CN102018953A - Pharmaceutical composition containing nocathiacin antibiotics - Google Patents
Pharmaceutical composition containing nocathiacin antibiotics Download PDFInfo
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- CN102018953A CN102018953A CN2010105481349A CN201010548134A CN102018953A CN 102018953 A CN102018953 A CN 102018953A CN 2010105481349 A CN2010105481349 A CN 2010105481349A CN 201010548134 A CN201010548134 A CN 201010548134A CN 102018953 A CN102018953 A CN 102018953A
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- nocathiacin
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- 229930187937 nocathiacin Natural products 0.000 title claims abstract description 58
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 38
- 239000003242 anti bacterial agent Substances 0.000 title abstract 3
- 229940088710 antibiotic agent Drugs 0.000 title abstract 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 45
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 33
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 32
- 239000002904 solvent Substances 0.000 claims abstract description 25
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 21
- 235000011187 glycerol Nutrition 0.000 claims abstract description 11
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 11
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 11
- 239000000126 substance Substances 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims abstract description 8
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229920001983 poloxamer Polymers 0.000 claims abstract description 7
- 229960000502 poloxamer Drugs 0.000 claims abstract description 7
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 7
- 239000003937 drug carrier Substances 0.000 claims abstract description 6
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims abstract description 5
- 239000000787 lecithin Substances 0.000 claims abstract description 5
- 235000010445 lecithin Nutrition 0.000 claims abstract description 5
- 229940067606 lecithin Drugs 0.000 claims abstract description 5
- 229920000136 polysorbate Polymers 0.000 claims abstract description 4
- 229950008882 polysorbate Drugs 0.000 claims abstract description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 3
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 3
- 239000000194 fatty acid Substances 0.000 claims abstract description 3
- 229930195729 fatty acid Natural products 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 116
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 104
- FFLJEMWVYVKPDW-UMNFMQIXSA-N chembl263049 Chemical compound O([C@H]1[C@H]2OCC3=C(N(C=4C=CC=C(C3=4)COC1=O)O)C(=O)OC[C@H]1C=3SC=C(N=3)C3=NC(=C(O)C=C3C=3SC=C(N=3)C(=O)N[C@H](C(=O)N/C(C=3SC=C(N=3)C(=O)N[C@@H]2C=2SC=C(N=2)C(=O)N1)=C(C)/OC)[C@@H](C)O)C=1SC=C(N=1)C(=O)NC(=C)C(N)=O)[C@H]1C[C@](C)(O)[C@H](N(C)C)[C@H](C)O1 FFLJEMWVYVKPDW-UMNFMQIXSA-N 0.000 claims description 64
- FFLJEMWVYVKPDW-VCUUIXPJSA-N nocathiacin I Natural products COC(=C1NC(=O)[C@@H](NC(=O)c2csc(n2)c3cc(O)c(nc3c4csc(n4)[C@@H]5COC(=O)c6c7CO[C@@H]([C@H](NC(=O)c8csc1n8)c9nc(cs9)C(=O)N5)[C@H](O[C@H]%10C[C@](C)(O)[C@@H]([C@H](C)O%10)N(C)C)C(=O)OCc%11cccc(c7%11)n6O)c%12nc(cs%12)C(=O)NC(=C)C(=O)N)[C@@H](C)O)C FFLJEMWVYVKPDW-VCUUIXPJSA-N 0.000 claims description 64
- 108010081596 nocathiacin I Proteins 0.000 claims description 64
- 239000011780 sodium chloride Substances 0.000 claims description 52
- 230000003115 biocidal effect Effects 0.000 claims description 23
- 239000003814 drug Substances 0.000 claims description 21
- 239000006184 cosolvent Substances 0.000 claims description 20
- 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 14
- 239000008103 glucose Substances 0.000 claims description 14
- 239000000758 substrate Substances 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 8
- 230000000149 penetrating effect Effects 0.000 claims description 8
- 239000000080 wetting agent Substances 0.000 claims description 8
- 239000003349 gelling agent Substances 0.000 claims description 7
- 230000035479 physiological effects, processes and functions Effects 0.000 claims description 7
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 claims description 6
- 229920001661 Chitosan Polymers 0.000 claims description 5
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 4
- JVTIXNMXDLQEJE-UHFFFAOYSA-N 2-decanoyloxypropyl decanoate 2-octanoyloxypropyl octanoate Chemical compound C(CCCCCCC)(=O)OCC(C)OC(CCCCCCC)=O.C(=O)(CCCCCCCCC)OCC(C)OC(=O)CCCCCCCCC JVTIXNMXDLQEJE-UHFFFAOYSA-N 0.000 claims description 4
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 claims description 4
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 4
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 4
- 239000005642 Oleic acid Substances 0.000 claims description 4
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 4
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- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 4
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 4
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 4
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 4
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 4
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- 235000011572 Pyrus ussuriensis Nutrition 0.000 claims description 2
- 244000173166 Pyrus ussuriensis Species 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 230000000996 additive effect Effects 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- 230000000202 analgesic effect Effects 0.000 claims description 2
- 230000002421 anti-septic effect Effects 0.000 claims description 2
- 239000000872 buffer Substances 0.000 claims description 2
- 150000004665 fatty acids Chemical class 0.000 claims description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- 235000010981 methylcellulose Nutrition 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000008213 purified water Substances 0.000 claims description 2
- 239000003381 stabilizer Substances 0.000 claims description 2
- 239000008227 sterile water for injection Substances 0.000 claims description 2
- 239000008215 water for injection Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 36
- 238000002360 preparation method Methods 0.000 abstract description 13
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- 206010059866 Drug resistance Diseases 0.000 abstract description 3
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- -1 sorbitan fatty acid Chemical class 0.000 abstract description 2
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- 229920001214 Polysorbate 60 Polymers 0.000 description 21
- 238000004128 high performance liquid chromatography Methods 0.000 description 19
- 238000001556 precipitation Methods 0.000 description 19
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- 239000007788 liquid Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 12
- 229920002582 Polyethylene Glycol 600 Polymers 0.000 description 8
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 6
- 230000000844 anti-bacterial effect Effects 0.000 description 6
- 230000008961 swelling Effects 0.000 description 6
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 5
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 5
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- 241000192125 Firmicutes Species 0.000 description 3
- 241000191967 Staphylococcus aureus Species 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 108010059993 Vancomycin Proteins 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 239000003910 polypeptide antibiotic agent Substances 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
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- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 3
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 2
- 241000193998 Streptococcus pneumoniae Species 0.000 description 2
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- 229940040371 lecithin 10 mg Drugs 0.000 description 2
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- 108010054044 nocathiacin II Proteins 0.000 description 2
- LKZVTFMHIPKLAI-UHFFFAOYSA-N nocathiacin II Natural products COC(C)=C1NC(=O)C(NC(=O)c2csc(n2)-c2cc(O)c(nc2-c2csc(n2)C2COC(=O)c3[nH]c4cccc5COC(=O)C(OC6CC(C)(O)C(C(C)O6)N(C)C)C(OCc3c45)C(NC(=O)c3csc1n3)c1nc(cs1)C(=O)N2)-c1nc(cs1)C(=O)NC(=C)C(N)=O)C(C)O LKZVTFMHIPKLAI-UHFFFAOYSA-N 0.000 description 2
- XYPCGIXYXJYRSJ-HDICTBRPSA-N nocathiacin III Natural products COC(=C1NC(=O)[C@@H](NC(=O)c2csc(n2)c3cc(O)c(nc3c4csc(n4)[C@@H]5COC(=O)c6c7CO[C@H]([C@H](O)C(=O)OCc8cccc(c78)n6O)[C@H](NC(=O)c9csc1n9)c%10nc(cs%10)C(=O)N5)c%11nc(cs%11)C(=O)NC(=C)C(=O)N)[C@@H](C)O)C XYPCGIXYXJYRSJ-HDICTBRPSA-N 0.000 description 2
- NJEUCGFXONNDPL-PIMXMZRMSA-N nocathiacin ii Chemical compound O([C@@H]1C(=O)OCC=2C=CC=C3NC=4C(=O)OC[C@H]5C=6SC=C(N=6)C6=NC(/C(=O)C=C6C=6SC=C(N=6)C(=O)N[C@H](C(=O)N/C(C=6SC=C(N=6)C(=O)N[C@@H]([C@@H]1OCC=4C3=2)C=1SC=C(N=1)C(=O)N5)=C(C)/OC)[C@@H](C)O)=C\1SC=C(N/1)C(=O)NC(=C)C(N)=O)[C@H]1C[C@](C)(O)[C@H](N(C)C)[C@H](C)O1 NJEUCGFXONNDPL-PIMXMZRMSA-N 0.000 description 2
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- DQJCDTNMLBYVAY-ZXXIYAEKSA-N (2S,5R,10R,13R)-16-{[(2R,3S,4R,5R)-3-{[(2S,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-5-(ethylamino)-6-hydroxy-2-(hydroxymethyl)oxan-4-yl]oxy}-5-(4-aminobutyl)-10-carbamoyl-2,13-dimethyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazaheptadecan-1-oic acid Chemical compound NCCCC[C@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)CC[C@H](C(N)=O)NC(=O)[C@@H](C)NC(=O)C(C)O[C@@H]1[C@@H](NCC)C(O)O[C@H](CO)[C@H]1O[C@H]1[C@H](NC(C)=O)[C@@H](O)[C@H](O)[C@@H](CO)O1 DQJCDTNMLBYVAY-ZXXIYAEKSA-N 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of pharmaceutical compositions and specially relates to a solution agent of a pharmaceutical composition containing nocathiacin antibiotics, in particular to the pharmaceutical composition containing the nocathiacin antibiotics, which comprises nocathiacin, a drug carrier and a hydrophilic substance, wherein the hydrophilic substance is selected from a latent solvent or a solubilizer; the drug carrier is a physiological dissolution medium with the pH of 4-9, the latent solvent is one or the mixture of more than two selected from ethanol, propylene glycol, glycerin or polyethylene glycol, and the solubilizer is one or the mixture of more than two selected from sorbitan fatty acid, polysorbate, polyvidone, poloxamer and lecithin. The pharmaceutical composition can significantly improve the solubility of the nocathiacin, the preparation process is safe, materials used by the pharmaceutical composition are economic, devices used for preparing the pharmaceutical composition are simple, and the process steps are few; and as the nocathiacin has significant anti-drug resistance activity, the pharmaceutical composition has important clinical application value.
Description
Technical field
The invention belongs to pharmaceutical composition, be specifically related to contain the solution and the corresponding gel thereof of the antibiotic pharmaceutical composition of Nocathiacin.
Background technology
In the history of human and disease fight, bacterial infection always is and causes human dead first killer, when using more and more antibiotic therapy disease along with people, also tempered the drug resistance ability of antibacterial, so tachytelic evolution along with antibiotic abuse and pathogenic bacteria, increasing Resistant strain has appearred clinically, the bacterial strain such as the methicillin resistant staphylococcus aureus (MRSA) that particularly multiple antibiotic are all had resistance, penicillin-fast streptococcus pneumoniae (PRSP), so that recent " superbacteria " found, people often seem at a loss what to do in the face of the quick infection rate of these class pathogenic bacterium.In addition, along with increasing gradually of the gram positive bacteria of vancomycin resistance clinically, the last-ditch status that the antibiotic of glycopeptide classes such as vancomycin is used as antimicrobial agent all the time also becomes precarious.So the medicine of seeking and develop some novel structures, active significant novel anti fastbacteria has become the focus and the difficult point of new drug research.
Nocathiacin is that a class is separated from soil and obtained, novel drug-resistance bacteria medicine with novel structure and significant antibacterial activity, he is a member of having potential applicability in clinical practice in the sulfur peptide antibiotics most (referring to J.Antibiot.2003,26:232～242).Nocathiacin has the unique chemical structure, form complex by 23S rRNA and L11 albumen with the big subunit of ribosome 50S, thereby influencing the proteinic conformation of L11 transforms, and then Profilin matter synthetic and reach powerful bactericidal action (referring to Nat Prod Rep, 1999,16 (2): 249～263).Nocathiacin is as the sulfur peptide antibiotics of latest find, in the level that is lower than μ g/ml just to most gram positive bacterias methicillin resistant staphylococcus aureus (MRSA) particularly, penicillin-fast streptococcus pneumoniae (PRSP), the enterococcus of vancomycin resistance (VRE) and have chemical sproof tubercule bacillus and superpower bactericidal activity is arranged (referring to J.Antibiot.2003,56:226～231), and there is report to point out Nocathiacin because it has unique dimethylamino sugar ring residue, thereby the mouse model of infection of staphylococcus aureus has also been presented significant curative effect (referring to Antimicrob Agents Chemother, 2004,48 (10): 3697～3701).
As the common trait of sulfur peptide antibiotics, the similar antibiotic with other of Nocathiacin is the same to have special strong-hydrophobicity multiring structure, causes the water solublity of its extreme difference, thereby has limited its medical value.In order to improve the water solublity of Nocathiacin, carried out studying at a series of chemistry and the bio-modification transformation of hydroxyl on its dehydroalanine side chain, indole and the pyridine ring in a large number, but all do not have successfully with factors such as causing safety issue because of preparing complexity (referring to: J Org Chem, 2002,67 (24): 8699～8702; J Nat Prod, 2005,68 (4): 550～553; Bioorg Med Chem Lett, 2004,14 (14): 3743～3746).So, seek the water miscible method of more effective raising Nocathiacin, have significant values and meaning to strengthening its DEVELOPMENT PROSPECT and clinical practice.
Summary of the invention
The object of the invention provides a kind of antibiotic pharmaceutical composition of Nocathiacin that contains, the material and the prescription that utilize economy to be easy to get, by simple technology, make the solution dosage or the gel dosage form of available Nocathiacin clinically, with increase Nocathiacin antibiotic dissolubility in the physiology dissolve medium, thereby solve the application limitations that its low aqueous solubility causes.
For achieving the above object, the technical solution used in the present invention is: a kind of antibiotic pharmaceutical composition of Nocathiacin that contains, comprise Nocathiacin and pharmaceutical carrier, and also comprise hydroaropic substance, described hydroaropic substance is selected from cosolvent or solubilizing agent; Described pharmaceutical carrier is the physiology dissolve medium of pH4～9; Described cosolvent is selected from: the mixture of one or more in ethanol, propylene glycol, glycerol or the Polyethylene Glycol (comprising two kinds), and content is 0%～80% of pharmaceutical composition volume; Described solubilizing agent is selected from: the fatty acid Pyrusussuriensis is smooth, the mixture of one or more (comprising two kinds) in Polysorbate, polyvidone, poloxamer and the lecithin, and content is 0%～5% of pharmaceutical composition volume; And the content of cosolvent and solubilizing agent is not 0 simultaneously.
In the technique scheme, described physiology dissolve medium is selected from: purified water, water for injection, sterilized water for injection, medicinal water, mass fraction are that 0.9% sodium chloride solution or mass fraction are a kind of in 5% the glucose solution.
In the technique scheme, the content of described cosolvent is preferably 0%～50% of pharmaceutical composition volume; The content of described solubilizing agent be preferably the pharmaceutical composition volume 0%～1%; Described " pharmaceutical composition volume " is meant the mixed volume of all components.
In the technique scheme, every 1mL pharmaceutical composition contains the above principal agent Nocathiacin of 0.1mg, make solution after, the content of principal agent Nocathiacin is greater than its medicinal minimum effective dose; In the optimized technical scheme, make solution after, the dissolubility of principal agent Nocathiacin can be up to about 9mg/mL, simultaneously, since it will be understood by those skilled in the art that the dissolubility of principal agent Nocathiacin can be up to about 9mg/mL, dissolubility also can be realized less than 9mg/mL so.
In the technique scheme, described Nocathiacin (English general Nocathiacin by name) is selected from: Nocathiacin I, Nocathiacin II or Nocathiacin III, and the general structure of described Nocathiacin is as follows:
Wherein, among the Nocathiacin I, R
1=OH,
Among the Nocathiacin II, R
1=H,
Among the Nocathiacin III, R
1=OH, R
2=OH; In the optimized technical scheme, described Nocathiacin is Nocathiacin I.
Further in the technical scheme, the described antibiotic pharmaceutical composition of Nocathiacin that contains also comprises other pharmaceutic adjuvant additives, comprises antiseptic, correctives, analgesic, buffer agent, pH regulator agent, wetting agent, stabilizing agent, short penetrating agent and substrate; Described will be 0%～80% of drug regimen amount with its content of adjuvant additive, preferred 0%～20%.
The said medicine solution can be for oral, external, an ear, eye drip, intramuscular injection, subcutaneous injection and intravenous injection; Can be used for treating clinically the infection and acute accordingly, the chronic inflammatory reaction that cause by various gram positive bacterias and fastbacteria.
Aforementioned pharmaceutical compositions is a solution, can be prepared by vortex vibration and ultransonic method commonly used in the art technology.
Further in the technical scheme, can make corresponding gel by in pharmaceutical solutions, adding water-soluble base; Described water-soluble base is selected from: the mixture of one or more in crosslinked polypropylene acid resin (Acritamer 940, carbomer 934 or Carbopol 941), hydroxypropyl cellulose, methylcellulose, sodium carboxymethyl cellulose, chitosan, the polyvidone, its content in every 1ml pharmaceutical composition is 5～15mg, preferred 10mg; Therefore; the present invention is claimed a kind of antibiotic medicament gelling agent of Nocathiacin that contains simultaneously; comprise: the husky star of principal agent Rocca, solubilizing agent, cosolvent, water-soluble base and pH regulator agent; described pH regulator agent is selected from: a kind of in triethanolamine, sodium hydroxide, ethylenediamine and the sodium bicarbonate, content is identical with water-soluble base.
In the technique scheme, the described antibiotic medicament gelling agent of Nocathiacin that contains also comprises wetting agent or short penetrating agent; Described wetting agent is selected from glycerol and propylene glycol, content be medicament gelling agent gross mass 0%～15%; Described short penetrating agent is selected from a kind of in azone or the oleic acid, and content is 0%～1%.
In the technique scheme, the preparation method of described medicament gelling agent makes it abundant swelling for earlier water-soluble base being scattered in the physiology dissolve medium, the while medicine is dissolved in solubilizing agent or cosolvent is made medicinal liquid, again medicinal liquid is injected substrate, stir evenly or ultrasonic, add the pH regulator agent at last, stir evenly and promptly get homodisperse gel; In addition, wetting agent and short penetrating agent both can with the substrate mixing after again medicinal liquid is added, also can with the medicinal liquid mixing after join in the substrate again.
Because the technique scheme utilization, the present invention compared with prior art has following advantage:
1, improve the method for Nocathiacin dissolubility in the prior art, all based on chemical constitution transformation and biotransformation, process relate to a large amount of toxic reagents and complex process, consuming time, cost is high, efficient is low; The method of raising Nocathiacin dissolubility provided by the present invention, based on physical method, preparation process does not relate to a large amount of toxic reagents, material therefor economy is easy to get, used instrument and equipment is simple and safe, processing step is few and easy to be capable, is the method (dissolubility of the Nocathiacin of one pack system in the physiology dissolve medium is less than 0.01mg/ml, and the dissolubility of Nocathiacin can improve hundreds and thousands of times among the present invention) of present the simplest most economical raising Nocathiacin dissolubility.
2, improve the method for Nocathiacin dissolubility in the prior art, Nocathiacin is converted into enhanced derivant of various water solublity or prodrug, the antibacterial activity of medicine all decreases, and medicine can produce toxic and side effects in the metabolism way; The method of raising Nocathiacin dissolubility provided by the present invention, with Nocathiacin I body is principal agent, without any chemical modification, can not produce any influence to the antibacterial activity and the metabolic way of medicine, can not cause toxicity in the preparation application process, be the method for present the most effective the safest raising Nocathiacin dissolubility.
3, improve the method for Nocathiacin dissolubility in the prior art, to improve the dissolubility of chemical compound itself, do not carry out the dissolution and the interior dissolubility of preparation body of corresponding preparations and investigate, it is little that the dissolubility of medicine improves ratio, can not guarantee effect; The method of raising Nocathiacin dissolubility provided by the present invention to improve the preparation dissolubility of medicine, makes medicine improve intravital dissolubility under the form of preparation, and dissolubility raising ratio reaches nearly thousand times, more helps the clinical practice of medicine.
4, the method for the raising Nocathiacin dissolubility of reporting both at home and abroad at present is owing to existing safety issue not have application example; The method of raising Nocathiacin dissolubility provided by the present invention, onset is rapid, and is easy to use, and route of administration is extensive, has greatly improved the using value of Nocathiacin.
The specific embodiment
Below in conjunction with embodiment the present invention is further described:
Embodiment one: the solution that contains cosolvent.
Prescription:
Nocathiacin I 10mg;
PEG?400 500μl；
0.9% sodium chloride solution (pH 7.4), 500 μ l.
Technology: add Nocathiacin I, 0.9% sodium chloride solution and the PEG400 of recipe quantity in the container successively, supersound process 30min behind the vortex vibration 10min mixing centrifugally removes insoluble Nocathiacin I, promptly gets as clear as crystal solution; High performance liquid chromatography detects wherein that the dissolubility of Nocathiacin I is 6.41mg/ml, and the volume fraction of PEG 400 is 50%; Solution does not have precipitation and separates out in the 72h after 0.9% sodium chloride solution dilutes 500～1000 times.
Embodiment two: the solution that contains cosolvent.
Prescription:
Nocathiacin I 10mg;
PEG?600 400μl；
5% glucose solution (pH 7.4), 600 μ l.
Technology: add the Nocathiacin I of recipe quantity, 5% glucose solution and PEG600 in the container successively, supersound process 30min behind the vortex vibration 10min mixing centrifugally removes insoluble Nocathiacin I, promptly gets as clear as crystal solution; High performance liquid chromatography detects wherein that the dissolubility of Nocathiacin I is 7.54mg/ml, and the volume fraction of PEG 600 is 40%; Solution does not have precipitation in the 72h and separates out after 500～1000 times of 5% glucose solution dilutions.
Embodiment three: the solution that contains solubilizing agent
Prescription:
Nocathiacin I 10mg;
Poloxamer 20mg;
5% glucose solution (pH 7.4), 1000 μ l.
Technology: add the Nocathiacin I, poloxamer of recipe quantity and 5% glucose solution in the container successively, supersound process 30min behind the vortex vibration 10min mixing centrifugally removes insoluble Nocathiacin I, promptly gets as clear as crystal solution; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 2.955mg/ml; Solution does not have precipitation in the 72h and separates out after 500～1000 times of 5% glucose solution dilutions.
Embodiment four: the solution that contains solubilizing agent
Prescription:
Nocathiacin I 10mg;
Polyvidone 10mg;
0.9% sodium chloride solution (pH 7.4), 1000 μ l.
Technology: add Nocathiacin I, polyvidone and 0.9% sodium chloride solution of recipe quantity in the container successively, supersound process 30min behind the vortex vibration 10min mixing centrifugally removes insoluble Nocathiacin I, promptly gets as clear as crystal solution; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 1.979mg/ml; Solution does not have precipitation and separates out in the 72h after 0.9% sodium chloride solution dilutes 500～1000 times.
Embodiment five: the solution that contains solubilizing agent
Prescription:
Nocathiacin I 10mg;
Lecithin 10mg;
0.9% sodium chloride solution (pH 7.4), 1000 μ l.
Technology: add Nocathiacin I, lecithin and 0.9% sodium chloride solution of recipe quantity in the container successively, the even back of vortex vibration 10min supersound process 30min centrifugally removes insoluble Nocathiacin I, promptly gets as clear as crystal solution; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 0.521mg/ml; Solution does not have precipitation and separates out in the 72h after 0.9% sodium chloride solution dilutes 500～1000 times.
Embodiment six: the solution that contains cosolvent and solubilizing agent simultaneously.
Prescription:
Nocathiacin I 10mg;
PEG?600 500μl；
0.9% sodium chloride solution (pH 7.4), 500 μ l;
Polysorbate 60 5 μ l.
Technology: add Nocathiacin I, polysorbate 60,0.9% sodium chloride solution and the PEG600 of recipe quantity in the container successively, the ultrasonic 30min of place behind the vortex vibration 10min mixing centrifugally removes insoluble Nocathiacin I, promptly gets as clear as crystal solution; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 8.13mg/ml; Solution does not have precipitation and separates out in the 72h after 0.9% sodium chloride solution dilutes 500～1000 times.
Embodiment seven: the solution that contains cosolvent and solubilizing agent simultaneously.
Prescription:
Nocathiacin I 10mg;
PEG?400 400μl；
0.9% sodium chloride solution (pH 7.4), 600 μ l;
Polyoxyethylene sorbitan monoleate 10 μ l.
Technology: add Nocathiacin I, polyoxyethylene sorbitan monoleate, 0.9% sodium chloride solution and the PEG400 of recipe quantity in the container successively, supersound process 30min behind the vortex vibration 10min mixing centrifugally removes insoluble Nocathiacin I, promptly gets as clear as crystal solution; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 8.25mg/ml; Solution does not have precipitation and separates out in the 72h after 0.9% sodium chloride solution dilutes 500～1000 times.
Embodiment eight: the solution that contains cosolvent and solubilizing agent simultaneously.
Prescription:
Nocathiacin I 10mg;
Ethanol 500 μ l;
5% glucose solution (pH 7.4), 500 μ l;
Polyvidone 10mg.
Technology: add the Nocathiacin I, polyvidone of recipe quantity, 5% glucose solution and ethanol in the container successively, supersound process 30min behind the vortex vibration 10min mixing centrifugally goes insolublely, promptly gets as clear as crystal solution; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 8.45mg/ml; Solution does not have precipitation in the 72h and separates out after 500～1000 times of 5% glucose solution dilutions.
Embodiment nine: the solution that contains cosolvent and solubilizing agent simultaneously.
Prescription:
Nocathiacin I 10mg;
Ethanol 500 μ l;
5% glucose solution (pH 7.4), 500 μ l;
Lecithin 10mg.
Technology: add the Nocathiacin I, lecithin of recipe quantity, 5% glucose solution and ethanol in the container successively, supersound process 30min behind the vortex vibration 10min mixing centrifugally goes insolublely, promptly gets as clear as crystal solution; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 7.93mg/ml; Solution does not have precipitation in the 72h and separates out after 500～1000 times of 5% glucose solution dilutions.
Embodiment ten: the solution that contains cosolvent and solubilizing agent simultaneously.
Prescription:
Nocathiacin I 10mg;
Ethanol 500 μ l;
0.9% sodium chloride solution (pH 7.4), 500 μ l;
Poloxamer 10mg.
Technology: add Nocathiacin I, poloxamer, 0.9% sodium chloride solution and the ethanol of recipe quantity in the container successively, supersound process 30min behind the vortex vibration 10min mixing centrifugally goes insolublely, promptly gets as clear as crystal solution; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 6.05mg/ml; Solution does not have precipitation and separates out in the 72h after 0.9% sodium chloride solution dilutes 500～1000 times.
Embodiment 11: the solution that contains two kinds of cosolvents and a kind of solubilizing agent simultaneously.
Prescription:
Nocathiacin I 10mg;
Ethanol 400 μ l;
0.9% sodium chloride solution (pH 7.4), 500 μ l;
Polyoxyethylene sorbitan monoleate 5 μ l;
PEG600 100μl；
Technology: add Nocathiacin I, polyoxyethylene sorbitan monoleate, ethanol, 0.9% sodium chloride solution and the PEG600 of recipe quantity in the container successively, supersound process 30min behind the vortex vibration 10min mixing centrifugally goes insolublely, promptly gets as clear as crystal solution; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 6.60mg/ml; Solution does not have precipitation and separates out in the 72h after 0.9% sodium chloride solution dilutes 500～1000 times.
Embodiment 12: the solution that contains two kinds of cosolvents and a kind of solubilizing agent simultaneously.
Prescription:
Nocathiacin I 10mg;
Ethanol 200 μ l;
0.9% sodium chloride solution (pH 7.4), 500 μ l;
Polysorbate 60 5 μ l;
PEG400 300μl；
Technology: add Nocathiacin I, polysorbate 60, ethanol, 0.9% sodium chloride solution and the PEG400 of recipe quantity in the container successively, supersound process 30min behind the vortex vibration 10min mixing centrifugally goes insolublely, promptly gets as clear as crystal solution; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 7.13mg/ml; Solution does not have precipitation and separates out in the 72h after 0.9% sodium chloride solution dilutes 500～1000 times.
Embodiment 13: pH is 9.0 solution
Prescription:
Nocathiacin I 10mg;
PEG600 100μl；
0.9% sodium chloride solution (pH 9.0), 900 μ l;
Polyoxyethylene sorbitan monoleate 5 μ l;
Technology: add Nocathiacin I, polyoxyethylene sorbitan monoleate, 0.9% sodium chloride solution and the PEG600 of recipe quantity in the container successively, supersound process 30min behind the vortex vibration 10min mixing centrifugally goes insolublely, promptly gets as clear as crystal solution; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 4.35mg/ml; Solution does not have precipitation and separates out in the 72h after 0.9% sodium chloride solution dilutes 500～1000 times.
Embodiment 14: pH is 4.0 solution
Prescription:
Nocathiacin I 10mg;
Ethanol 200 μ l;
0.9% sodium chloride solution (pH 4.0), 800 μ l;
Polyoxyethylene sorbitan monoleate 5 μ l;
Technology: add Nocathiacin I, polyoxyethylene sorbitan monoleate, 0.9% sodium chloride solution and the ethanol of recipe quantity in the container successively, supersound process 30min behind the vortex vibration 10min mixing centrifugally goes insolublely, promptly gets as clear as crystal solution; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 4.12mg/ml; Solution does not have precipitation and separates out in the 72h after 0.9% sodium chloride solution dilutes 500～1000 times.
Embodiment 15: substrate is the gel of Acritamer 940.
Prescription:
Acritamer 940 10mg; Ethanol 200 μ l;
Polysorbate 60 2 μ l; Nocathiacin I 10mg;
Triethanolamine 10 μ l; 0.9% sodium chloride solution (pH7.4), 800 μ l.
Preparation technology: the Acritamer 940 of recipe quantity is dissolved in 600 μ l, 0.9% sodium chloride solution makes it abundant swelling, simultaneously principal agent, polysorbate 60, ethanol, 200 μ l, the 0.9% sodium chloride solution mixing of recipe quantity are made medicinal liquid, subsequently medicinal liquid is slowly injected the substrate under stirring, add the triethanolamine of recipe quantity behind the mixing, stir evenly and promptly get homodisperse gel; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 5.15mg/ml; Gel does not have precipitation and separates out in the 72h after 0.9% sodium chloride solution dilutes 500～1000 times.
Embodiment 16: the gel that contains wetting agent.
Prescription:
Carbopol 941 10mg; PEG600 200 μ l;
Polyoxyethylene sorbitan monoleate 2 μ l; Nocathiacin I 10mg;
Triethanolamine 10 μ l; Glycerol 100 μ l;
0.9% sodium chloride solution (pH7.4), 700 μ l.
Preparation technology: the Carbopol 941 of recipe quantity is dissolved in glycerol and 500 μ l, 0.9% sodium chloride solution makes it abundant swelling, simultaneously principal agent, polyoxyethylene sorbitan monoleate, PEG600,200 μ l, the 0.9% sodium chloride solution mixing of recipe quantity are made medicinal liquid, subsequently medicinal liquid is slowly injected the substrate under stirring, add the triethanolamine of recipe quantity behind the mixing, stir evenly and promptly get homodisperse gel; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 4.77mg/ml; Gel does not have precipitation and separates out in the 72h after 0.9% sodium chloride solution dilutes 500～1000 times.
Embodiment 17: the gel that contains short penetrating agent.
Prescription:
Carbomer 934 10mg; PEG400 200 μ l;
Polyoxyethylene sorbitan monoleate 2 μ l; Nocathiacin I 10mg;
Triethanolamine 10 μ l; Glycerol 100 μ l;
Azone 10 μ l; 0.9% sodium chloride solution (pH7.4), 700 μ l.
Preparation technology: the carbomer 934 of recipe quantity is dissolved in glycerol and 500 μ l, 0.9% sodium chloride solution makes it abundant swelling, simultaneously principal agent, azone, polyoxyethylene sorbitan monoleate, PEG400,200 μ l, the 0.9% sodium chloride solution mixing of recipe quantity are made medicinal liquid, subsequently medicinal liquid is slowly injected the substrate under stirring, add the triethanolamine of recipe quantity behind the mixing, stir evenly and promptly get homodisperse gel; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 4.11mg/ml; Gel does not have precipitation and separates out in the 72h after 0.9% sodium chloride solution dilutes 500～1000 times.
Embodiment 18: substrate is the gel of chitosan.
Prescription:
Chitosan 10mg; Ethanol 200 μ l;
Polyoxyethylene sorbitan monoleate 2 μ l; Nocathiacin I 10mg;
Diethylamine 10 μ l; Glycerol 100 μ l;
Azone 10 μ l; 0.9% sodium chloride solution (pH7.4), 700 μ l.
Preparation technology: the chitosan of recipe quantity is dissolved in azone, glycerol and 500 μ l, 0.9% sodium chloride solution makes it abundant swelling, simultaneously principal agent, polyoxyethylene sorbitan monoleate, ethanol, 200 μ l, the 0.9% sodium chloride solution mixing of recipe quantity are made medicinal liquid, subsequently medicinal liquid is slowly injected the substrate under stirring, add the ethylenediamine of recipe quantity behind the mixing, stir evenly and promptly get homodisperse gel; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 4.32mg/ml; Gel does not have precipitation and separates out in the 72h after 0.9% sodium chloride solution dilutes 500～1000 times.
Embodiment 19: the gel that contains two kinds of substrate.
Prescription:
Sodium carboxymethyl cellulose 10mg; Polyvidone 5mg;
Ethanol 200 μ l; Polyoxyethylene sorbitan monoleate 5 μ l;
Nocathiacin I 10mg; Sodium hydroxide 15mg;
Propylene glycol 100 μ l; Oleic acid 3 μ l;
0.9% sodium chloride solution (pH7.4), 700 μ l.
Preparation technology: sodium carboxymethyl cellulose, the polyvidone of recipe quantity be dissolved in oleic acid, propylene glycol and the 500 μ l0.9% sodium chloride solutions make it abundant swelling, simultaneously principal agent, polyoxyethylene sorbitan monoleate, ethanol, 200 μ l, the 0.9% sodium chloride solution mixing of recipe quantity are made medicinal liquid, subsequently medicinal liquid is slowly injected the substrate under stirring, add the sodium hydroxide of recipe quantity behind the mixing, stir evenly and promptly get homodisperse gel; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 4.37mg/ml; Gel does not have precipitation and separates out in the 72h after 0.9% sodium chloride solution dilutes 500～1000 times.
Claims (9)
1. one kind contains the antibiotic pharmaceutical composition of Nocathiacin, comprises Nocathiacin and pharmaceutical carrier, it is characterized in that: also comprise hydroaropic substance, described hydroaropic substance is selected from cosolvent or solubilizing agent; Described pharmaceutical carrier is the physiology dissolve medium of pH4～9; Described cosolvent is selected from: the mixture of one or more in ethanol, propylene glycol, glycerol or the Polyethylene Glycol, content are 0%～80% of pharmaceutical composition volume; Described solubilizing agent is selected from: the fatty acid Pyrusussuriensis is smooth, one or more the mixture in Polysorbate, polyvidone, poloxamer and the lecithin, and content is 0%～5% of pharmaceutical composition volume; And the content of cosolvent and solubilizing agent is not 0 simultaneously.
2. the antibiotic pharmaceutical composition of Nocathiacin that contains according to claim 1 is characterized in that described Nocathiacin is Nocathiacin I.
3. the antibiotic pharmaceutical composition of Nocathiacin that contains according to claim 1 is characterized in that, every 1mL pharmaceutical composition contains the above principal agent Nocathiacin of 0.1mg.
4. the antibiotic pharmaceutical composition of Nocathiacin that contains according to claim 1, it is characterized in that described physiology dissolve medium is selected from: purified water, water for injection, sterilized water for injection, medicinal water, mass fraction are that 0.9% sodium chloride solution or mass fraction are a kind of in 5% the glucose solution.
5. the antibiotic pharmaceutical composition of Nocathiacin that contains according to claim 1 is characterized in that the content of described cosolvent is 0%～50% of pharmaceutical composition volume.
6. the antibiotic pharmaceutical composition of Nocathiacin that contains according to claim 1 is characterized in that the content of described solubilizing agent is 0%～1% of pharmaceutical composition volume.
7. the antibiotic pharmaceutical composition of Nocathiacin that contains according to claim 1, it is characterized in that, describedly contain the antibiotic drug solution agent of Nocathiacin and also comprise other pharmaceutic adjuvant additives, comprise antiseptic, correctives, analgesic, buffer agent, pH regulator agent, wetting agent, stabilizing agent, short penetrating agent and substrate; Described will be 0%～80% of drug regimen amount with its content of adjuvant additive.
8. the antibiotic pharmaceutical composition of Nocathiacin that contains according to claim 1, it is characterized in that, described pharmaceutical composition is a medicament gelling agent, comprise: the husky star of principal agent Rocca, solubilizing agent, cosolvent, water-soluble base and pH regulator agent, described water-soluble base is selected from: the mixture of one or more in Acritamer 940, carbomer 934, Carbopol 941, hydroxypropyl cellulose, methylcellulose, sodium carboxymethyl cellulose, chitosan, the polyvidone, and the water-soluble base content in every 1ml pharmaceutical composition is 5～15mg; Described pH regulator agent is selected from: a kind of in triethanolamine, sodium hydroxide, ethylenediamine and the sodium bicarbonate, content is identical with water-soluble base.
9. the antibiotic pharmaceutical composition of Nocathiacin that contains according to claim 8 is characterized in that described medicament gelling agent also comprises wetting agent or short penetrating agent; Described wetting agent is selected from glycerol and propylene glycol, content be medicament gelling agent gross mass 0%～15%; Described short penetrating agent is selected from a kind of in azone or the oleic acid, and content is 0%～1%.
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| CN103040770A (en) * | 2013-02-05 | 2013-04-17 | 南京碧迪可医药科技有限公司 | Preparation method of nocathiacin freeze-dried powder injection |
| CN103040769A (en) * | 2013-02-05 | 2013-04-17 | 南京碧迪可医药科技有限公司 | Stable nocathiacin lyophilized power injection agent |
| CN104415336A (en) * | 2013-08-28 | 2015-03-18 | 沈阳药科大学 | Composition capable of eliminating poloxamer clouding phenomenon and application of composition to pharmaceutical preparation |
| CN105363018A (en) * | 2015-12-02 | 2016-03-02 | 南京碧迪可医药科技有限公司 | New application of thiopeptcin |
| CN107469068A (en) * | 2017-08-04 | 2017-12-15 | 南京碧迪可医药科技有限公司 | A kind of pharmaceutical composition of sulphur peptide ring element |
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| AU2013377601B2 (en) * | 2013-02-05 | 2017-02-02 | Nanjing Biotica Pharmaceutical Company | Stable nocathiacin lyophilized powder injection agent |
| WO2014121610A1 (en) * | 2013-02-05 | 2014-08-14 | 南京碧迪可医药科技有限公司 | Method for preparing nocathiacin freeze-dried powder injection |
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| CN103040770A (en) * | 2013-02-05 | 2013-04-17 | 南京碧迪可医药科技有限公司 | Preparation method of nocathiacin freeze-dried powder injection |
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| CN104415336B (en) * | 2013-08-28 | 2019-05-03 | 沈阳药科大学 | The composition and its application in pharmaceutical preparation that poloxamer plays phenomenon covered with clouds can be eliminated |
| WO2017092630A1 (en) * | 2015-12-02 | 2017-06-08 | 南京碧迪可医药科技有限公司 | New use of thiopeptin |
| CN105363018A (en) * | 2015-12-02 | 2016-03-02 | 南京碧迪可医药科技有限公司 | New application of thiopeptcin |
| CN105363018B (en) * | 2015-12-02 | 2019-08-30 | 南京碧迪可医药科技有限公司 | A kind of new application of sulphur peptide ring element |
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