspofungin and buffer agent |
| CN104116716A (en) * | 2013-04-25 | 2014-10-29 | 四川海思科制药有限公司 | Pharmaceutical composition of freeze-dried powder injection containing caspofungin |
| CN103911422B (en) * | 2014-04-21 | 2015-06-17 | 北京市药品检验所 | Sterility testing method of antifungal pharmaceutical preparation |
| CN103911422A (en) * | 2014-04-21 | 2014-07-09 | 北京市药品检验所 | Sterility testing method of antifungal pharmaceutical preparation |
| CN105434343A (en) * | 2016-01-06 | 2016-03-30 | 青岛辰达生物科技有限公司 | Irinotecan hydrochloride injection and preparation method thereof |
| CN107158359A (en) * | 2017-05-26 | 2017-09-15 | 江苏恒瑞医药股份有限公司 | A kind of Caspofungin freeze-dried composition of stabilization and preparation method thereof |
| CN113368038A (en) * | 2020-03-10 | 2021-09-10 | 鲁南制药集团股份有限公司 | Caspofungin acetate injection and preparation method thereof |
| CN113368038B (en) * | 2020-03-10 | 2023-12-22 | 鲁南制药集团股份有限公司 | Caspofungin acetate injection and preparation method thereof |
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Application publication date: 20110831 |