CN103212059A - Composition containing antifungal drug and lactate buffering liquid - Google Patents
Composition containing antifungal drug and lactate buffering liquid Download PDFInfo
- Publication number
- CN103212059A CN103212059A CN2012104475763A CN201210447576A CN103212059A CN 103212059 A CN103212059 A CN 103212059A CN 2012104475763 A CN2012104475763 A CN 2012104475763A CN 201210447576 A CN201210447576 A CN 201210447576A CN 103212059 A CN103212059 A CN 103212059A
- Authority
- CN
- China
- Prior art keywords
- caspofungin
- pharmaceutical composition
- compositions
- pharmaceutically acceptable
- preferred
- 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.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 81
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 title claims abstract description 24
- 230000003139 buffering effect Effects 0.000 title abstract 3
- 239000007788 liquid Substances 0.000 title abstract 3
- 239000003429 antifungal agent Substances 0.000 title description 3
- 108010020326 Caspofungin Proteins 0.000 claims abstract description 81
- 229960003034 caspofungin Drugs 0.000 claims abstract description 49
- 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 48
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 35
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 24
- 239000000872 buffer Substances 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 229930006000 Sucrose Natural products 0.000 claims description 13
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 13
- 239000005720 sucrose Substances 0.000 claims description 13
- 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 12
- 229930195725 Mannitol Natural products 0.000 claims description 12
- 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 12
- 239000004310 lactic acid Substances 0.000 claims description 12
- 235000014655 lactic acid Nutrition 0.000 claims description 12
- 239000000594 mannitol Substances 0.000 claims description 12
- 235000010355 mannitol Nutrition 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 8
- 239000008176 lyophilized powder Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 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 7
- 239000000600 sorbitol Substances 0.000 claims description 7
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 4
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 206010017533 Fungal infection Diseases 0.000 claims description 3
- 208000031888 Mycoses Diseases 0.000 claims description 3
- 102000009027 Albumins Human genes 0.000 claims description 2
- 108010088751 Albumins Proteins 0.000 claims description 2
- 229930091371 Fructose Natural products 0.000 claims description 2
- 239000005715 Fructose Substances 0.000 claims description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 2
- 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 claims description 2
- 229920001612 Hydroxyethyl starch Polymers 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- 235000001014 amino acid Nutrition 0.000 claims description 2
- 150000001413 amino acids Chemical class 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 239000008121 dextrose Substances 0.000 claims description 2
- 230000002496 gastric effect Effects 0.000 claims description 2
- 229940027278 hetastarch Drugs 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- 241001289435 Astragalus brachycalyx Species 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- 235000002917 Fraxinus ornus Nutrition 0.000 claims 1
- 235000015598 salt intake Nutrition 0.000 claims 1
- 239000007857 degradation product Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 230000007423 decrease Effects 0.000 abstract 1
- 238000004321 preservation Methods 0.000 abstract 1
- 229960000730 caspofungin acetate Drugs 0.000 description 32
- 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 32
- 239000012535 impurity Substances 0.000 description 22
- 239000000243 solution Substances 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 235000011121 sodium hydroxide Nutrition 0.000 description 8
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 7
- 239000008351 acetate buffer Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000006260 foam Substances 0.000 description 7
- 238000004108 freeze drying Methods 0.000 description 7
- 230000007062 hydrolysis Effects 0.000 description 7
- 238000006460 hydrolysis reaction Methods 0.000 description 7
- 239000012982 microporous membrane Substances 0.000 description 7
- 238000012856 packing Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 230000015556 catabolic process Effects 0.000 description 6
- 238000006731 degradation reaction Methods 0.000 description 6
- 238000003556 assay Methods 0.000 description 5
- 238000005070 sampling Methods 0.000 description 5
- 238000009472 formulation Methods 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- 229920001503 Glucan Polymers 0.000 description 2
- 239000000337 buffer salt Substances 0.000 description 2
- 229940126601 medicinal product Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- OLXIURNGEYFIGA-UPNFTXAFSA-N CCC(C)CC(C)CCCCCCCCC(NC(C[C@H]([C@@H](NCCN)NC([C@H]([C@H](CC1)O)N1C([C@H]([C@@H](CCN)O)NC(C([C@H]([C@H](C)c(cc1)ccc1O)O)NC([C@H](C[C@H](C1)O)N1C([C@H]([C@@H](C)O)N1)=O)=O)=O)=O)=O)O)C1=O)=O Chemical compound CCC(C)CC(C)CCCCCCCCC(NC(C[C@H]([C@@H](NCCN)NC([C@H]([C@H](CC1)O)N1C([C@H]([C@@H](CCN)O)NC(C([C@H]([C@H](C)c(cc1)ccc1O)O)NC([C@H](C[C@H](C1)O)N1C([C@H]([C@@H](C)O)N1)=O)=O)=O)=O)=O)O)C1=O)=O OLXIURNGEYFIGA-UPNFTXAFSA-N 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- -1 Caspofungin chemical compound Chemical class 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 108010049047 Echinocandins Proteins 0.000 description 1
- 241001136487 Eurotium Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 229960003942 amphotericin b Drugs 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- 230000009477 glass transition Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
- 238000004383 yellowing Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention relates to a drug composition, containing caspofungin or pharmaceutically acceptable salts thereof, and a lactate buffering liquid in a pharmaceutically acceptable amount. By addition of the lactate buffering liquid, the composition greatly decreases generation of caspofungin degradation product, greatly raises stability of caspofungin, and is convenient for preservation and clinic usage, thereby raising usage security of caspofungin.
Description
Technical field
The present invention relates to treat and/or prevent the pharmaceutical composition of fungal infection, it comprises Caspofungin or its officinal salt and lactate buffer.
Background technology
Caspofungin has following structural formula,
It belongs to the antifungal agent of azacyclo-six peptides of echinocandin class, and its preparation method is at US5378804 (ZL94191487.9), US5552521, and US595230, US6136783, CN101305018A, CN101792486A is described and discloses.Caspofungin can suppress the synthetic of β-(1,3)-D-glucosan, and this is then not have β-(1,3)-D-glucosan in the cell of a kind of fundamental component mammal of many filamentous fungis and yeast cell wall.Caspofungin has antibacterial activity to pathogenic Eurotium of many kinds and Candida fungus, and effective to the fungus of anti-amphotericin B and fluconazol.
Caspofungin chemical compound itself is highly unstable, can degrade in every way, and described mode includes, but is not limited to hydrolysis, dimerization and oxidation.Because the unstability of Caspofungin for long-time stability and the medication stability that guarantees Caspofungin, needs a kind of technical scheme and preparation thereof that can guarantee that Caspofungin is stable of exploitation, with the generation of the unwanted degradation product of minimizing of trying one's best.
Disclosed the Pharmaceutical composition that contains acetate buffer of Caspofungin among patent ZL97195514.X or the US6136783, think and prolonged the storage life of compositions because of having used acetate buffer to make, and the lyophilized products ratio uses the buffer of other salt more stable, contains unwanted degradation product still less,, it does not provide the data of clear and definite catabolite but disclosing some embodiment schemes, through inventor's test, this contains the Pharmaceutical composition of acetate buffer and stable inadequately.
Disclosed the use nonreducing sugar among the WO2009002481A1, as trehalose, prepare freeze-dried composition, think that the use nonreducing sugar can improve the glass transition temperature (Tg) of lyophilized powder and improve the stability of freeze-dried composition to heat, what it still used is acetate buffer, play the still acetate buffer of Stabilization, whole invention does not break away from the invention scope of patent ZL97195514.X or US6136783, and this pharmaceutical composition is also stable inadequately.
Disclosed among patent application CN101516397A or the WO2008012310A1 and used the acetic acid of minute quantity can prepare the Caspofungin pharmaceutical composition that has good stability as the pH regulator agent, still be to have adopted the acetate buffer system, invention is still at the invention scope of patent ZL97195514.X or US6136783, and this pharmaceutical composition is more more unstable than disclosed pharmaceutical composition among patent ZL97195514.X or the US6136783, can't adopt in the practice.
CN102166186A claims and has made a kind of sulfate that contains, citrate, phosphate, or Lactated Caspofungin compositions, and think that the combination that adds sorbitol or sorbitol and other excipient is for improving stability of formulation greatly, but through investigating, experimental data and practical situation differ greatly in the document, Caspofungin is extremely unstable, lyophilized powder needs to preserve down at 2-8 ℃, and meeting produces a large amount of impurity rapidly behind the redissolution contact water, and according to this application, place down for 40 ℃, commercially available Caspofungin also has good stability after redissolution, with practical situation contradiction, the inventor tests the back and finds that sorbitol not only can not improve stability of formulation, makes stability of formulation descend on the contrary.
As seen, the utmost point need be developed a kind of pharmaceutical composition of stable Caspofungin, makes it easily to preserve, and convenient clinical use improves its safety.
Summary of the invention
The inventor has found a kind of pharmaceutical composition better more stable than the Caspofungin pharmaceutical composition that contains acetate buffer that have unexpectedly, and this is fully for the beyong contemplation to existing open source literature and known technology.
Compositions of the present invention can improve the chemical stability of Caspofungin or its pharmaceutically acceptable salt, and the raising of stability can guarantee that it is as the business-like probability of medicinal product and its storage life as medicinal product of prolongation.
Pharmaceutical composition of the present invention, it contains Caspofungin or its pharmaceutically acceptable salt, also contains the lactate buffer of pharmaceutically acceptable amount.The inventor finds pleasantly surprisedly, behind the interpolation lactate buffer, can reduce the degraded of Caspofungin or its pharmaceutically acceptable salt greatly.
Described pharmaceutical composition can be injectable gastrointestinal external medicine preparation, and preferred described compositions is the lyophilized powder form.
For making the suitable injection of described pharmaceutical composition, the consumption of lactate buffer makes described pharmaceutical composition effectively obtain pH value between the 4-8, preferred 5-7, the more preferably pH value of 5.5-6.5 in the preferred pharmaceutical composition of the present invention.
In preferred embodiments, pharmaceutical composition of the present invention also contains the excipient of pharmaceutically acceptable amount, and described excipient does not contain sorbitol.In a preferred embodiment, described excipient is selected from one or more in sodium chloride, mannitol, sucrose, fructose, xylitol, dextrose, trehalose, albumin, aminoacid, the hetastarch, preferred mannitol, sucrose or their mixture.
In a preferred embodiment, compositions of the present invention comprises a) Caspofungin or its pharmaceutically acceptable salt in the 0.1-500mg/mL of Caspofungin alkali, preferred 5-200mg/mL, more preferably 10-70mg/mL; B) lactate buffer of pharmaceutically acceptable amount effectively obtains the pH value between the 4-8, preferred 5-7, the more preferably pH value of 5.5-6.5; C) excipient of 10-200mg/mL, the excipient of preferred 30-70mg/mL.
The inventor is surprised to find, the consumption of described lactate buffer has produced comparatively significantly influence to the stability of compositions, the consumption of lactate buffer is excessive or too small, stability is all produced negative effect, and select suitable amount ranges, then can greatly improve stability, reduce the generation of related substance.In the preferred embodiment of the invention, the consumption of described lactate buffer is 10-60mM, preferred 20-60mM, more preferably 25-50mM.Usually, the material consumption that plays Stabilization is high more, and compositions should be stable more, but the inventor finds that when also continuing to increase consumption, not only the stability of compositions does not continue raising, step-down on the contrary more than 60mM.
In embodiment preferred more, compositions of the present invention comprises a) Caspofungin or its pharmaceutically acceptable salt in the 30-50mg/mL of Caspofungin alkali; B) lactic acid of 10-60mM or lactate buffer; C) excipient of 30-70mg/mL, and water.
In another preferred embodiment, compositions of the present invention comprises a) Caspofungin or its pharmaceutically acceptable salt in the 42mg/mL of Caspofungin alkali; B) lactic acid of 25-50mM or lactate buffer; C) sucrose of 30mg/mL, the mannitol of 20mg/mL, and water.
In preferred embodiments, the pharmaceutically acceptable salt of Caspofungin is oxalic acid Caspofungin (or claiming caspofungin acetate) in the pharmaceutical composition of the present invention.
The present invention provides above-mentioned pharmaceutical composition to be used for the treatment of or to prevent purposes on the medicine of fungal infections in mannals in preparation on the other hand.
The present invention also provides above-mentioned preparation of drug combination method method, and this method comprises the following steps, and is a) that excipient and lactic acid is soluble in water; B) add and dissolving Caspofungin or its pharmaceutically acceptable salt, and be adjusted to required pH value with alkali; In a preferred embodiment, also comprise the cryodesiccated step of described pharmaceutical composition.
The specific embodiment
Following examples are in order to set forth invention, and limit the scope of the invention never in any form.
Embodiment 1(contrast)
The compositions 1 for preparing caspofungin acetate according to the embodiment 1 of ZL97195514.X.
The mannitol of 2g and the sucrose of 3g are joined in the volumetric flask of 100ml, add about 70ml water, the dissolving back adds the acetic acid solution 2mL mix homogeneously of 75mg/mL, adds the caspofungin acetate (being equivalent to the 4.2g Caspofungin) of 4.66g afterwards, jolting makes it dissolving gently, avoids producing foam.Use the pH of the sodium hydrate regulator solution of 1mol/mL to add water to final volume then then and be 100mL to 6.0..After using the 0.22um filtering with microporous membrane, divide the 10mL cillin bottle of packing into, carry out lyophilization, prepare the lyophilized cake of caspofungin acetate according to 1.3mL/vial.
Embodiment 2(contrast)
The compositions 2 that does not add the caspofungin acetate of buffer salt.
The mannitol of 2g and the sucrose of 3g are joined in the volumetric flask of 100ml, add about 70ml water, stirring and dissolving adds the caspofungin acetate (being equivalent to the 4.2g Caspofungin) of 4.66g afterwards, and jolting makes it dissolving gently, avoids producing foam.Adding water to final volume then is 100mL.After using the 0.22um filtering with microporous membrane, divide the 10mL cillin bottle of packing into, carry out lyophilization, prepare the lyophilized cake of caspofungin acetate according to 1.3mL/vial.
Embodiment 3
The Caspofungin compositions 3 that contains lactate buffer.
The mannitol of 2g and the sucrose of 3g are joined in the volumetric flask of 100ml, add about 60ml water, the dissolving back adds the lactic acid solution 10mL mix homogeneously of 22.50mg/mL, the caspofungin acetate (being equivalent to the 4.2g Caspofungin) that adds 4.66g afterwards, jolting makes it dissolving gently, avoids producing foam.Use the pH of the sodium hydrate regulator solution of 1mol/mL to add water to final volume then then and be 100mL to 6.0..After using the 0.22um filtering with microporous membrane, divide the 10mL cillin bottle of packing into, carry out lyophilization, prepare the lyophilized cake of caspofungin acetate according to 1.3mL/vial.
Embodiment 4
The sucrose of 5g is joined in the volumetric flask of 100ml, add about 60ml water, the dissolving back adds the lactic acid solution 10mL mix homogeneously of 22.50mg/mL, adds the caspofungin acetate (being equivalent to the 4.2g Caspofungin) of 4.66g afterwards, jolting makes it dissolving gently, avoids producing foam.Use the pH to 5.0 of the sodium hydrate regulator solution of 1mol/mL then, adding water to final volume then is 100mL.After using the 0.22um filtering with microporous membrane, divide the 10mL cillin bottle of packing into, carry out lyophilization, prepare the lyophilized cake of caspofungin acetate according to 1.3mL/vial.Through observing, the stability of caspofungin acetate is suitable with compositions 3 in the said composition.
Embodiment 5
The mannitol of 5g is joined in the volumetric flask of 100ml, add about 60ml water, the dissolving back adds the lactic acid solution 10mL mix homogeneously of 22.50mg/mL, adds the caspofungin acetate (being equivalent to the 4.2g Caspofungin) of 4.66g afterwards, jolting makes it dissolving gently, avoids producing foam.Use the pH to 6.0 of the sodium hydrate regulator solution of 1mol/mL then, adding water to final volume then is 100mL.After using the 0.22um filtering with microporous membrane, divide the 10mL cillin bottle of packing into, carry out lyophilization, prepare the lyophilized cake of caspofungin acetate according to 1.3mL/vial.Through observing, the stability of caspofungin acetate is suitable with compositions 3 in the said composition.
Embodiment 6
The trehalose of 5g is joined in the volumetric flask of 100ml, add about 60ml water, the dissolving back adds the lactic acid solution 10mL mix homogeneously of 22.50mg/mL, adds the caspofungin acetate (being equivalent to the 4.2g Caspofungin) of 4.66g afterwards, jolting makes it dissolving gently, avoids producing foam.Use the pH to 7.0 of the sodium hydrate regulator solution of 1mol/mL then, adding water to final volume then is 100mL.After using the 0.22um filtering with microporous membrane, divide the 10mL cillin bottle of packing into, carry out lyophilization, prepare the lyophilized cake of caspofungin acetate according to 1.3mL/vial.Through observing, the stability of caspofungin acetate is suitable with compositions 3 in the said composition.
Embodiment 7
Method by embodiment 3 prepares compositions 7,8,9,10,11, these compositionss are except that the consumption difference of lactate buffer, all the other compositions and content are all identical, wherein the pH value of compositions uses NaOH to regulate, each composition consumption unit is mg/ml, through converting, the consumption of lactate buffer is respectively 5mM, 20mM, 50mM, 60mM, 70mM in each compositions.
| Component | Compositions 7 | Compositions 8 | Compositions 9 | Compositions 10 | Compositions 11 |
| Caspofungin acetate | 46.6 | 46.6 | 46.6 | 46.6 | 46.6 |
| Mannitol | 20.0 | 20.0 | 20.0 | 20.0 | 20.0 |
| Sucrose | 30.0 | 30.0 | 30.0 | 30.0 | 30.0 |
| Lactic acid | 0.45 | 1.8 | 4.5 | 5.4 | 6.3 |
| pH | 6.0 | 6.0 | 6.0 | 6.0 | 6.0 |
Embodiment 8
Prepare compositions 12,13,14 by embodiment 3 similar methods, wherein the pH value of compositions uses NaOH to regulate, and each composition consumption unit is mg/ml.
| Component | Compositions 12 | Compositions 13 | Compositions 14 |
| Caspofungin acetate | 46.6 | 46.6 | 46.6 |
| Mannitol | 20.0 | 20.0 | - |
| Sucrose | 30.0 | - | - |
| Sorbitol | - | 30.0 | 50 |
| Lactic acid | 1.8 | 1.8 | 1.8 |
| pH | 6.6 | 6.6 | 6.6 |
Embodiment 9
Stability of solution is investigated contrast
Respectively according to compositions 3 prescriptions among 1 prescription of the compositions among the embodiment 1 and the embodiment 3, the solution of preparation caspofungin acetate, and the stability of solution under 4 ℃ and 25 ℃ of conditions is investigated in contrast, main contrast impurity L-747969, L-404339, L-404340 and total assorted variation, wherein impurity L-747969 is the main hydrolysis and the thermal degradation impurity of caspofungin acetate.
The stability of solution of compositions 1 under 4 ℃ and 25 ℃ of conditions
The stability of solution of compositions 3 under 4 ℃ and 25 ℃ of conditions
By the stability of solution comparing result of compositions 1 and compositions 3 as can be known, compositions 3 is compared than compositions 1 has better stability of solution.
Embodiment 10
With compositions 1 and compositions 3 freeze-dried powders that obtain,, store under 25 ℃ of conditions respectively at 30 ℃, and sampling regularly, sample is carried out assay determination, contrast impurity L-747969 and total assorted variation, wherein impurity L-747969 is the main hydrolysis and the thermal degradation impurity of caspofungin acetate.The results are shown in following table:
Compositions 1 and compositions 3 stability under 30 ℃ and 25 ℃ of conditions
By the stable comparing result of compositions 1 and compositions 3 as can be known, compositions 3 is compared than compositions 1 has better stability, significantly reduces the generation of impurity.
Embodiment 11
Will be according to embodiment 2(contrast) and embodiment 3 prepare the compositions 2 and compositions 3 freeze-dried powders that obtain, under 40 ℃ of conditions, store respectively, and sampling regularly, sample is carried out assay determination, contrast impurity L-747969 and total assorted variation, wherein impurity L-747969 is the main hydrolysis and the thermal degradation impurity of caspofungin acetate.The results are shown in following table:
Compositions 2 and compositions 3 stability under 40 ℃ of conditions
By the stable comparing result of compositions 2 and compositions 3 as can be known, compositions 3 is compared than compositions 2 has better stability, and the existence of lactate buffer salt can significantly reduce the generation of impurity.
Embodiment 12
Investigate contrast under the caspofungin acetate lyophilized powder preparation of different pH value and 30 ℃ of conditions
The mannitol of 2g and the sucrose of 3g are joined in the volumetric flask of 100ml, add about 60ml water, the dissolving back adds the lactic acid solution 10mL mix homogeneously of 22.50mg/mL, the caspofungin acetate (being equivalent to the 4.2g Caspofungin) that adds 4.66g afterwards, jolting makes it dissolving gently, avoids producing foam.Use the pH to 5.0 of the sodium hydrate regulator solution of 1mol/mL then.Adding water to final volume then is 100mL.After using the 0.22um filtering with microporous membrane, divide the 10mL cillin bottle of packing into, carry out lyophilization, prepare the lyophilized cake of caspofungin acetate according to 1.3mL/vial.
PH6.0,7.0,8.0 sample preparation and top identical preparation process preparation.
With the lyophilized powder that makes, under 30 ℃ of conditions, keep sample and investigate, respectively at 5 days, sampling in 10 days, sample is carried out assay determination, contrast impurity L-747969 and total assorted variation, wherein impurity L-747969 is the main hydrolysis and the thermal degradation impurity of caspofungin acetate.The results are shown in following table:
By the stable comparing result of the caspofungin acetate lyophilized powder of different pH value as can be known, in the scope of pH5.0-8.0, the existence of lactic acid or lactate buffer can guarantee the stable of caspofungin acetate and the significantly generation of minimizing impurity.
Embodiment 13
The compositions 7,8,9,10,11 that embodiment 7 is made, under 30 ℃ of conditions, store respectively, and sampling regularly, sample is carried out assay determination, contrast impurity L-747969 and total assorted variation, wherein impurity L-747969 is the main hydrolysis and the thermal degradation impurity of caspofungin acetate.
Embodiment 13
The compositions 12,13,14 that embodiment 8 is made, under 30 ℃ of conditions, store respectively, and sampling regularly, sample is carried out assay determination, contrast impurity L-747969 and total assorted variation, wherein impurity L-747969 is the main hydrolysis and the thermal degradation impurity of caspofungin acetate, in form, represent with single mixing, find that through observing the compositions 13,14 that contains sorbitol metachromatism just occurs, white lyophilized powder yellowing after placing 1 day under 30 ℃ of conditions.
Claims (14)
1. a pharmaceutical composition contains Caspofungin or its pharmaceutically acceptable salt, it is characterized in that also containing the lactate buffer of pharmaceutically acceptable amount.
2. pharmaceutical composition according to claim 1, the consumption of wherein said lactate buffer make described pharmaceutical composition effectively obtain pH value between the 4-8, the pH value of preferred 5-7, the more preferably pH value of 5.5-6.5.
3. pharmaceutical composition according to claim 1 and 2, wherein said pharmaceutical composition are injectable gastrointestinal external medicine preparations, and preferred described compositions is the lyophilized powder form.
4. pharmaceutical composition according to claim 3, the excipient that wherein also contains pharmaceutically acceptable amount, described excipient is selected from one or more in sodium chloride, mannitol, sucrose, fructose, xylitol dextrose, trehalose, albumin, aminoacid, the hetastarch, preferred mannitol, sucrose or their mixture.
5. pharmaceutical composition according to claim 3, wherein said compositions does not contain sorbitol.
6. according to claim 4 or 5 described pharmaceutical compositions, wherein Caspofungin or its pharmaceutically acceptable salt consumption are 0.1-500mg/mL in Caspofungin alkali consumption, preferred 5-200mg/mL, more preferably 10-70mg/mL.
7. pharmaceutical composition according to claim 6, wherein the consumption of lactate buffer agent is 10-60mM, preferred 20-60mM, most preferably 25-50mM.
8. pharmaceutical composition according to claim 6, wherein the consumption of excipient is 10-200mg/mL, preferred 30-70mg/mL.
9. pharmaceutical composition according to claim 8 contains Caspofungin or its pharmaceutically acceptable salt in the 30-50mg/mL of Caspofungin alkali, the lactate buffer agent of 10-60mM, the excipient of 30-70mg/mL and water.
10. pharmaceutical composition according to claim 9 contains Caspofungin or its pharmaceutically acceptable salt in the 42mg/mL of Caspofungin alkali, the lactate buffer agent of 25mM-50mM, the sucrose of 30mg/mL, the manna alcohol and water of 20mg/mL.
11. according to any described pharmaceutical composition of claim 1 to 10, wherein said Caspofungin pharmaceutically acceptable salt is the oxalic acid Caspofungin.
12. any described pharmaceutical composition of claim 1 to 11 is used for the treatment of or prevents purposes on the medicine of fungal infections in mannals in preparation.
13. prepare the method for any described pharmaceutical composition of claim 4 to 11, this method comprises the following steps:
A) excipient and lactic acid is soluble in water;
B) add and dissolving Caspofungin or its pharmaceutically acceptable salt, and be adjusted to required pH value with alkali.
14. method according to claim 13, it also comprises the cryodesiccated step of described pharmaceutical composition.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012104475763A CN103212059A (en) | 2012-01-18 | 2012-11-09 | Composition containing antifungal drug and lactate buffering liquid |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210015959 | 2012-01-18 | ||
| CN201210015959.3 | 2012-01-18 | ||
| CN2012104475763A CN103212059A (en) | 2012-01-18 | 2012-11-09 | Composition containing antifungal drug and lactate buffering liquid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103212059A true CN103212059A (en) | 2013-07-24 |
Family
ID=48810444
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012104475763A Pending CN103212059A (en) | 2012-01-18 | 2012-11-09 | Composition containing antifungal drug and lactate buffering liquid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103212059A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1132624C (en) * | 1996-04-19 | 2003-12-31 | 麦克公司 | Compsns. comprising antifungal agent and acetate buffer |
| CN101516387A (en) * | 2006-07-26 | 2009-08-26 | 桑多斯股份公司 | Caspofungin formulations |
| CN102166186A (en) * | 2011-04-18 | 2011-08-31 | 深圳市健元医药科技有限公司 | More stable nitrogen heterocyclic peptide preparation |
| CN103118663A (en) * | 2010-09-20 | 2013-05-22 | 赛利亚医药公司 | Caspofungin composition |
-
2012
- 2012-11-09 CN CN2012104475763A patent/CN103212059A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1132624C (en) * | 1996-04-19 | 2003-12-31 | 麦克公司 | Compsns. comprising antifungal agent and acetate buffer |
| CN101516387A (en) * | 2006-07-26 | 2009-08-26 | 桑多斯股份公司 | Caspofungin formulations |
| CN103118663A (en) * | 2010-09-20 | 2013-05-22 | 赛利亚医药公司 | Caspofungin composition |
| CN102166186A (en) * | 2011-04-18 | 2011-08-31 | 深圳市健元医药科技有限公司 | More stable nitrogen heterocyclic peptide preparation |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102614491B (en) | Pharmaceutical composition containing echinocandin antifungal agent micafungin, its preparation method and application | |
| JP5914486B2 (en) | Caspofungin composition | |
| JP2019214592A (en) | Formulations of bendamustine | |
| CN105434373A (en) | Oxiracetam freeze-drying preparation for injection and preparation method thereof | |
| CN101500571A (en) | Stable lyophilized formulation | |
| CN111375057B (en) | Pharmaceutical formulation comprising anti-Her 2 monoclonal antibody | |
| CN102247319B (en) | Thymalfasin-containing medicinal composition and preparation method thereof | |
| CN102614492B (en) | Liquid pharmaceutical composition containing echinocandin antifungal agent micafungin | |
| CN103212058A (en) | Composition containing antifungal drug and lactate buffering agent | |
| CN102302462B (en) | Gemcitabine hydrochloride lyophilized preparation | |
| CN103212059A (en) | Composition containing antifungal drug and lactate buffering liquid | |
| CN102648978B (en) | Stable protein pharmaceutical preparation and preparation method thereof | |
| CN103330933B (en) | Pharmaceutical composition containing MFG or its salt | |
| CN102274171A (en) | Oxaliplatin injection | |
| CN102357081A (en) | Composite fat-soluble vitamin freeze-dried powder injection and preparation method thereof | |
| CN101780084A (en) | Injection composition using levo leucovorin or salt thereof as major ingredients | |
| JP6179939B2 (en) | Method for reducing viscosity of high-concentration gamma globulin preparation | |
| CN103330932B (en) | The pharmaceutical composition of a kind of MFG or its salt | |
| CN102772373B (en) | A kind of injection vinorelbine tartrate injectable powder and preparation method thereof | |
| JP6204349B2 (en) | Injectable composition | |
| CN101190213A (en) | A kind of docetaxel injection and preparation method thereof | |
| JPH0321252A (en) | Cysplatin high tension liquid | |
| AU2013290827B2 (en) | Injectable antibiotic formulations and their methods of use | |
| CN103845725A (en) | Relatively stable caspofungin composition | |
| CN102512659A (en) | Medicinal composition containing echinocandin antifungal agent and its preparing method and its use |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20130724 |