CN102784099A - Combined preparation containing fospropofol disodium, and preparation method and application thereof - Google Patents
Combined preparation containing fospropofol disodium, and preparation method and application thereof Download PDFInfo
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- CN102784099A CN102784099A CN2012101910306A CN201210191030A CN102784099A CN 102784099 A CN102784099 A CN 102784099A CN 2012101910306 A CN2012101910306 A CN 2012101910306A CN 201210191030 A CN201210191030 A CN 201210191030A CN 102784099 A CN102784099 A CN 102784099A
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- Prior art keywords
- sodium
- injection
- adds
- phosphorus propofol
- acid
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Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- LWYLQNWMSGFCOZ-UHFFFAOYSA-L disodium 2,6-bis(propan-2-yl)phenoxymethyl phosphate Chemical compound [Na+].[Na+].CC(C)C1=CC=CC(C(C)C)=C1OCOP([O-])([O-])=O LWYLQNWMSGFCOZ-UHFFFAOYSA-L 0.000 title abstract description 8
- 229960001026 fospropofol disodium Drugs 0.000 title abstract description 8
- 238000002347 injection Methods 0.000 claims abstract description 52
- 239000007924 injection Substances 0.000 claims abstract description 52
- 239000002904 solvent Substances 0.000 claims abstract description 34
- 238000000034 method Methods 0.000 claims abstract description 16
- 230000003204 osmotic effect Effects 0.000 claims abstract description 9
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 8
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 8
- 229960004134 propofol Drugs 0.000 claims description 84
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 claims description 83
- 229910052698 phosphorus Inorganic materials 0.000 claims description 76
- 239000011574 phosphorus Substances 0.000 claims description 76
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 75
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 74
- 239000011734 sodium Substances 0.000 claims description 74
- 229910052708 sodium Inorganic materials 0.000 claims description 74
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 42
- 239000007788 liquid Substances 0.000 claims description 31
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 23
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 20
- 239000008215 water for injection Substances 0.000 claims description 20
- 230000001954 sterilising effect Effects 0.000 claims description 18
- 238000004659 sterilization and disinfection Methods 0.000 claims description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 16
- 239000003610 charcoal Substances 0.000 claims description 16
- 229940105082 medicinal charcoal Drugs 0.000 claims description 16
- 239000012528 membrane Substances 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 8
- 239000011780 sodium chloride Substances 0.000 claims description 8
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 8
- 235000006708 antioxidants Nutrition 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims 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 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 229960001305 cysteine hydrochloride Drugs 0.000 claims description 5
- 239000008103 glucose Substances 0.000 claims description 5
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 4
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 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 4
- 239000001110 calcium chloride Substances 0.000 claims description 4
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 4
- 239000004220 glutamic acid Substances 0.000 claims description 4
- 235000013922 glutamic acid Nutrition 0.000 claims description 4
- 239000004310 lactic acid Substances 0.000 claims description 4
- 235000014655 lactic acid Nutrition 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 239000001103 potassium chloride Substances 0.000 claims description 4
- 235000011164 potassium chloride Nutrition 0.000 claims description 4
- 230000001105 regulatory effect Effects 0.000 claims description 4
- 239000001488 sodium phosphate Substances 0.000 claims description 4
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 4
- 235000011008 sodium phosphates Nutrition 0.000 claims description 4
- 235000010265 sodium sulphite Nutrition 0.000 claims description 4
- 239000001117 sulphuric acid Substances 0.000 claims description 4
- 235000011149 sulphuric acid Nutrition 0.000 claims description 4
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 4
- 239000004475 Arginine Substances 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 3
- 235000010323 ascorbic acid Nutrition 0.000 claims description 3
- 239000011668 ascorbic acid Substances 0.000 claims description 3
- 229960005070 ascorbic acid Drugs 0.000 claims description 3
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 2
- 239000004471 Glycine Substances 0.000 claims description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- 235000009697 arginine Nutrition 0.000 claims description 2
- 235000003704 aspartic acid Nutrition 0.000 claims description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 239000001509 sodium citrate Substances 0.000 claims description 2
- 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 description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 2
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- 150000008064 anhydrides Chemical class 0.000 claims 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims 1
- 235000019799 monosodium phosphate Nutrition 0.000 claims 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims 1
- 230000008901 benefit Effects 0.000 abstract description 12
- 230000008569 process Effects 0.000 abstract description 6
- 230000003444 anaesthetic effect Effects 0.000 abstract description 4
- 238000002156 mixing Methods 0.000 abstract description 2
- 239000007857 degradation product Substances 0.000 abstract 1
- 230000000638 stimulation Effects 0.000 abstract 1
- 229940090044 injection Drugs 0.000 description 37
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 20
- 239000000243 solution Substances 0.000 description 14
- 206010002091 Anaesthesia Diseases 0.000 description 7
- 230000037005 anaesthesia Effects 0.000 description 7
- 235000011121 sodium hydroxide Nutrition 0.000 description 7
- 241000282472 Canis lupus familiaris Species 0.000 description 6
- 235000015165 citric acid Nutrition 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000013618 particulate matter Substances 0.000 description 4
- 239000006184 cosolvent Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 2
- 230000003187 abdominal effect Effects 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 239000002510 pyrogen Substances 0.000 description 2
- 230000011514 reflex Effects 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 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 description 1
- 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 description 1
- 206010067482 No adverse event Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 239000008156 Ringer's lactate solution Substances 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000002567 autonomic effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- BMLSTPRTEKLIPM-UHFFFAOYSA-I calcium;potassium;disodium;hydrogen carbonate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].OC([O-])=O BMLSTPRTEKLIPM-UHFFFAOYSA-I 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- OKBPCTLSPGDQBO-UHFFFAOYSA-L disodium;dichloride Chemical compound [Na+].[Na+].[Cl-].[Cl-] OKBPCTLSPGDQBO-UHFFFAOYSA-L 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 238000005562 fading Methods 0.000 description 1
- 229940093181 glucose injection Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000010247 heart contraction Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000002357 laparoscopic surgery Methods 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000003040 nociceptive effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- -1 phosphorus propofol sodium compound Chemical class 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 230000004799 sedative–hypnotic effect Effects 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 230000002557 soporific effect Effects 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention provides a fospropofol disodium-containing combined preparation, which contains an fospropofol disodium injection and a special solvent, and a preparation method and application thereof. The injection comprises fospropofol disodium, a pH regulator, an osmotic pressure regulator and an antioxidant. The combined preparation is mainly used as an anesthetic in an operation. The invention has the following advantages: an appropriate range of pH is employed to produce the least degradation products of fospropofol disodium at a high temperature of 121 DEG C; the special solvent is injected into the fospropofol disodium injection during a usage process, so that pH of the fospropofol disodium injection reaches a tolerance range of human; the preparation is convenient for clinical usage and reduces stimulation; and the injection and the special solvent can maintain stable at room temperature, and maintain stable for 8 h after mixing of the two.
Description
Technical field:
The present invention relates to method for preparing and purposes that a kind of combination preparation contains phosphorus propofol sodium, wherein comprise phosphorus propofol sodium injection and special solvent thereof.
Technical background:
Propofol is colorless oil, and is water insoluble, because its low water solublity, then this medicine uses cosolvent to prepare as carrier usually, but has document to show that cosolvent can cause serious adverse in vivo, and clinical drug safety can't ensure.For addressing this problem, people have done big quantity research, and final the discovery is made into the deutero-prodrug of phosphoric acid, can effectively solve the extremely low problem of its water solublity, thereby phosphorus propofol sodium is able to come out.
Phosphorus propofol sodium (Fospropofol disodium), chemistry is by name 2,6-diisopropyl benzene oxygen methyl acid phosphate disodium, phosphorus propofol sodium is the water-soluble prodrug of propofol, is a kind of sedative hypnotic that is applied to diagnose with treatment stage.The phosphorus propofol sodium good water solubility, thus in the process of preparation directly water make solvent, avoid the use of cosolvent and surfactant has improved drug safety.Phosphorus propofol sodium is the precursor medicine of propofol, and itself does not have pharmaceutically active, but this medicine good water solubility, the back is the propofol active component through the effect metabolism of alkali phosphatase in the entering body, thus the performance pharmaceutically active.
Phosphorus propofol sodium is under lower pH, and the ehter bond easy fracture in its structure is for guaranteeing its injection heat stability; Usually its pH value of solution is controlled greater than 8, yet after the solution of too high pH got into human body, its zest was stronger; Cause all untoward reaction,, use special solvent the pH of injection to be dropped to about 7.5 so we add special solvent especially for this reason; Make human body more acceptant, zest reduces, and reaches the clinical administration purpose.
Summary of the invention
The present invention provides a kind of combination preparation that contains phosphorus propofol sodium, and comprising phosphorus propofol sodium injection and special solvent, this injection formulation comprises effective normal phosphorus propofol sodium, pH regulator agent, antioxidant, osmotic pressure regulator.In the process of preparation, use suitable pH regulator agent, with pH regulator to the suitable scope of injection, make medicine under 121 ℃ of conditions of high temperature with long term store during catabolite be reduced to minimum; Special solvent comprises the acid of effective dose, and purpose is the scope that the pH regulator the pure man body with the phosphorus propofol sodium injection can tolerate.
Of the present invention specifying
Preparation of the present invention comprises that the phosphorus propofol sodium structural formula is following:
The object of the present invention is to provide a kind of combination preparation that contains phosphorus propofol sodium, wherein comprise phosphorus propofol sodium injection and special solvent thereof.
Phosphorus propofol sodium injection of the present invention is a kind of intravenous administration formulation that phosphorus propofol sodium is an effective ingredient that contains.
Also comprise antioxidant, pH regulator agent, osmotic pressure regulator in the phosphorus propofol sodium injection formulation.
The amount ranges of phosphorus propofol sodium in the preparation process is 0.5～25% (w/v).
The pH of phosphorus propofol sodium injection can control phosphorus propofol sodium and under the high temperature sterilize condition, being not easy degraded among the present invention, so select suitable pH, could let phosphorus propofol sodium stable during long term store, and it is minimum that catabolite is reduced.Pass through test of many times; PH is in 10～13 scopes; Can effectively suppress the generation of catabolite; Wherein use the pH regulator agent that in sodium carbonate, sodium hydroxide, sodium phosphate, dibastic sodium phosphate, sodium hydrogen phosphate, arginine, glycine, the tromethane one or more are arranged, wherein consumption is that 0～20% (W/V) can be with injection pH regulator to 10～13.
The osmotic pressure regulator that uses among the present invention has one or more in sodium chloride, glucose, potassium chloride, sodium citrate, calcium chloride, the lactic acid.Wherein use amount is that 0～5% (W/V) can be adjusted to the injection osmotic pressure etc. and ooze.Can use sodium chloride to process corresponding phosphorus propofol sodium sodium chloride injection separately; Also can use glucose to process corresponding phosphorus propofol sodium glucose injection, can also use lactose, sodium chloride, potassium chloride, calcium chloride to process the phosphorus propofol sodium ringer's injection.
The antioxidant that uses among the present invention have citric acid, ascorbic acid, monothioglycerol, sodium sulfite, sodium sulfite, EDTA, cysteine hydrochloride, sodium metabisulfite one or more, wherein the scope of use amount is 0～1% (W/V).
Special solvent purpose described in the present invention is with phosphorus propofol sodium injection pH regulator 6～9; Make a kind of sterile solution that contains acidic materials in the tolerant scope of human body; The acidic materials that its special solvent uses have hydrochloric acid, phosphoric acid, acetic acid, citric acid, glutamic acid, aspartic acid, succinic acid, sulphuric acid one or more, wherein use amount is that 0～5% (W/V) can be 6～9 scopes with the pH regulator of injection.
Another object of the present invention is to provide a kind of method for preparing that contains the combination preparation of phosphorus propofol sodium, comprising the method for preparing of phosphorus propofol sodium injection and the method for preparing of special solvent.
Phosphorus propofol sodium injection and special solvent mentioned among the present invention obtain through following measure:
The method for preparing of phosphorus propofol sodium injection, its preparation process is: main constituent phosphorus propofol sodium, osmotic pressure regulator and antioxidant are dissolved in the water for injection, and it is 10.0～13.0 that medicinal liquid pH is regulated in the pH regulator agent; Add the activated carbon adsorption pyrogen again, filter packing; Zha Gai, sterilization.
Phosphorus propofol sodium injection preparation of the present invention comprises following a few step, in liquid dispensing container, adds 10%～95% water for injection, adds phosphorus propofol sodium, 0～0.5% (W/V) sodium chloride, 0～0.5% (W/V) cysteine hydrochloride of recipe quantity 95%～105%; Stirring makes dissolving, regulates pH to 10.0～13.0 with 10%NaOH solution, mends and adds water to full dose; The medicinal charcoal that adds 0.01%～1% (W/V) then, 40 ℃ were stirred 10～60 minutes, and it is qualified to filter to clarity with the filter membrane of 0.45 μ m; After mensuration intermediate content is qualified; Decide loading amount and be sub-packed in the pharmaceutical containers, roll lid, 121 ℃ of sterilization 8min promptly get.
The product pH regulator is 10.0～13.0 in the method for preparing of phosphorus propofol sodium injection according to the invention, finds in the test, under this pH, can effectively be controlled at the generation of catabolite under the hot conditions.
The method for preparing of special solvent, its preparation process is: the acid of effective dose is dissolved in water for injection, adds the activated carbon adsorption pyrogen again, filter, packing, Zha Gai, sterilization.
Special solvent method for preparing of the present invention comprises following a few step, in liquid dispensing container, adds 10%～95% water for injection, adds the acetic acid of recipe quantity 95%～105%; After the stirring and dissolving, mend and add water to full dose, add the medicinal charcoal of 0.01%～1% (W/V) then; 40 ℃ were stirred 10～60 minutes, and it is qualified to filter to clarity with the filter membrane of 0.45 μ m, after mensuration intermediate content is qualified; Decide loading amount and be sub-packed in the pharmaceutical containers, roll lid, 121 ℃ of sterilization 8min promptly get.
A further object of the invention is to provide a kind of combination preparation that is used for tranquilizing soporific, is mainly used in the anesthetis in the operation, before use special solvent is injected the phosphorus propofol sodium injection, fully mixing, intravenously administrable then.Its dosage be initial intravenous injection 6.5mg/kg when needing then through replenishing dosage 1.6mg/kg, predose must not be crossed 577.5mg, boost must not be crossed 140mg.Be used for operation anesthesia.
Phosphorus propofol sodium is through being metabolized to propofol, propofol that from phosphorus propofol sodium, discharges and propofol difference to some extent on pharmacological effect in good time.Give these article of the quick intravenous injection of health volunteer 10mg/kg, sedation effect is with the result of improvement observer's awakening/calmness scoring (MOAA/S) and comprehensive PK and PD.Propofol blood drug level peak value (2.1 ± 0.6) the μ g/mL that from phosphorus propofol sodium, discharges, on average about 8min, the time of the effect that regains one's nerve fully behind these article of study subject application is 20min to 45min.
The specific embodiment
Below in conjunction with embodiment the present invention is done further explain, but should understand the non-scope that only limits to these embodiment of scope of the present invention.
Embodiment 1: the preparation of phosphorus propofol sodium injection
The water for injection that in liquid dispensing container, adds 20000ml adds the recipe quantity phosphorus propofol sodium, stirs and makes dissolving, regulates the pH to 10 of medicinal liquid with 10%NaOH solution; Benefit adds water to full dose, adds the medicinal charcoal of 0.05% (W/V) then, and 40 ℃ were stirred 60 minutes; It is qualified to filter to clarity with the filter membrane of 0.45 μ m, measure intermediate content qualified after, decide loading amount and be sub-packed in the pharmaceutical containers; Roll lid, 121 ℃ of sterilization 8min promptly get.
Embodiment 2: the preparation of phosphorus propofol sodium injection
The water for injection that in liquid dispensing container, adds 20000ml adds recipe quantity phosphorus propofol sodium, citric acid, stirs and makes dissolving, regulates the pH to 11 of medicinal liquid with trometamol solution; Benefit adds water to full dose, adds the medicinal charcoal of 0.05% (W/V) then, stirring at room 20 minutes; It is qualified to filter to clarity with the filter membrane of 0.45 μ m, measure intermediate content qualified after, decide loading amount and be sub-packed in the pharmaceutical containers; Roll lid, 121 ℃ of sterilization 8min promptly get.
Embodiment 3: the preparation of phosphorus propofol sodium injection
The water for injection that in liquid dispensing container, adds 20000ml adds recipe quantity phosphorus propofol sodium, sodium chloride, cysteine hydrochloride, stirs and makes dissolving, regulates medicinal liquid pH to 12 with sodium carbonate liquor; Benefit adds water to full dose, adds the medicinal charcoal of 0.02% (W/V) then, and 40 ℃ were stirred 45 minutes; It is qualified to filter to clarity with the filter membrane of 0.45 μ m, measure intermediate content qualified after, decide loading amount and be sub-packed in the pharmaceutical containers; Roll lid, 121 ℃ of sterilization 8min promptly get.
Embodiment 4: the preparation of phosphorus propofol sodium injection
The water for injection that in liquid dispensing container, adds 20000ml adds recipe quantity phosphorus propofol sodium, glucose, sodium sulfite, stirs and makes dissolving; Regulate medicinal liquid pH to 13 with arginine solution, add the medicinal charcoal of 0.02% (W/V) then, stirred 30 minutes; It is qualified to filter to clarity with the filter membrane of 0.45 μ m, measure intermediate content qualified after, decide loading amount and be sub-packed in the pharmaceutical containers; Roll lid, 121 ℃ of sterilization 8min promptly get.
Embodiment 5: the preparation of phosphorus propofol sodium injection
The water for injection that in liquid dispensing container, adds 20000ml adds recipe quantity phosphorus propofol sodium, lactic acid, ascorbic acid, stirs and makes dissolving, regulates medicinal liquid pH to 12 with 10%NaOH solution; Benefit adds water to full dose, adds the medicinal charcoal of 1% (W/V) then, and 60 ℃ were stirred 10 minutes; It is qualified to filter to clarity with the filter membrane of 0.45 μ m, measure intermediate content qualified after, decide loading amount and be sub-packed in the pharmaceutical containers; Roll lid, 121 ℃ of sterilization 8min promptly get.
Embodiment 6: the preparation of phosphorus propofol sodium injection
The water for injection that in liquid dispensing container, adds 15000ml adds recipe quantity phosphorus propofol sodium, glucose, monothioglycerol, stirs and makes dissolving, regulates the pH to 11 of medicinal liquid with sodium radio-phosphate,P-32 solution; Benefit adds water to full dose, adds the medicinal charcoal of 0.5% (W/V) then, stirs 10 minutes; It is qualified to filter to clarity with the filter membrane of 0.45 μ m, measure intermediate content qualified after, decide loading amount and be sub-packed in the pharmaceutical containers; Roll lid, 121 ℃ of sterilization 8min promptly get.
Embodiment 7: the preparation of phosphorus propofol sodium injection
The water for injection that in liquid dispensing container, adds 20000ml adds recipe quantity phosphorus propofol sodium hydrate, sodium chloride, cysteine hydrochloride, stirs and makes dissolving, regulates medicinal liquid pH to 12 with 10%NaOH solution; Benefit adds water to full dose, adds the medicinal charcoal of 0.05% (W/V) then, and 40 ℃ were stirred 20 minutes; It is qualified to filter to clarity with the filter membrane of 0.45 μ m, measure intermediate content qualified after, decide loading amount and be sub-packed in the pharmaceutical containers; Roll lid, 121 ℃ of sterilization 8min promptly get.
Embodiment 8: the preparation of phosphorus propofol sodium injection
The water for injection that in liquid dispensing container, adds 16000ml adds recipe quantity phosphorus propofol sodium solvated compounds, lactic acid, sodium chloride, potassium chloride, calcium chloride, citric acid, stirs and makes dissolving, regulates medicinal liquid pH to 12 with 10%NaOH solution; Benefit adds water to full dose, adds the medicinal charcoal of 0.05% (W/V) then, stirs 60 minutes; It is qualified to filter to clarity with the filter membrane of 0.45 μ m, measure intermediate content qualified after, decide loading amount and be sub-packed in the pharmaceutical containers; Roll lid, 121 ℃ of sterilization 8min promptly get.
Embodiment 9: the preparation of special solvent
The water for injection that in liquid dispensing container, adds 4000ml, the citric acid of adding recipe quantity stirs and makes dissolving; Benefit adds water to full dose, adds the medicinal charcoal of 0.05% (W/V) then, stirs 60 minutes; It is qualified to filter to clarity with the filter membrane of 0.45 μ m, measure citric acid intermediate content qualified after, decide loading amount and be sub-packed in the pharmaceutical containers; Roll lid, 121 ℃ of sterilization 8min promptly get.
Embodiment 10: the preparation of special solvent
The water for injection that in liquid dispensing container, adds 8000ml, the glutamic acid of adding recipe quantity stirs and makes dissolving; Benefit adds water to full dose, adds the medicinal charcoal of 0.1% (W/V) then, stirs 20 minutes; It is qualified to filter to clarity with the filter membrane of 0.45 μ m, measure glutamic acid intermediate content qualified after, decide loading amount and be sub-packed in the pharmaceutical containers; Roll lid, 121 ℃ of sterilization 8min promptly get.
Embodiment 11: the preparation of special solvent
The water for injection that in liquid dispensing container, adds 4000ml, the acetic acid of adding recipe quantity stirs and makes dissolving; Benefit adds water to full dose, adds the medicinal charcoal of 0.02% (W/V) then, stirs 40 minutes; It is qualified to filter to clarity with the filter membrane of 0.45 μ m, measure acetic acid intermediate content qualified after, decide loading amount and be sub-packed in the pharmaceutical containers; Roll lid, 121 ℃ of sterilization 8min promptly get.
Embodiment 12: the preparation of special solvent
The water for injection that in liquid dispensing container, adds 8000ml, the sulphuric acid of adding recipe quantity stirs and makes dissolving; Benefit adds water to full dose, adds the medicinal charcoal of 0.05% (W/V) then, stirs 60 minutes; It is qualified to filter to clarity with the filter membrane of 0.45 μ m, measure sulphuric acid intermediate content qualified after, decide loading amount and be sub-packed in the pharmaceutical containers; Roll lid, 121 ℃ of sterilization 8min promptly get.
Embodiment 13: phosphorus propofol sodium injection study on the stability
Get the phosphorus propofol sodium injection of embodiment 7 gained, be positioned over relative humidity 75%, in 40 ℃ of biochemical incubators of temperature,, investigate outward appearance, pH, particulate matter, visible foreign matters, related substance, content respectively at 1,2,3,6 sampling at the end of month.The result sees table 1
Table 1 phosphorus propofol sodium injection formulation study on the stability
Through investigating, to quicken to place 6 months, this quality does not have significant change.
Embodiment 14: the special solvent study on the stability
Get the special solvent of embodiment 9 gained, be positioned over relative humidity 75%, in 40 ℃ of biochemical incubators of temperature,, investigate outward appearance, particulate matter respectively at 1,2,3,6 sampling at the end of month, visible foreign matters, content, the result sees table 2.
Table 2 special solvent study on the stability
| Time | Outward appearance | Particulate matter | Visible foreign matters | Content % |
| 0 month | Colourless clear liquid | Up to specification | Up to specification | 99.1 |
| January | Colourless clear liquid | Up to specification | Up to specification | 99.4 |
| February | Colourless clear liquid | Up to specification | Up to specification | 99.7 |
| March | Colourless clear liquid | Up to specification | Up to specification | 99.2 |
| June | Colourless clear liquid | Up to specification | Up to specification | 99.6 |
Through investigating, this special solvent acceleration environment was placed 6 months, and stability of solution is good.
Embodiment 15: the phosphorus propofol sodium injection mixes the study on the stability of back solution with special solvent
Get each one bottle of phosphorus propofol sodium injection and special solvent; Special solvent is injected the phosphorus propofol sodium injection, and room temperature is positioned over 8 hours respectively at sampling in 0,2,4,6,8 hour, investigates outward appearance, particulate matter; Visible foreign matters, pH, related substance, content, the result sees table 3.
Table 3 phosphorus propofol sodium injection mixes the study on the stability result of back solution with special solvent
This combination preparation mixed 8 hours, and each detection all meets the requirements as a result, and stability of solution is better.
Embodiment 16: the effect experiment of combination preparation of the present invention in the experimental dog surgical operation
13 experimental dogs are all done out laparoscopic surgery.24h fasting water before the art.Skin clean is handled, the abdominal part preserved skin.Intravenous injection phosphorus propofol sodium combination preparation 20mg/Kg.Breathe after the anesthesia onset and slow down, limb activity reduces gradually and even disappears, and eyeball is fixing blunt in fading away with corneal reflex.Carry out tracheal intubation rapidly.
The anaesthetic effect evaluation index: animal limb action, nociceptive reflex and eye situation etc. are observed in the injection back; Understand depth of anesthesia, record anesthesia onset time, single dose anesthesia are held time, repeated doses is held time, the evaluation index of number of repetition and the anaesthetic effects such as death condition of animal in experiment.
Statistical analysis: adopt SPSS13.0 software that data are analyzed
The result: (body weight 18.5 ± 2.2Kg) all adopts the anesthesia of phosphorus propofol sodium compound formulation to 13 experimental dogs, carries out abdominal regulating liver-QI road and carries out the part operation.Onset time (35.8 ± 4.1) s; Initial dose (15.8 ± 4.3) min that holds time, operating time (65.2 ± 11.5) min, repeat administration 3.8 times; Repeated doses is held time, and experimental dog does not have the tractive reaction in (14.9 ± 5.8) min. operation; Degree of flaccid muscles is satisfied, and anaesthetic effect is steady, and no heart beating stops to wait the anesthesia emergency to occur.Postoperative recovery time 6-24min, the back experimental dog of reviving has no adverse reaction, and mental status is good, recovers autonomous respiration and autonomic activities, survival rate 100% at once.The experimental dog survival time after surgical operation all reaches requirement of experiment.
Claims (11)
1. medicine composition is comprising phosphorus propofol sodium injection and special solvent.
2. to include 0.5～25% (W/V) phosphorus propofol sodium, regulate injection be that its consumption of isoosmotic osmotic pressure regulator is 0～5% (W/V), 0～1% (W/V) antioxidant, its consumption of pH regulator agent of regulating pH to 10～13 is 0～20% (W/V), water for injection to the phosphorus propofol sodium injection formula.
3. to comprise its consumption of acidic materials of regulating phosphorus propofol sodium injection pH to 6～9 consumptions be 0～5% (W/V) and water for injection to the prescription of special solvent.
4. the method for preparing of phosphorus propofol sodium injection is characterized in that the water for injection that in liquid dispensing container, adds, adds 95%～105% phosphorus propofol sodium, osmotic pressure regulator, the antioxidant of recipe quantity; Stirring makes dissolving, with pH regulator agent adjustment medicinal liquid pH to 10～13, mends and adds water to full dose; The medicinal charcoal that adds 0.01%～2% (W/V) then stirred 10～60 minutes; It is qualified to filter to clarity with microporous filter membrane, measure intermediate content qualified after, decide loading amount and be sub-packed in the pharmaceutical containers; Roll lid, sterilization promptly gets.
5. the method for preparing of special solvent is characterized in that the water for injection that in liquid dispensing container, adds, adds the acidic materials of recipe quantity 95%～105% (W/V); Stirring makes mix homogeneously, mends and adds water to full dose, and the medicinal charcoal that adds 0.01%～2% (W/V) then stirred 10～60 minutes; It is qualified to filter to clarity with microporous filter membrane, measure intermediate content qualified after, decide loading amount and be sub-packed in the pharmaceutical containers; Roll lid, sterilization promptly gets.
6. like claim 1,2 said phosphorus propofol sodium injections, it is characterized in that related phosphorus propofol sodium comprises its hydrate, anhydride and solvated compounds.
7. like claim 1,2 said phosphorus propofol sodium injections, it is characterized in that related osmotic pressure regulator is a kind of extremely several kinds in sodium chloride, glucose, potassium chloride, sodium citrate, calcium chloride, the lactic acid.
8. like claim 1,2 said phosphorus propofol sodium injections, it is characterized in that related antioxidant is a kind of extremely several kinds in citric acid, ascorbic acid, monothioglycerol, sodium sulfite, EDTA, cysteine hydrochloride, the sodium metabisulfite.
9. like claim 1,2 said phosphorus propofol sodium injections, it is characterized in that related pH regulator agent is a kind of extremely several kinds in sodium carbonate, sodium bicarbonate, sodium phosphate, dibastic sodium phosphate, sodium dihydrogen phosphate, arginine, glycine, the tromethane.
10. like claim 1,3 said special solvents, it is characterized in that containing the acid of effective dose, related acid be hydrochloric acid, phosphoric acid, acetic acid, citric acid, glutamic acid, aspartic acid, succinic acid, sulphuric acid one or more.
11. the purposes of phosphorus propofol sodium injection and special solvent combination preparation is mainly used in the anesthetis in the operation.
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