CN1775214A - Rifapentine, rifampicin, rifabutin or rifadin injection and preparation method thereof - Google Patents
Rifapentine, rifampicin, rifabutin or rifadin injection and preparation method thereof Download PDFInfo
- Publication number
- CN1775214A CN1775214A CN 200510019838 CN200510019838A CN1775214A CN 1775214 A CN1775214 A CN 1775214A CN 200510019838 CN200510019838 CN 200510019838 CN 200510019838 A CN200510019838 A CN 200510019838A CN 1775214 A CN1775214 A CN 1775214A
- Authority
- CN
- China
- Prior art keywords
- injection
- rifampicin
- rifapentine
- rifandin
- mycobutin
- 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.)
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- 239000007924 injection Substances 0.000 title claims abstract description 79
- 229960002599 rifapentine Drugs 0.000 title claims abstract description 78
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- 229960001225 rifampicin Drugs 0.000 title claims abstract description 67
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 title abstract 4
- ZWBTYMGEBZUQTK-PVLSIAFMSA-N [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17,32-tetrahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-1'-(2-methylpropyl)-6,23-dioxospiro[8,33-dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta-1(32),2,4,9,19,21,24,26,30-nonaene-28,4'-piperidine]-13-yl] acetate Chemical compound CO[C@H]1\C=C\O[C@@]2(C)Oc3c(C2=O)c2c4NC5(CCN(CC(C)C)CC5)N=c4c(=NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)c(O)c2c(O)c3C ZWBTYMGEBZUQTK-PVLSIAFMSA-N 0.000 title abstract 3
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- MOKBFXZQXUZAMV-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCOCCOCCOCCOCCOCCOCCOCCO MOKBFXZQXUZAMV-UHFFFAOYSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- NDVRMMQXKLXWQV-UHFFFAOYSA-L O.[Na+].[Na+].O=C.[O-]S[O-] Chemical compound O.[Na+].[Na+].O=C.[O-]S[O-] NDVRMMQXKLXWQV-UHFFFAOYSA-L 0.000 description 1
- 229920002582 Polyethylene Glycol 600 Polymers 0.000 description 1
- 229920002593 Polyethylene Glycol 800 Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000001467 acupuncture Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 238000011021 bench scale process Methods 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000000249 desinfective effect Effects 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002070 germicidal effect Effects 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- XGZOMURMPLSSKQ-UHFFFAOYSA-N n,n-bis(2-hydroxyethyl)octadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(=O)N(CCO)CCO XGZOMURMPLSSKQ-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 229920002523 polyethylene Glycol 1000 Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229940049413 rifampicin and isoniazid Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229940083608 sodium hydroxide Drugs 0.000 description 1
- JJICLMJFIKGAAU-UHFFFAOYSA-M sodium;2-amino-9-(1,3-dihydroxypropan-2-yloxymethyl)purin-6-olate Chemical compound [Na+].NC1=NC([O-])=C2N=CN(COC(CO)CO)C2=N1 JJICLMJFIKGAAU-UHFFFAOYSA-M 0.000 description 1
- RMLUKZWYIKEASN-UHFFFAOYSA-M sodium;2-amino-9-(2-hydroxyethoxymethyl)purin-6-olate Chemical compound [Na+].O=C1[N-]C(N)=NC2=C1N=CN2COCCO RMLUKZWYIKEASN-UHFFFAOYSA-M 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- PRXRUNOAOLTIEF-WUOFIQDXSA-N sorbitan trioleate Chemical compound CCCCCCCC\C=C\CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C\CCCCCCCC)C1OCC(O)C1OC(=O)CCCCCCC\C=C\CCCCCCCC PRXRUNOAOLTIEF-WUOFIQDXSA-N 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to a kind of rifapentine, rifampicin, rifabutine or rifandin injection and its preparation method. It includes main medicine, medicinal organic cosolvent, alkaline antioxidant, injection water surfactant and sodium hydroxide. Its main medicine can be rifapentine, rifampicin, rifabutine or rifandin. Said invention also provides the concrete steps of its preparation method.
Description
Technical field
The present invention relates to class wide spectrums such as rifapentine or rifampicin and kill tubercule bacillus antibiolics composition injection and filling agent and compound injection and filling agent novel form and preparation method thereof; Relate to rifapentine, rifampicin, Mycobutin or rifandin simply connected powder pin, aqueous injection and its combination drug powder pin, aqueous injection and preparation method thereof particularly.
Background technology
Rifapentine (Rickfer), rifampicin, Mycobutin, rifandin are the antibiotic medicines that a class wide spectrum is killed tubercule bacillus, are widely used in pulmonary tuberculosis and other treatment lungy.Because such medicine is water-soluble hardly, makes its application be subjected to very big restriction, domestic so far do not have the injection injection as yet for clinical treatment, can only oral administration.
What China mainly used clinically at present is the encapsulated and tablet of the former medicated powder of rifapentine and rifampicin.Though these medicines are strong to the penetration power of tissue, better by oral absorbance, must could arrive pulmonary through liver, peak time is long, and active drug concentration is low, and the effect of directionality sustained release is poor.Because rifapentine, rifampicin, Mycobutin, rifandin poorly water-soluble, solid preparation absorbs slow, peak reaching time of blood concentration is long, and the obstinate tuberculotherapy cycle, all between 6 months to 1 year, long-term heavy dose of oral its toxic and side effects and the harmful effect that causes were also very remarkable; And such antibiotic of life-time service, drug-resistance of bacteria also increases rapidly.
Preparation Microencapsulation 1995 about the rifampicin microemulsion; 12 (4) 401 have reported a kind of method, and rifampicin is dissolved in the sorbester p37 preparation becomes oil droplet shape suspension, are used for tubercule bacillus sterilization experiment, and this emulsion dispersion is good inadequately, and less stable is not used for clinical so far as yet.The domestic purposes that also has report rifampicin to be prepared into microcapsule and attempt to develop them with the degradable high polymer material polylactic acid, because its preparation is complicated, the granularity that generates is bigger than normal, and skewness is difficult to be used for pulmonary tuberculosis and other clinical treatment lungy as injection injection or infusion liquid.
Summary of the invention
In order to overcome rifapentine or rifampicin etc. in the defective aspect the clinical practice, overcome the bacterial drug resistance problem, the inventor is devoted to study a series of short treating periods, prevents to produce folk prescription, compound injection and filling agents such as chemical sproof rifapentine of Secondary cases or rifampicin.
The object of the present invention is to provide rifapentine, rifampicin, Mycobutin or rifandin injection and preparation method thereof, be used for intractable quick, effectively treatment lungy.
Technical scheme of the present invention: rifapentine, rifampicin, Mycobutin or rifandin injection, comprise principal agent, medicinal organic cosolvent, alkaline antioxidant and water for injection and surfactant and sodium hydroxide, principal agent is rifapentine, rifampicin, Mycobutin or rifandin, wherein the each component weight ratio is, principal agent: medicinal organic cosolvent: sodium hydroxide: alkaline antioxidant: surfactant: water for injection=1～10: 10～40: 0.001～1: 0.001～2: 0.05～3: 36～80; Addition amount of sodium hydroxide is 90%～110% of a principal agent mole.
Above-mentioned alkaline antioxidant is alkaline antioxidant such as sodium formaldehyde sulphoxylate, sodium thiosulfate, sodium sulfite.
Used surfactant is tween (20～80), OP8～50; Span (20～85); Fatty monoethanol amide (for example: lauroyl monoethanolamine, oleoyl monoethanolamine, coconut palm acyl monoethanolamine, stearyl monoethanolamine), C
6～C
10The acyl monoethanolamine; Fatty diglycollic amide (for example: lauroyl diethanolamine, oleoyl diethanolamine, coconut palm acyl diethanolamine, stearoyl diethanolamine), C
6～C
10The acyl diglycollic amide; Polyoxyethylene fatty acid ester (LAE-9,24 etc.); Polyethers (polyoxyethylene polyoxypropylene block polymer, F38, F68, F88, P75 etc.); Fatty acid and oxirane condensation polymer (SG12,20,40,50,100 etc.); Oleum Ricini and ethylene oxide condensate (EL20～130); Cithrol (PEG400MS, PEG400DS, PEG400ML, PEG400DL, PEG400MO, PEG400DO etc.); Fatty acid glyceride, methyl glycol fatty acid ester; Methyl glucoside stearate (MS), polyoxyethylene methyl glucoside stearate (MSE), alkyl polyglycoside (APG), PEG (400-5000), isopropyl myristate etc.; Synthetic phosphatidyl monoethanolamine, synthetic phosphatidyl diethanolamine and/or PHOSPHATIDYL ETHANOLAMINE etc.
Above-mentioned organic cosolvent is propylene glycol, ethanol, glycerol formal, ethylenediamine, PEG (400-5000), ethanolamine and/or other fatty amine etc.
The present invention also can contain the auxilliary thing that makes up a prescription, and the auxilliary thing that makes up a prescription is antituberculotics and/or synthesising bacteria anti-reflecting medicine and/or antiviral drugs, and its consumption is 0.01～10 times of principal agent weight.
Antituberculotics is isoniazid, ethambutol, sodium aminosalicylate, pyrazinamide, capreomycin, viomycin and/or cycloserine etc., the synthesising bacteria anti-reflecting medicine ofloxacin, ciprofloxacin, sparfloxacin, levofloxacin, good for husky star, lomefloxacin, Pu Lusha star, fleroxacin, Lu's Flucloxacillin, Q-35, trovafloxacin and/or Ge Qisha magnitude, antiviral drugs zidovudine, didanosine, zalcitabine, Si Tanfuding, Lei Mifuding; Chloromycetin, acyclovir, valaciclovir, desciclovir, penciclovir and/or ganciclovir etc.
Above-mentioned wide spectrum is killed the preparation method of tubercule bacillus antibiolics composition injection, carry out according to the following steps: get principal agent, auxilliary thing, organic cosolvent, surfactant, alkaline antioxidant and normal saline or the water for injection of making up a prescription places Agitation Tank to be dissolved into homogeneous phase earlier, add sodium hydroxide solution and stir adjust pH to 7.0～9.0, make each composition fully be dissolved in the aqueous solution, clear solution takes on a red color, filter, the ampoule bottle packing, fill nitrogen and seal, steam sterilization promptly gets wide spectrum and kills tubercule bacillus antibiolics agent.
The present invention also can be dissolved in organic solvent with principal agent (or principal agent+accessory drugs), adds active carbon, refluxes; Filter, reclaim solvent, recrystallization is pulverized, and sieve is got the above fine powder of 120 orders, makes injectable sterile powder; Cosolvent, surfactant, antioxidant and normal saline or water for injection, sodium hydroxide solution dropped in the reactor in the prescription ratio mix, add the 1-10wt% active carbon, reflux, filter, the ampoule bottle packing is filled nitrogen and is sealed, steam sterilization is prepared into powder pin double solvents; Constitute rifapentine, rifampicin, Mycobutin or rifandin injection by injectable sterile powder and powder pin double solvents.
The use of the double solvents that surfactant of the present invention, alkaline antioxidant and sodium hydroxide, medicinal organic cosolvent, water for injection (or normal saline) are formed is a key point of the present invention.The applicant finds that any one or the two or more mixed solvent in propylene glycol, ethanol, glycerol formal, ethylenediamine, ethanolamine and other fatty amine is medicinal good organic cosolvents such as rifapentine.This kind solvent and surfactant are used all good dissolving and solubilization.Glycerol formal and rifapentine, rifampicin, sodium hydroxide solution dissolve each other under Action of Surfactant.5～40% glycerol formal aqueous solution adds small amounts of sodium hydroxide, middle long-chain fatty acid acyl diethanolamine can make solubilisings such as rifapentine, rifampicin reach 5%～20%, and be controlled within the available pH.
Composite auxiliary solvent has the latent solvent characteristic.The double solvents that certain density sodium chloride solution and normal saline are formed has the inhibition haemolysis.Double solvents constitutes and uses not only increases the dissolubility of medicine in water such as rifapentine, rifampicin, and reduces in the compound preparation auxilliary negative responses of making up a prescription between the thing such as medicine such as rifapentine, rifampicin and isoniazid.
The present invention has broken through medicines such as rifapentine and only has been used for oral limitation, raising widely bioavailability, reduce the using dosage of medicine, formulated single, the compound filling agent of medicines such as novel rifapentine or rifampicin and the laboratory and the industrialized process for preparing of injection (comprising liquid drugs injection and powder pin).Above-mentioned medicament can be used as injection and is used for the empyema treatment, and the lymphoid tuberculosis treatment realizes many existing dosage form (as rifapentine, rifampicin oral preparation) Expected Results that are beyond one's reach of a line tuberculosis medicine that are insoluble in water, becomes specific drug.The serial injection of rifapentine, rifampicin and combination drug thereof is applied to fibre bronchus mirror and directly is filled into pulmonary, at the focus sustained-release and controlled release, has improved curative effect.Rifapentine, rifampicin injection novel form are in that extremely significant effect is arranged aspect pulmonary tuberculosis, the tuberculosis clinical treatment, for modern times treatment lungy provides multiple new pharmaceutical dosage form.Select different formulation optimization pharmaceutical dosage forms, increased multiple route of administration and drug effect.For example adding rifapentine that the lung membrane permeablizer makes or rifampicin injection again uses as infusion liquid and has improved curative effect; In above-mentioned preparation, add different antibacterials and promptly can be made into combination drug forms, not only reduce or eliminate the drug resistance of tubercule bacillus, and promote and quicken the healing of open empyema ulceration., easy to use before rifapentine or rifampicin and compound recipe powder acupuncture thereof are treated with the double solvents dissolving, safety, efficacy stability is convenient to storage and transport, and the shelf-life is identical with rifapentine or rifampicin crude drug, has solved the difficult problem in this medicine market accumulating.
The extracorporal dialysis experimental result shows: made rifapentine or rifampicin list, compound recipe aqueous injection, rifapentine or rifampicin and compound recipe powder pin thereof all have controlled-release function.Rifapentine and rifampicin in the clinical observation discovery solution can be kept 1～2 day at pulmonary's sustained release.
The extracorporeal disinfecting experimental result shows: made rifapentine or rifampicin aqueous injection and compound recipe aqueous injection thereof, rifapentine or rifampicin and compound recipe powder pin thereof have identical or slightly high germicidal efficiency with equivalent rifapentine or rifampicin crude drug.
Can develop single, compound injection aqueous injection such as multiple rifapentine according to the present invention, rifapentine etc. are single, compound recipe powder pin solution, are fit to the use of various syringes, comprise infusion solutions.Above-mentioned preparation method not only is fit to bench scale preparation, also is applicable to suitability for industrialized production.
Aqueous injection such as rifapentine or rifampicin and compound injection aqueous injection thereof, powder pin such as rifapentine or rifampicin and compound recipe powder pin thereof meet the requirement of injection, and technology is simple, is fit to suitability for industrialized production.
The specific embodiment:
Rifapentine, rifampicin etc. is dissolved in the double solvents of organic cosolvent, sodium hydroxide, alkaline antioxidant, surfactant, water for injection (or normal saline) composition, form simply connected powder pin, aqueous injection and its combination drug powder pin, the aqueous injection of medicines such as rifapentine or rifampicin, contain between the principal agent concentration 0.5%～10%.
Rifapentine or rifampicin, Mycobutin, rifandin are water-soluble hardly, and the double solvents that adds sodium hydroxide, cosolvent, water for injection (or normal saline) pH regulator agent composition has good dissolubility to rifapentine, and concentration reaches as high as 10%.
Add amount of sodium hydroxide and be 90%～110% of medicine mole such as rifapentine, generate rifapentine sodium salt solubilising, regulate the pH value of injection.Alkalescence antioxidant makes generation rifapentine sodium salt stable.Surfactant, organic cosolvent increase the dissolubility of medicines such as rifapentine, and cushioning effect are arranged.
The pharmacological toxicology experimental result shows, made rifapentine, rifampicin, Mycobutin or rifandin aqueous injection, injectable powder, rifapentine, rifampicin, Mycobutin or rifandin combination drug aqueous injection, injectable powder not haemolysis, do not have irritated phenomenon, LD
50=650mg～850mg/kg nonirritant can be used as intravenous injection, and local injection agent and filling agent use.
Stability experiment is the result show, made rifapentine, rifampicin, Mycobutin or rifandin powder pin, and rifapentine, rifampicin, Mycobutin or rifandin compound recipe injectable powder are 1～2 year with the crude drug identical shelf-life of stability.Made rifapentine, rifampicin, Mycobutin or rifandin aqueous injection, rifapentine, rifampicin, Mycobutin or rifandin combination drug aqueous injection content of dispersion can reach 10%, and the no solid matter of conventional filtration is residual.Good stability fills nitrogen and preserves below 4 ℃ and physicochemical change did not take place in 6～10 months, and it is constant to be used for injection injection curative effect, is convenient to store transportation and clinical use.
Made rifapentine, rifampicin, Mycobutin or rifandin aqueous injection and compound injection thereof are suitable for pulmonary's perfusion, intramuscular injection and intravenous injection treatment.
Made rifapentine, rifampicin, Mycobutin or rifandin aqueous injection and compound injection aqueous injection thereof, rifapentine, rifampicin, Mycobutin or rifandin and compound recipe powder pin thereof can be done the intravenous injection treatment with tubercular and other pathogenic bacterial infections patient.
Embodiment 1:
5 parts of rifapentines (in rifampicin, Mycobutin, the rifandin crude drug a kind of), 40 parts of organic cosolvents (the added-time does not supply with water for injection or normal saline), the auxilliary thing that makes up a prescription (does not add during folk prescription for 5 parts, supply with water for injection or normal saline), 0.05 part in surfactant (the added-time does not supply with water for injection or normal saline), 0.0057 part of sodium hydroxide, 0.1 part in alkaline antioxidant, 49.85 parts of normal saline (or water for injection), pH are 7.8～9.0.
Aqueous injection preparation method: place Agitation Tank to be dissolved into homogeneous phase earlier by the accurate weighting raw materials of above-mentioned prescription, organic cosolvent, surfactant, the auxilliary thing that makes up a prescription, alkaline antioxidant, normal saline (or water for injection), add sodium hydroxide solution and stir adjust pH to 8.9, each composition is fully dissolved be dispersed in the aqueous solution, clear solution takes on a red color.
Thin film filters, and the ampoule packing is filled nitrogen and sealed, steam sterilization.Finished product is rifapentine folk prescription or compound recipe aqueous injection.
The preparation method of injectable powder: by above-mentioned prescription crude drug is dissolved in organic solvent, adds active carbon, refluxed 10 minutes.Filter, recrystallization is pulverized, and sieve is got the above fine powder of 120 orders, and 0.25 gram bottle packing makes injectable sterile powder.
Cosolvent, sodium hydroxide, pH regulator agent, alkaline antioxidant, normal saline (or water for injection) are mixed in Agitation Tank by formula proportion, add the 1-10wt% active carbon, refluxed 10 minutes, the pressurization thin film filters, the packing of 5ml ampoule bottle, fill nitrogen and seal, sterilization is prepared into powder pin double solvents.
During clinical practice, the powder pin solvent injection powdered medicine bottle of drawing preparation with syringe dissolves, and generates aqueous injection, for perfusion, intramuscular injection and used for intravenous injection.Add other auxilliary thing or auxilliary thing solution and powder pin solvents of making up a prescription of making up a prescription as required and make rifapentine compound recipe injectable powder.
Embodiment 2:
Rifapentine (rifampicin, Mycobutin or rifandin) aqueous injection prescription and preparation method (part by weight):
| Component | Example 1 | Example 2 | Example 3 |
| Rifapentine (rifampicin, Mycobutin or rifandin) propylene glycol Polyethylene Glycol sodium formaldehyde sulphoxylate sodium hydroxide * normal saline | 3 30 10(PEG 1000) 0.05 0.0034 56.95 | 5 35 10(PEG 800) 0.1 0.0057 49.89 | 8 40 15(PEG 600) 0.1 0.0091 36.89 |
* sodium hydroxide adds with 0.005%～0.15% solution
According to the prescription metering, accurately take by weighing rifapentine (rifampicin, Mycobutin or rifandin), cosolvent, Polyethylene Glycol, antioxidant, normal saline and place Agitation Tank, each composition is fully dissolved, add sodium hydroxide solution adjust pH to 8.7, generate red clear solution.Filter, fill is filled nitrogen and is sealed, and sterilization makes the rifapentine injection.
Embodiment 3
Rifapentine (rifampicin, Mycobutin or rifandin) combination drug aqueous injection prescription and preparation method (part by weight):
| Component | Example 1 | Example 2 | Example 3 |
| Rifapentine (rifampin, Mycobutin or R-76-1) isoniazid lauroyl diethanolamine propane diols sodium formaldehyde sulphoxylate NaOH physiological saline | 3 3 1 30 0.05 0.0034 62.95 | 5 4 1.5 40 0.1 0.0057 49.394 | 8 5 2 40 0.1 0.0091 44.891 |
Taking by weighing rifapentine (rifampicin, Mycobutin or rifandin), lauroyl diethanolamine, isoniazid, propylene glycol, sodium hydroxide, sodium formaldehyde sulphoxylate, normal saline according to prescription metering places Agitation Tank to stir, make abundant dissolving, filter, obtain transparent red solution, be rifampicin combination drug injection.Packing is filled nitrogen and is sealed, and sterilization is for use.
Embodiment 4
Rifapentine injectable powder and preparation method:
According to embodiment 2 prescription dosage, accurately take by weighing cosolvent, Polyethylene Glycol, sodium hydroxide, sodium formaldehyde sulphoxylate, lauroyl diethanolamine, normal saline and place Agitation Tank, stirring is fully dissolved each composition, activated carbon decolorizing, filter, packing is filled nitrogen and is sealed, powder pin injection double solvents is made in 125 ℃ of water vapour sterilizations.
Rifapentine is dissolved in medicinal organic solvent, adds the active carbon of 2wt%, reflux; Filter, recrystallization is pulverized, and sieve is got the above fine powder of 120 orders, makes injectable sterile powder, and packing is standby.
Face with preceding injection double solvents with preparation and inject the bottle that the rifapentine sterilized powder is housed, make its dissolving, the aqueous injection of making is directly used in injection for curing.
Embodiment 5
Mycobutin injectable powder and preparation method:
In 10 parts: 0.002 part: 0.1 part: the ratio of 1: 20 part (parts by weight), take by weighing ethylenediamine, sodium hydroxide, sodium thiosulfate, Tween 80, normal saline and place Agitation Tank, stirring is fully dissolved each composition, activated carbon decolorizing, filter, packing is filled nitrogen and is sealed, powder pin injection double solvents is made in 125 ℃ of water vapour sterilizations.
2 parts of Mycobutins are dissolved in medicinal organic solvent, add the active carbon of 2wt%, reflux; Filter, recrystallization is pulverized, and sieve is got the above fine powder of 120 orders, makes injectable sterile powder, and packing is standby.
Face with preceding injection double solvents with preparation and inject the bottle that the Mycobutin sterilized powder is housed, make its dissolving, the aqueous injection of making is directly used in injection for curing.
Embodiment 6
Rifapentine combination drug injectable powder and preparation method:
According to embodiment 3 prescription dosage, take by weighing lauroyl diethanolamine, propylene glycol, sodium hydroxide, sodium formaldehyde sulphoxylate, isoniazid, normal saline and place Agitation Tank, stirring is fully dissolved each composition, activated carbon decolorizing, filter, packing is filled nitrogen and is sealed, powder pin injection double solvents is made in 125 ℃ of water vapour sterilizations.
Rifapentine is dissolved in organic solvent, adds the active carbon of 3wt%, reflux; Filter, recrystallization is pulverized, and sieve is got the above fine powder of 120 orders, makes injectable sterile powder, and packing is standby.
Face the bottle that the rifapentine sterilized powder is housed with preceding injection double solvents injection and make its dissolving, make rifapentine-isoniazid composite solution and can be directly used in injection for curing preparation.
Mycobutin, rifampicin, rifandin medicine DANFU side medicine injectable powder prepare with method.
Press embodiment 1～6 formula proportion and amplify, can carry out the industrial mass preparation and produce, the material proportion of suitability for industrialized production, processing step, process conditions (temperature, pressure etc.) are constant.
Claims (8)
1. rifapentine, rifampicin, Mycobutin or rifandin injection, comprise principal agent, medicinal organic cosolvent, alkaline antioxidant and water for injection and surfactant and sodium hydroxide, principal agent is rifapentine, rifampicin, Mycobutin or rifandin, wherein the each component weight ratio is, principal agent: medicinal organic cosolvent: sodium hydroxide: alkaline antioxidant: surfactant: water for injection=1～10: 10～40: 0.001～1: 0.001～2: 0.05～3: 36～80; Addition amount of sodium hydroxide is 90 %～110% of principal agent mole.
2. injection according to claim 1 is characterized in that: alkaline antioxidant is sodium formaldehyde sulphoxylate, sodium thiosulfate or sodium sulfite; Surfactant is polysorbas20～80, OP8～50, span 20～85, fatty monoethanol amide, C
6～C
10Acyl single ethanol amide, fatty diglycollic amide, C
6～C
10Acyl diglycollic amide, polyoxyethylene fatty acid ester, cithrol, fatty acid glyceride, methyl glycol fatty acid ester, methyl glucoside stearate, polyoxyethylene methyl glucoside stearate, alkyl polyglycoside, PEG400-5000, isopropyl myristate, synthetic phosphatidyl monoethanolamine, synthetic phosphatidyl diethanolamine and/or PHOSPHATIDYL ETHANOLAMINE; Medicinal organic cosolvent is propylene glycol, ethanol, glycerol formal, ethylenediamine, PEG, ethanolamine and/or other fatty amine.
3. injection according to claim 1 and 2 is characterized in that: contain the auxilliary thing that makes up a prescription, the auxilliary thing that makes up a prescription is antituberculotics and/or synthesising bacteria anti-reflecting medicine and/or antiviral drugs, and its consumption is 0.01～10 times of principal agent weight.
4. injection according to claim 3, it is characterized in that: antituberculotics is an isoniazid, ethambutol, sodium aminosalicylate, pyrazinamide, streptomycin, capreomycin, viomycin and/or cycloserine, synthesising bacteria anti-reflecting medicine is an ofloxacin, ciprofloxacin, sparfloxacin, levofloxacin, good for husky star, lomefloxacin, the Pu Lusha star, fleroxacin, Lu's Flucloxacillin, Q-35, trovafloxacin and/or Ge Qisha star, antiviral drugs are zidovudine, didanosine, zalcitabine, Si Tanfuding, Lei Mifuding, chloromycetin, acyclovir, valaciclovir, desciclovir, penciclovir and/or ganciclovir.
5. the preparation method of claim 1 or 2 described rifapentines, rifampicin, Mycobutin or rifandin injection, it is characterized in that, carry out according to the following steps: get principal agent, organic cosolvent, alkaline antioxidant, surfactant and water for injection and place Agitation Tank to be dissolved into homogeneous phase earlier, add sodium hydroxide solution and stir adjust pH to 7.0～9.0, filter, the ampoule bottle packing is filled nitrogen and is sealed, and sterilization promptly gets rifapentine, rifampicin, Mycobutin or rifandin injection.
6. the preparation method of the described rifapentine of claim 3, rifampicin, Mycobutin or rifandin injection, it is characterized in that: carry out according to the following steps: get principal agent, auxilliary thing, organic cosolvent, alkaline antioxidant, surfactant and the water for injection of making up a prescription places Agitation Tank to dissolve, add sodium hydroxide solution and stir adjust pH to 7.0～9.0, filter, the ampoule bottle packing, fill nitrogen and seal, sterilization promptly gets rifapentine, rifampicin, Mycobutin or rifandin compound injection.
7. the preparation method of claim 1 or 2 described rifapentines, rifampicin, Mycobutin or rifandin injection is characterized in that: principal agent is dissolved in medicinal organic solvent, adds active carbon, reflux; Filter, recrystallization is pulverized, and sieve is got fine powder, makes injectable sterile powder; Place Agitation Tank to dissolve organic cosolvent, surfactant, alkaline antioxidant and water for injection, sodium hydroxide solution, add active carbon, reflux, filter, the ampoule bottle packing is filled nitrogen and is sealed, and sterilization is prepared into powder pin double solvents; Constitute rifapentine, rifampicin, Mycobutin or rifandin injection by injectable sterile powder and powder pin double solvents.
8. the preparation method of the described rifapentine of claim 3, rifampicin, Mycobutin or rifandin compound injection is characterized in that: principal agent is dissolved in medicinal organic solvent, adds active carbon, reflux; Filter, recrystallization is pulverized, and sieve is got the above fine powder of 120 orders, makes injectable sterile powder; To assist the thing that makes up a prescription, organic cosolvent, surfactant, alkaline antioxidant and water for injection, sodium hydroxide solution and place Agitation Tank to dissolve, and add active carbon, and reflux, and filter, the ampoule bottle packing is filled nitrogen and is sealed, and sterilization is prepared into powder pin double solvents; Constitute rifapentine, rifampicin, Mycobutin or rifandin compound injection by injectable sterile powder and powder pin double solvents.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510019838 CN1775214A (en) | 2005-11-18 | 2005-11-18 | Rifapentine, rifampicin, rifabutin or rifadin injection and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510019838 CN1775214A (en) | 2005-11-18 | 2005-11-18 | Rifapentine, rifampicin, rifabutin or rifadin injection and preparation method thereof |
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| CN1775214A true CN1775214A (en) | 2006-05-24 |
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| CN 200510019838 Pending CN1775214A (en) | 2005-11-18 | 2005-11-18 | Rifapentine, rifampicin, rifabutin or rifadin injection and preparation method thereof |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2481109C1 (en) * | 2012-03-20 | 2013-05-10 | Закрытое акционерное общество "Брынцалов-А" | Parenteral drug preparation of rifabutin for therapy of human and animal infectious diseases |
| CN103976959A (en) * | 2013-02-07 | 2014-08-13 | 黑龙江天行健医药科技开发有限公司 | Rifampicin freeze-dried powder injection and preparation process thereof |
| CN104027314A (en) * | 2014-06-16 | 2014-09-10 | 浙江佐力药业股份有限公司 | Freeze-dried preparation of rifampicin and preparation method thereof |
| CN106860468A (en) * | 2017-03-01 | 2017-06-20 | 新乡医学院第附属医院 | A kind of formula for treating phthisical pharmaceutical composition and preparation method thereof |
| CN110964039A (en) * | 2019-12-06 | 2020-04-07 | 重庆华邦胜凯制药有限公司 | Compound and preparation method thereof |
| CN113015519A (en) * | 2019-09-12 | 2021-06-22 | 生物验证系统股份公司 | Rifabutin treatment methods, uses and compositions |
| CN113164471A (en) * | 2018-11-30 | 2021-07-23 | 淀粉样蛋白解决方案株式会社 | A composition for treating amyloid cranial nerve disease and its treatment method |
| CN113908129A (en) * | 2021-10-29 | 2022-01-11 | 南京海纳医药科技股份有限公司 | Rifampicin freeze-dried powder for injection and production method thereof |
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2005
- 2005-11-18 CN CN 200510019838 patent/CN1775214A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2481109C1 (en) * | 2012-03-20 | 2013-05-10 | Закрытое акционерное общество "Брынцалов-А" | Parenteral drug preparation of rifabutin for therapy of human and animal infectious diseases |
| CN103976959A (en) * | 2013-02-07 | 2014-08-13 | 黑龙江天行健医药科技开发有限公司 | Rifampicin freeze-dried powder injection and preparation process thereof |
| CN103976959B (en) * | 2013-02-07 | 2016-05-25 | 瑞阳制药有限公司 | Rifampin freeze-dried powder and preparation technology thereof |
| CN104027314A (en) * | 2014-06-16 | 2014-09-10 | 浙江佐力药业股份有限公司 | Freeze-dried preparation of rifampicin and preparation method thereof |
| CN106860468A (en) * | 2017-03-01 | 2017-06-20 | 新乡医学院第附属医院 | A kind of formula for treating phthisical pharmaceutical composition and preparation method thereof |
| CN113164471A (en) * | 2018-11-30 | 2021-07-23 | 淀粉样蛋白解决方案株式会社 | A composition for treating amyloid cranial nerve disease and its treatment method |
| CN113015519A (en) * | 2019-09-12 | 2021-06-22 | 生物验证系统股份公司 | Rifabutin treatment methods, uses and compositions |
| CN110964039A (en) * | 2019-12-06 | 2020-04-07 | 重庆华邦胜凯制药有限公司 | Compound and preparation method thereof |
| CN113908129A (en) * | 2021-10-29 | 2022-01-11 | 南京海纳医药科技股份有限公司 | Rifampicin freeze-dried powder for injection and production method thereof |
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