CN103800913A - Composition capable of eliminating clouding formation phenomenon of TPGS and application thereof in medicinal preparation - Google Patents
Composition capable of eliminating clouding formation phenomenon of TPGS and application thereof in medicinal preparation Download PDFInfo
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- CN103800913A CN103800913A CN201210456014.5A CN201210456014A CN103800913A CN 103800913 A CN103800913 A CN 103800913A CN 201210456014 A CN201210456014 A CN 201210456014A CN 103800913 A CN103800913 A CN 103800913A
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Abstract
The invention relates to a composition capable of eliminating HS15 clouding formation phenomenon of TPGS (tocopheryl polyethylene glycol succinate), which comprises an insoluble drug, TPGS, polyethylene oxide-polypropylene oxide copolymer, a polyhydroxylated compound and water, wherein the weight ratio of insoluble drug to TPGS to polyethylene oxide-polypropylene oxide copolymer to the polyhydroxylated compound is (0.001-2):1:(0.5-5):(2-20), and the rest is water. When the composition is used for preparing injection of common insoluble drug, the obtained preparation can bear sterilization at 100DEG C for 30 min and 121 DEG C for 8 min without clouding formation, so as to ensure the controllability of the entire preparation process and avoid negative results arising from clouding formation phenomenon during sterilization of the preparation. The composition disclosed by the invention eliminates the clouding formation phenomenon of TPGS, and solves the serious problem when TPGS is applied in industrial production.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to a kind of TPGS of elimination and play the combination of phenomenon covered with clouds and the application in pharmaceutical preparation thereof.
Background technology
Alpha-tocopherol Polyethylene Glycol (PEG) 1000 succinates, being TPGS, is by alpha-tocofecol succinic acid ester and PEG1000 esterification and obtain the hydrophilic group that contains tocopherol lipophilic group and polyethylene glycol long chain, be a kind of nonionic surfactant, loaded American Pharmacopeia.Its mean molecule quantity is about 1513, and structural formula is as follows:
TPGS is produced and is gone on the market by Eastman company of the U.S. as far back as nineteen fifty, and nineteen sixty finds that it can be used as solubilizing agent application, and then also occurs about the report of its toxicity, safety thereupon.Start the eighties in 20th century by TPGS treatment tocopherol deficiency disease, feature and the application of himself paid close attention in increasing research afterwards, particularly as the absorption enhancer of difficult absorbing material and the topical application of hemorrhage carrier etc. such as ring robe element, vitamin D, so far produce for many years after deliberation and continuously existing amprenavir oral liquid and the capsule listing using TPGS as adjuvant of the U.S. at present.
Due to the amphipathic and good water solublity of TPGS, be good solubilizing agent for lipophilic substance, in the time that forming micelle or Emulsion, itself and insoluble drug can significantly improve the absorption of medicine in gastrointestinal tract.Compared with other surfactants, TPGS also has antioxidation, and this is more conducive to improve the stability of preparation.
Deducibility thus, TPGS will become the surfactant of high-efficiency low-toxicity of new generation in the near future.Aspects such as the carriers in solubilizing agent, emulsifying agent, fat-soluble medicine transmission system is had boundless application prospect by it.
Although TPGS has above-mentioned plurality of advantages, it also exists very serious shortcoming, in TPGS structure, exists and limits it needing the hydrophilic polyoxyethylene fragment-Polyethylene Glycol of extensive use in high temperature sterilize preparation.
Under anhydrous state, polyoxyethylene chain indention state in TPGS, be dissolved in the oxygen atom on ehter bond and the hydrogen atom in water after aquation and form faint hydrogen bond, strand is meander-like, hydrophilic oxygen atom is positioned at the outside of chain, and ethylidine (-CH2CH2-) is positioned at the inner side of chain, thereby chain is around just like a hydrophilic entirety.
Heat release because form the reaction of hydrogen bond, and this hydrogen bonded power a little less than, so TPGS aqueous solution, in the time that temperature raises, because the hydrogen bond of combination is destroyed, weakens its hydrophilic, thereby is become the emulsion of white casse by original clear solution.
If in industrialized great production, TPGS plays the serious consequence that phenomenon covered with clouds may cause: a collection of several the injections take TPGS as solubilizing agent even are continuously in the time carrying out sterilizing, owing to playing the scrapping of preparation that cause covered with clouds, this not only causes the multiple unnecessary loss of business manpower, material resources, financial resources etc., but also causes the uncontrollability of technique and the randomness of qualified preparation in the relevant sterilization preparation preparation process of TPGS.
In addition, to play the serious consequence that phenomenon covered with clouds also may cause be that its application prospect is had a greatly reduced quality to TPGS.
Summary of the invention
The above-mentioned serious problems that exist for TPGS-play phenomenon covered with clouds, the object of the invention is that screening can eliminate that TPGS plays the combination of phenomenon covered with clouds and by this combination for the preparation of the fat-soluble medicine sterilization preparation take TPGS as solubilizing agent.
For realizing object of the present invention, inventor provides following technical scheme:
A kind of TPGS of elimination plays the combination of phenomenon covered with clouds and the application in the fat-soluble medicine sterilization preparation take TPGS as solubilizing agent thereof.
The TPGS of elimination provided by the present invention plays the combination of phenomenon covered with clouds, comprises insoluble drug, TPGS, poloxalkol and or polyoxyethylene (hydrogenation) Oleum Ricini, polyol and water.
Insoluble drug in combination of the present invention should comprise ubiquinone
10, fatsoluble vitamin (A, D, E, K), nimodipine, ginsenoside, Alprostadil, adenosine cyclophosphate, acyclovir, paclitaxel, Docetaxel, hydroxy camptothecin, ribavirin, cucurbitacin etc. are at interior poorly water-soluble, can be with the medicine of TPGS increase-volume.
Inventor studies discovery, adopts the ubiquinone of this combination preparation
10, the injection such as fatsoluble vitamin (A, D, E, K), ginsenoside, Alprostadil, adenosine cyclophosphate, acyclovir, paclitaxel, Docetaxel, ribavirin, nimodipine, cucurbitacin, respectively when 100 ℃ of 30 min and the 121 ℃ of 8 min sterilizing, all be there is not to phenomenon covered with clouds in these injection.
Poloxalkol of the present invention, its structural formula is EOn-POm-EOn, it is ABA type triblock copolymer, is the novel macromolecule non-ionic surface active agent of a class.In theory, the compound of this type of basic structure can have countless versions, its molecular weight from 1000 to more than 7000 not etc., be copolymerized into the different compound of hydrophile-lipophile balance value by the polyoxypropylene of appropriate amount and the polyoxyethylene of appropriate amount.As preferably, be decided to be EO
76-PO
30-EO
76, i.e. Pluronic 188(F68).
Polyoxyethylene of the present invention (hydrogenation) Oleum Ricini comprises the poly-hydrogen-oxygen ester 35(Cremophor EL of polyoxyl 40 hydrogenated castor oil (RH40), Oleum Ricini), the poly-hydrogen-oxygen ester 35(purification level of Oleum Ricini) (Cremophor ELP).
In the time that combination of the present invention is made up of insoluble drug, TPGS, poloxalkol, polyol and water, wherein insoluble drug: TPGS: poloxalkol: polyol: the weight ratio of water is 0.001-2:1:0.5-5:2-20, surplus is water.
When combination of the present invention is by insoluble drug, TPGS, polyoxyethylene (hydrogenation) Oleum Ricini, when polyol and water composition, wherein insoluble drug: TPGS: polyoxyethylene (hydrogenation) Oleum Ricini: polyol: the weight ratio of water is 0.001-2:1:0.5-5:2-20:30-50, as preferably, insoluble drug: TPGS: polyoxyethylene (hydrogenation) Oleum Ricini: polyol: the weight ratio of water is 0.001-2:1:1-4:3-15:30-50, as more preferably, insoluble drug: TPGS: polyoxyethylene (hydrogenation) Oleum Ricini: polyol weight ratio is 0.001-2:1:1.5-4:3-10, surplus is water 30-50.
When combination of the present invention is by insoluble drug, TPGS, poloxalkol and polyoxyethylene hydrogenated Oleum Ricini (Oleum Ricini), polyol and water., wherein insoluble drug: TPGS: poloxalkol and polyoxyethylene hydrogenated Oleum Ricini (Oleum Ricini): polyol: the weight ratio of water is 0.001-2:1:0.5-5:2-20:30-50, as preferably, insoluble drug: TPGS: poloxalkol and polyoxyethylene hydrogenated Oleum Ricini (Oleum Ricini): polyol: the weight ratio of water is 0.001-2:1:1-4:3-15:30-50, as more preferably, insoluble drug: TPGS: poloxalkol and polyoxyethylene hydrogenated Oleum Ricini (Oleum Ricini): polyol weight ratio is 0.001-2:1:1.5-4:3-10, surplus is water.
Polyol of the present invention, comprises a kind of or several mixture in glucose, xylose, fructose, sucrose, maltose, lactose, galactose, trehalose, mannitol, xylitol, maltol, propylene glycol, glycerol, PEG200, PEG300, PEG400, PEG600, PEG1000, PEG2000, PEG4000, PEG6000 etc.; As preferably, the polyol in described compositions is decided to be xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, glycerol, PEG200, PEG300, PEG400, PEG600; As more preferably, the polyol in described compositions is decided to be propylene glycol, glycerol, PEG300, PEG400.
Water of the present invention can be the one in purified water, distilled water, water for injection, sterilizing purified water, sterilized water for injection etc.As preferred version, water of the present invention is decided to be sterilizing purified water or sterilized water for injection.
Inventor research also finds, adopt separately the polyol in combination of the present invention or use separately poloxalkol with or the ubiquinone prepared together with TPGS of polyoxyethylene (hydrogenation) Oleum Ricini
10, the injection such as fatsoluble vitamin (A, D, E, K), ginsenoside, Alprostadil, adenosine cyclophosphate, acyclovir, paclitaxel, Docetaxel, hydroxy camptothecin, ribavirin, nimodipine, cucurbitacin, in the time of 100 ℃ of 30 min and 121 ℃ of 8 min sterilizing, it is muddy that preparation all can become, in part preparation, also can separate out gelatinous precipitate, show and very significantly play phenomenon covered with clouds.And only have when by the polyol in combination of the present invention and poloxalkol and or polyoxyethylene (hydrogenation) Oleum Ricini while share, in order to the above-mentioned injection take TPGS as solubilizing agent of preparation, in the time of 100 ℃ of 30 min and 121 ℃ of 8 min sterilizing, there is not phenomenon covered with clouds.
The present invention also provides the above-mentioned TPGS of elimination to play the application in the insoluble drug oral liquid take TPGS as solubilizing agent that is combined in of phenomenon covered with clouds.
The present invention also provides the above-mentioned TPGS of elimination to play the application in the insoluble drug injectable emulsion take TPGS as emulsifying agent that is combined in of phenomenon covered with clouds.
The present invention also provides the above-mentioned TPGS of elimination to play the application in the insoluble drug Orally taken emulsion take TPGS as emulsifying agent that is combined in of phenomenon covered with clouds.
The present invention has proposed to eliminate TPGS and has risen the scheme of phenomenon covered with clouds first, pay close attention to TPGS and easily ignored by everybody the phenomenon covered with clouds that rises that but has very big risk in production application, make the pharmaceutical preparation that needs sterilizing relevant to TPGS in suitability for industrialized production, conscientiously the controllability of each step process and the homogeneity of preparation and safety have been met, the appearance that avoided that a collection of even several the preparations that phenomenon covered with clouds may cause are completely unavailable because rising, formulation content, particle diameter and particle size distribution changes huge etc. various negative results before and after sterilizing.
The specific embodiment
For a more clear understanding of the present invention, the present invention is described in further detail for the embodiment completing according to technical scheme of the present invention providing below in conjunction with inventor.
Be below the embodiment that the inventor provides, the present invention is not limited to these embodiment, and any pro forma accommodation that the present invention is made and/or change all will fall into protection domain of the present invention.
embodiment 1:the independent ubiquinone with TPGS solubilising
10the preparation of injection
Prescription 1:
Ubiquinone
1075 mg
TPGS 600 mg
Water for injection 28 mL
30 mL
Technique:
Take the ubiquinone of recipe quantity
10, TPGS forms oil phase; Measure the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After material in oil phase dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, half preparation is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: gained preparation is yellow transparent solution.
After sterilizing, observe: preparation becomes muddy, and the bottle end has claret jelly to separate out, illustrate that the certain existence of TPGS significantly plays phenomenon covered with clouds.
embodiment 2: with the ubiquinone without a phenomenon covered with clouds of TPGS solubilising
10the preparation (fixing TPGS:F68=1:1 (m/m), polyol is selected not commensurability propylene glycol) of injection
Prescription:
| Prescription 2 | Prescription 3 | Prescription 4 | Prescription 5 | Prescription 6 | Prescription 7 | |
| Ubiquinone 10 | 75 mg | 75 mg | 75 mg | 75 mg | 75 mg | 75 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| Propylene glycol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
Take the ubiquinone of recipe quantity
10, TPGS forms oil phase; Measure F68, propylene glycol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are yellow transparent solution.
After sterilizing, observe at once preparation state: be yellow transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, glycerol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace propylene glycol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 3:with the ubiquinone without a phenomenon covered with clouds of TPGS solubilising
10the preparation (fixing TPGS:F68=1:3 (m/m), polyol is selected not commensurability glycerol) of injection
Prescription:
| Prescription 8 | Prescription 9 | Prescription 10 | Prescription 11 | Prescription 12 | Prescription 13 | |
| Ubiquinone 10 | 75 mg | 75 mg | 75 mg | 75 mg | 75 mg | 75 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg |
| Glycerol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
Take the ubiquinone of recipe quantity
10, TPGS forms oil phase; Measure F68, glycerol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are yellow transparent solution.
After sterilizing, observe at once preparation state: be yellow transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace glycerol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 4: with the ubiquinone without a phenomenon covered with clouds of TPGS solubilising
10the preparation (fixing TPGS:RH40=1:1 (m/m), polyol is selected not commensurability propylene glycol) of injection
Prescription:
| Prescription 14 | Prescription 15 | Prescription 16 | Prescription 17 | Prescription 18 | Prescription 19 | |
| Ubiquinone 10 | 75 mg | 75 mg | 75 mg | 75 mg | 75 mg | 75 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| RH40 | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| Propylene glycol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
Take the ubiquinone of recipe quantity
10, TPGS, RH40 form oil phase; Measure the propylene glycol of recipe quantity and water for injection as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are yellow transparent solution.
After sterilizing, observe at once preparation state: be yellow transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, glycerol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace propylene glycol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 5:with the ubiquinone without a phenomenon covered with clouds of TPGS solubilising
10the preparation (fixing TPGS:RH40=1:3 (m/m), polyol is selected not commensurability glycerol) of injection
Prescription:
| Prescription 20 | Prescription 21 | Prescription 22 | Prescription 23 | Prescription 24 | Prescription 25 | |
| Ubiquinone 10 | 75 mg | 75 mg | 75 mg | 75 mg | 75 mg | 75 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| RH40 | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg |
| Glycerol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
Take the ubiquinone of recipe quantity
10, TPGS, RH40 form oil phase; Measure the glycerol of recipe quantity and water for injection as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are yellow transparent solution.
After sterilizing, observe at once preparation state: be yellow transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace glycerol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 6: with the ubiquinone without a phenomenon covered with clouds of TPGS solubilising
10preparation (fixing the TPGS:(F68+RH40)=1:1 (m/m) of injection, polyol is selected not commensurability propylene glycol)
Prescription:
| Prescription 26 | Prescription 27 | Prescription 28 | Prescription 29 | Prescription 30 | Prescription 31 | |
| Ubiquinone 10 | 75 mg | 75 mg | 75 mg | 75 mg | 75 mg | 75 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg |
| RH40 | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg |
| Propylene glycol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
Take the ubiquinone of recipe quantity
10, TPGS, RH40 form oil phase; Measure F68, propylene glycol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are yellow transparent solution.
After sterilizing, observe at once preparation state: be yellow transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, glycerol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace propylene glycol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 7:with the ubiquinone without a phenomenon covered with clouds of TPGS solubilising
10preparation (fixing the TPGS:(F68+RH40)=1:3 (m/m) of injection, polyol is selected not commensurability glycerol)
Prescription:
| Prescription 32 | Prescription 33 | Prescription 34 | Prescription 35 | Prescription 36 | Prescription 37 | |
| Ubiquinone 10 | 75 mg | 75 mg | 75 mg | 75 mg | 75 mg | 75 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg |
| RH40 | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg |
| Glycerol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
Take the ubiquinone of recipe quantity
10, TPGS, RH40 form oil phase; Measure F68, glycerol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are yellow transparent solution.
After sterilizing, observe at once preparation state: be yellow transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace glycerol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 8:with the ubiquinone that has had phenomenon covered with clouds of TPGS solubilising
10the preparation (do not add F68 and RH40, use separately not commensurability polyol PEG400) of injection
Prescription:
| Prescription 38 | Prescription 39 | Prescription 40 | Prescription 41 | Prescription 42 | Prescription 43 | |
| Ubiquinone 10 | 75 mg | 75 mg | 75 mg | 75 mg | 75 mg | 75 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| PEG400 | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
Take the ubiquinone of recipe quantity
10, TPGS forms oil phase; Measure the PEG400 of recipe quantity and water for injection as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are yellow transparent solution.
After sterilizing, observe at once preparation state: all change muddinesses in various degree of above-mentioned six prescription gained preparations, the bottle end, has claret jelly to separate out, it is covered with clouds that to be HS15 rise in the time of 100 ℃, 30 min and 121 ℃, 8 min sterilizing, room temperature place after jelly do not recover dissolved state.
Use xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, glycerol, PEG200, PEG300, the PEG600 of same amount to replace PEG400 to obtain consistent experimental result, using separately not commensurability polyol is the phenomenon covered with clouds that rises that can not eliminate TPGS.
embodiment 9:with the ubiquinone that has had phenomenon covered with clouds of TPGS solubilising
10the preparation (do not add polyol, use separately not commensurability F68) of injection
Prescription:
| Prescription 44 | Prescription 45 | Prescription 46 | Prescription 47 | Prescription 48 | Prescription 49 | |
| Ubiquinone 10 | 75 mg | 75 mg | 75 mg | 75 mg | 75 mg | 75 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 600 mg | 900 mg | 1200 mg | 1800 mg | 2100 mg | 2400 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
Take the ubiquinone of recipe quantity
10, TPGS forms oil phase; Measure the F68, water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are yellow transparent solution.
After sterilizing, observe at once preparation state:
All change muddinesses in various degree of above-mentioned six prescription gained preparations, a bottle end, has claret jelly to separate out, and HS15 rises covered with cloudsly in the time of 100 ℃, 30 min and 121 ℃, 8 min sterilizing, and after room temperature is placed 24h, jelly does not recover dissolved state.
Using separately F68 is the phenomenon covered with clouds that rises that can not eliminate TPGS.
embodiment 10:with the ubiquinone that has had phenomenon covered with clouds of TPGS solubilising
10the preparation (do not add polyol, use separately not commensurability RH40) of injection
Prescription:
| Prescription 50 | Prescription 51 | Prescription 52 | Prescription 53 | Prescription 54 | Prescription 55 | |
| Ubiquinone 10 | 75 mg | 75 mg | 75 mg | 75 mg | 75 mg | 75 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| RH40 | 300 mg | 600 mg | 900 mg | 1200 mg | 1800 mg | 2400 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
Take the ubiquinone of recipe quantity
10, TPGS, RH40 form oil phase; Measure the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are yellow transparent solution.
After sterilizing, observe at once preparation state:
All change muddinesses in various degree of above-mentioned six prescription gained preparations, a bottle end, has claret jelly to separate out, and HS15 rises covered with cloudsly in the time of 100 ℃, 30 min and 121 ℃, 8 min sterilizing, and after room temperature is placed 24h, jelly does not recover dissolved state.
Using separately RH40 is the phenomenon covered with clouds that rises that can not eliminate TPGS.
embodiment 11:the preparation of the independent vitamin K 1 injection with TPGS solubilising
Prescription 56:
Vitamin K1 60 mg
TPGS 600 mg
Water for injection 28 mL
30 mL
Technique:
The vitamin K1, the TPGS that take recipe quantity form oil phase; Measure the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After material in oil phase dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, half preparation is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: gained preparation is yellow transparent solution.
After sterilizing, observe: preparation becomes muddy, and the bottle end has claret jelly to separate out, illustrate that the certain existence of TPGS significantly plays phenomenon covered with clouds.
embodiment 12: with TPGS solubilising without the preparation (fixing TPGS:F68=1:1 (m/m), polyol is selected not commensurability propylene glycol) of vitamin K1 injection that plays phenomenon covered with clouds
Prescription:
| Prescription 57 | Prescription 58 | Prescription 59 | Prescription 60 | Prescription 61 | Prescription 62 | |
| Vitamin K1 | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| Propylene glycol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The vitamin K1, the TPGS that take recipe quantity form oil phase; Measure F68, propylene glycol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are yellow transparent solution.
After sterilizing, observe at once preparation state: be yellow transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, glycerol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace propylene glycol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 13:with TPGS solubilising without the preparation (fixing TPGS:F68=1:3 (m/m), polyol is selected not commensurability glycerol) of vitamin K1 injection that plays phenomenon covered with clouds
Prescription:
| Prescription 63 | Prescription 64 | Prescription 65 | Prescription 66 | Prescription 67 | Prescription 68 | |
| Vitamin K1 | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg |
| Glycerol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The vitamin K1, the TPGS that take recipe quantity form oil phase; Measure F68, glycerol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are yellow transparent solution.
After sterilizing, observe at once preparation state: be yellow transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace glycerol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 14: with TPGS solubilising without the preparation (fixing TPGS:RH40=1:1 (m/m), polyol is selected not commensurability propylene glycol) of vitamin K1 injection that plays phenomenon covered with clouds
Prescription:
| Prescription 69 | Prescription 70 | Prescription 71 | Prescription 72 | Prescription 73 | Prescription 74 | |
| Vitamin K1 | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| RH40 | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| Propylene glycol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The vitamin K1, TPGS, the RH40 that take recipe quantity form oil phase; Measure the propylene glycol of recipe quantity and water for injection as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are yellow transparent solution.
After sterilizing, observe at once preparation state: be yellow transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, glycerol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace propylene glycol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 15:with TPGS solubilising without the preparation (fixing TPGS:RH40=1:3 (m/m), polyol is selected not commensurability glycerol) of vitamin K1 injection that plays phenomenon covered with clouds
Prescription:
| Prescription 75 | Prescription 76 | Prescription 77 | Prescription 78 | Prescription 79 | Prescription 80 | |
| Vitamin K1 | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| RH40 | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg |
| Glycerol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The vitamin K1, TPGS, the RH40 that take recipe quantity form oil phase; Measure the glycerol of recipe quantity and water for injection as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are yellow transparent solution.
After sterilizing, observe at once preparation state: be yellow transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace glycerol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 16: with TPGS solubilising without preparation (fixing the TPGS:(F68+RH40)=1:1 (m/m) of vitamin K1 injection that plays phenomenon covered with clouds, polyol is selected not commensurability propylene glycol)
Prescription:
| Prescription 81 | Prescription 82 | Prescription 83 | Prescription 84 | Prescription 85 | Prescription 86 | |
| Vitamin K1 | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg |
| RH40 | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg |
| Propylene glycol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The vitamin K1, TPGS, the RH40 that take recipe quantity form oil phase; Measure F68, propylene glycol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are yellow transparent solution.
After sterilizing, observe at once preparation state: be yellow transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, glycerol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace propylene glycol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 17:with TPGS solubilising without preparation (fixing the TPGS:(F68+RH40)=1:3 (m/m) of vitamin K1 injection that plays phenomenon covered with clouds, polyol is selected not commensurability glycerol)
Prescription:
| Prescription 87 | Prescription 88 | Prescription 89 | Prescription 90 | Prescription 91 | Prescription 92 | |
| Vitamin K1 | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg |
| RH40 | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg |
| Glycerol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The vitamin K1, TPGS, the RH40 that take recipe quantity form oil phase; Measure F68, glycerol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are yellow transparent solution.
After sterilizing, observe at once preparation state: be yellow transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace glycerol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 18:the preparation of the independent alprostadil injection with TPGS solubilising
Prescription 93:
Alprostadil 6 mg
TPGS 600 mg
Water for injection 28 mL
30 mL
Technique:
The Alprostadil, the TPGS that take recipe quantity form oil phase; Measure the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After material in oil phase dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, half preparation is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: gained preparation is colourless transparent solution.
After sterilizing, observe: preparation becomes muddy, and the bottle end has jelly to separate out, illustrate that the certain existence of TPGS significantly plays phenomenon covered with clouds.
embodiment 19: with TPGS solubilising without the preparation (fixing TPGS:F68=1:1 (m/m), polyol is selected not commensurability propylene glycol) of alprostadil injection agent that plays phenomenon covered with clouds
Prescription:
| Prescription 94 | Prescription 95 | Prescription 96 | Prescription 97 | Prescription 98 | Prescription 99 | |
| Alprostadil | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| Propylene glycol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The Alprostadil, the TPGS that take recipe quantity form oil phase; Measure F68, propylene glycol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, glycerol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace propylene glycol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 20:with TPGS solubilising without the preparation (fixing TPGS:F68=1:3 (m/m), polyol is selected not commensurability glycerol) of alprostadil injection agent that plays phenomenon covered with clouds
Prescription:
| Prescription 100 | Prescription 101 | Prescription 102 | Prescription 103 | Prescription 104 | Prescription 105 | |
| Alprostadil | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg |
| Glycerol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The Alprostadil, the TPGS that take recipe quantity form oil phase; Measure F68, glycerol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace glycerol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 21: with TPGS solubilising without the preparation (fixing TPGS:RH40=1:1 (m/m), polyol is selected not commensurability propylene glycol) of alprostadil injection agent that plays phenomenon covered with clouds
Prescription:
| Prescription 106 | Prescription 107 | Prescription 108 | Prescription 109 | Prescription 110 | Prescription 111 | |
| Alprostadil | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| RH40 | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| Propylene glycol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The Alprostadil, TPGS, the RH40 that take recipe quantity form oil phase; Measure the propylene glycol of recipe quantity and water for injection as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, glycerol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace propylene glycol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 22:with TPGS solubilising without the preparation (fixing TPGS:RH40=1:3 (m/m), polyol is selected not commensurability glycerol) of alprostadil injection agent that plays phenomenon covered with clouds
Prescription:
| Prescription 112 | Prescription 113 | Prescription 114 | Prescription 115 | Prescription 116 | Prescription 117 | |
| Alprostadil | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| RH40 | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg |
| Glycerol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The Alprostadil, TPGS, the RH40 that take recipe quantity form oil phase; Measure the glycerol of recipe quantity and water for injection as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace glycerol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 23: with TPGS solubilising without preparation (fixing the TPGS:(F68+RH40)=1:1 (m/m) of alprostadil injection agent that plays phenomenon covered with clouds, polyol is selected not commensurability propylene glycol)
Prescription:
| Prescription 118 | Prescription 119 | Prescription 120 | Prescription 121 | Prescription 122 | Prescription 123 | |
| Alprostadil | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg |
| RH40 | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg |
| Propylene glycol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The Alprostadil, TPGS, the RH40 that take recipe quantity form oil phase; Measure F68, propylene glycol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, glycerol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace propylene glycol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 24:with TPGS solubilising without preparation (fixing the TPGS:(F68+RH40)=1:3 (m/m) of alprostadil injection agent that plays phenomenon covered with clouds, polyol is selected not commensurability glycerol)
Prescription:
| Prescription 124 | Prescription 125 | Prescription 126 | Prescription 127 | Prescription 128 | Prescription 129 | |
| Alprostadil | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg |
| RH40 | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg |
| Glycerol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The Alprostadil, TPGS, the RH40 that take recipe quantity form oil phase; Measure F68, glycerol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace glycerol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 25:the preparation of the independent cyclic AMP injecta with TPGS solubilising
Prescription 130:
Adenosine cyclophosphate 6 mg
TPGS 600 mg
Water for injection 28 mL
30 mL
Technique:
The adenosine cyclophosphate, the TPGS that take recipe quantity form oil phase; Measure the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After material in oil phase dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, half preparation is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: gained preparation is colourless transparent solution.
After sterilizing, observe: preparation becomes muddy, and the bottle end has jelly to separate out, illustrate that the certain existence of TPGS significantly plays phenomenon covered with clouds.
embodiment 26: with TPGS solubilising without the preparation (fixing TPGS:F68=1:1 (m/m), polyol is selected not commensurability propylene glycol) of adenosine cyclophosphate injection that plays phenomenon covered with clouds
Prescription:
| Prescription 131 | Prescription 132 | Prescription 133 | Prescription 134 | Prescription 135 | Prescription 136 | |
| Adenosine cyclophosphate | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| Propylene glycol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The adenosine cyclophosphate, the TPGS that take recipe quantity form oil phase; Measure F68, propylene glycol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, glycerol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace propylene glycol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 27:with TPGS solubilising without the preparation (fixing TPGS:F68=1:3 (m/m), polyol is selected not commensurability glycerol) of adenosine cyclophosphate injection that plays phenomenon covered with clouds
Prescription:
| Prescription 137 | Prescription 138 | Prescription 139 | Prescription 140 | Prescription 141 | Prescription 142 | |
| Adenosine cyclophosphate | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg |
| Glycerol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The adenosine cyclophosphate, the TPGS that take recipe quantity form oil phase; Measure F68, glycerol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace glycerol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 28: with TPGS solubilising without the preparation (fixing TPGS:RH40=1:1 (m/m), polyol is selected not commensurability propylene glycol) of adenosine cyclophosphate injection that plays phenomenon covered with clouds
Prescription:
| Prescription 143 | Prescription 144 | Prescription 145 | Prescription 146 | Prescription 147 | Prescription 148 | |
| Adenosine cyclophosphate | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| RH40 | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| Propylene glycol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The adenosine cyclophosphate, TPGS, the RH40 that take recipe quantity form oil phase; Measure the propylene glycol of recipe quantity and water for injection as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, glycerol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace propylene glycol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 29:with TPGS solubilising without the preparation (fixing TPGS:RH40=1:3 (m/m), polyol is selected not commensurability glycerol) of adenosine cyclophosphate injection that plays phenomenon covered with clouds
Prescription:
| Prescription 149 | Prescription 150 | Prescription 151 | Prescription 152 | Prescription 153 | Prescription 154 | |
| Adenosine cyclophosphate | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| RH40 | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg |
| Glycerol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The adenosine cyclophosphate, TPGS, the RH40 that take recipe quantity form oil phase; Measure the glycerol of recipe quantity and water for injection as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace glycerol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 30: with TPGS solubilising without preparation (fixing the TPGS:(F68+RH40)=1:1 (m/m) of adenosine cyclophosphate injection that plays phenomenon covered with clouds, polyol is selected not commensurability propylene glycol)
Prescription:
| Prescription 155 | Prescription 156 | Prescription 157 | Prescription 158 | Prescription 159 | Prescription 160 | |
| Adenosine cyclophosphate | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg |
| RH40 | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg |
| Propylene glycol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The adenosine cyclophosphate, TPGS, the RH40 that take recipe quantity form oil phase; Measure F68, propylene glycol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, glycerol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace propylene glycol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 31:with TPGS solubilising without preparation (fixing the TPGS:(F68+RH40)=1:3 (m/m) of adenosine cyclophosphate injection that plays phenomenon covered with clouds, polyol is selected not commensurability glycerol)
Prescription:
| Prescription 161 | Prescription 162 | Prescription 163 | Prescription 164 | Prescription 165 | Prescription 166 | |
| Adenosine cyclophosphate | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg |
| RH40 | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg |
| Glycerol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The adenosine cyclophosphate, TPGS, the RH40 that take recipe quantity form oil phase; Measure F68, glycerol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace glycerol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 32:the preparation of independent ginsenoside's injection with TPGS solubilising
Prescription 167:
Ginsenoside 60 mg
TPGS 600 mg
Water for injection 28 mL
30 mL
Technique:
The ginsenoside, the TPGS that take recipe quantity form oil phase; Measure the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After material in oil phase dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, half preparation is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: gained preparation is colourless transparent solution.
After sterilizing, observe: preparation becomes muddy, and the bottle end has jelly to separate out, illustrate that the certain existence of TPGS significantly plays phenomenon covered with clouds.
embodiment 33: with TPGS solubilising without the preparation (fixing TPGS:F68=1:1 (m/m), polyol is selected not commensurability propylene glycol) of ginsenoside's injection that plays phenomenon covered with clouds
Prescription:
| Prescription 168 | Prescription 169 | Prescription 170 | Prescription 171 | Prescription 172 | Prescription 173 | |
| Ginsenoside | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| Propylene glycol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The ginsenoside, the TPGS that take recipe quantity form oil phase; Measure F68, propylene glycol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, glycerol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace propylene glycol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 34:with TPGS solubilising without the preparation (fixing TPGS:F68=1:3 (m/m), polyol is selected not commensurability glycerol) of ginsenoside's injection that plays phenomenon covered with clouds
Prescription:
| Prescription 174 | Prescription 175 | Prescription 176 | Prescription 177 | Prescription 178 | Prescription 179 | |
| Ginsenoside | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg |
| Glycerol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The ginsenoside, the TPGS that take recipe quantity form oil phase; Measure F68, glycerol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace glycerol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 35: with TPGS solubilising without the preparation (fixing TPGS:RH40=1:1 (m/m), polyol is selected not commensurability propylene glycol) of ginsenoside's injection that plays phenomenon covered with clouds
Prescription:
| Prescription 180 | Prescription 181 | Prescription 182 | Prescription 183 | Prescription 184 | Prescription 185 | |
| Ginsenoside | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| RH40 | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| Propylene glycol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30 ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The ginsenoside, TPGS, the RH40 that take recipe quantity form oil phase; Measure the propylene glycol of recipe quantity and water for injection as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, glycerol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace propylene glycol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 36:with TPGS solubilising without the preparation (fixing TPGS:RH40=1:3 (m/m), polyol is selected not commensurability glycerol) of ginsenoside's injection that plays phenomenon covered with clouds
Prescription:
| Prescription 186 | Prescription 187 | Prescription 188 | Prescription 189 | Prescription 190 | Prescription 191 | |
| Ginsenoside | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| RH40 | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg |
| Glycerol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The ginsenoside, TPGS, the RH40 that take recipe quantity form oil phase; Measure the glycerol of recipe quantity and water for injection as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace glycerol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 37: with TPGS solubilising without preparation (fixing the TPGS:(F68+RH40)=1:1 (m/m) of ginsenoside's injection that plays phenomenon covered with clouds, polyol is selected not commensurability propylene glycol)
Prescription:
| Prescription 192 | Prescription 193 | Prescription 194 | Prescription 195 | Prescription 196 | Prescription 197 | |
| Ginsenoside | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg |
| RH40 | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg |
| Propylene glycol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The ginsenoside, TPGS, the RH40 that take recipe quantity form oil phase; Measure F68, propylene glycol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, glycerol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace propylene glycol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 38:with TPGS solubilising without preparation (fixing the TPGS:(F68+RH40)=1:3 (m/m) of ginsenoside's injection that plays phenomenon covered with clouds, polyol is selected not commensurability glycerol)
Prescription:
| Prescription 198 | Prescription 199 | Prescription 200 | Prescription 201 | Prescription 202 | Prescription 203 | |
| Ginsenoside | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg |
| RH40 | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg |
| Glycerol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The ginsenoside, TPGS, the RH40 that take recipe quantity form oil phase; Measure F68, glycerol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace glycerol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 39:the preparation of the independent Acyclovir injection with TPGS solubilising
Prescription 204:
Acyclovir 60 mg
TPGS 600 mg
Water for injection 28 mL
30 mL
Technique:
The acyclovir, the TPGS that take recipe quantity form oil phase; Measure the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After material in oil phase dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, half preparation is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: gained preparation is colourless transparent solution.
After sterilizing, observe: preparation becomes muddy, and the bottle end has jelly to separate out, illustrate that the certain existence of TPGS significantly plays phenomenon covered with clouds.
embodiment 40: with TPGS solubilising without the preparation (fixing TPGS:F68=1:1 (m/m), polyol is selected not commensurability propylene glycol) of acyclovir injection that plays phenomenon covered with clouds
Prescription:
| Prescription 205 | Prescription 206 | Prescription 207 | Prescription 208 | Prescription 209 | Prescription 210 | |
| Acyclovir | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| Propylene glycol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The acyclovir, the TPGS that take recipe quantity form oil phase; Measure F68, propylene glycol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, glycerol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace propylene glycol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 41:with TPGS solubilising without the preparation (fixing TPGS:F68=1:3 (m/m), polyol is selected not commensurability glycerol) of acyclovir injection that plays phenomenon covered with clouds
Prescription:
| Prescription 211 | Prescription 212 | Prescription 213 | Prescription 214 | Prescription 215 | Prescription 216 | |
| Acyclovir | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg |
| Glycerol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The acyclovir, the TPGS that take recipe quantity form oil phase; Measure F68, glycerol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace glycerol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 42: with TPGS solubilising without the preparation (fixing TPGS:RH40=1:1 (m/m), polyol is selected not commensurability propylene glycol) of acyclovir injection that plays phenomenon covered with clouds
Prescription:
| Prescription 217 | Prescription 218 | Prescription 219 | Prescription 220 | Prescription 221 | Prescription 222 | |
| Acyclovir | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| RH40 | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| Propylene glycol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The acyclovir, TPGS, the RH40 that take recipe quantity form oil phase; Measure the propylene glycol of recipe quantity and water for injection as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, glycerol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace propylene glycol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 43:with TPGS solubilising without the preparation (fixing TPGS:RH40=1:3 (m/m), polyol is selected not commensurability glycerol) of acyclovir injection that plays phenomenon covered with clouds
Prescription:
| Prescription 223 | Prescription 224 | Prescription 225 | Prescription 226 | Prescription 227 | Prescription 228 | |
| Acyclovir | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| RH40 | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg |
| Glycerol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The acyclovir, TPGS, the RH40 that take recipe quantity form oil phase; Measure the glycerol of recipe quantity and water for injection as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace glycerol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 44: with TPGS solubilising without preparation (fixing the TPGS:(F68+RH40)=1:1 (m/m) of acyclovir injection that plays phenomenon covered with clouds, polyol is selected not commensurability propylene glycol)
Prescription:
| Prescription 229 | Prescription 230 | Prescription 231 | Prescription 232 | Prescription 233 | Prescription 234 | |
| Acyclovir | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg |
| RH40 | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg |
| Propylene glycol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The acyclovir, TPGS, the RH40 that take recipe quantity form oil phase; Measure F68, propylene glycol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, glycerol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace propylene glycol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 45:with TPGS solubilising without preparation (fixing the TPGS:(F68+RH40)=1:3 (m/m) of acyclovir injection that plays phenomenon covered with clouds, polyol is selected not commensurability glycerol)
Prescription:
| Prescription 235 | Prescription 236 | Prescription 237 | Prescription 238 | Prescription 239 | Prescription 240 | |
| Acyclovir | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg |
| RH40 | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg |
| Glycerol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The acyclovir, TPGS, the RH40 that take recipe quantity form oil phase; Measure F68, glycerol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace glycerol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 46:the preparation of the independent ribavirin injection with TPGS solubilising
Prescription 241:
Ribavirin 60 mg
TPGS 600 mg
Water for injection 28 mL
30 mL
Technique:
The ribavirin, the TPGS that take recipe quantity form oil phase; Measure the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After material in oil phase dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, half preparation is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: gained preparation is colourless transparent solution.
After sterilizing, observe: preparation becomes muddy, and the bottle end has jelly to separate out, illustrate that the certain existence of TPGS significantly plays phenomenon covered with clouds.
embodiment 47: with TPGS solubilising without the preparation (fixing TPGS:F68=1:1 (m/m), polyol is selected not commensurability propylene glycol) of ribavirin injection that plays phenomenon covered with clouds
Prescription:
| Prescription 242 | Prescription 243 | Prescription 244 | Prescription 245 | Prescription 246 | Prescription 247 | |
| Ribavirin | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| Propylene glycol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The ribavirin, the TPGS that take recipe quantity form oil phase; Measure F68, propylene glycol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, glycerol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace propylene glycol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 48:with TPGS solubilising without the preparation (fixing TPGS:F68=1:3 (m/m), polyol is selected not commensurability glycerol) of ribavirin injection that plays phenomenon covered with clouds
Prescription:
| Prescription 248 | Prescription 249 | Prescription 250 | Prescription 251 | Prescription 252 | Prescription 253 | |
| Ribavirin | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg |
| Glycerol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The ribavirin, the TPGS that take recipe quantity form oil phase; Measure F68, glycerol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace glycerol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 49: with TPGS solubilising without the preparation (fixing TPGS:RH40=1:1 (m/m), polyol is selected not commensurability propylene glycol) of ribavirin injection that plays phenomenon covered with clouds
Prescription:
| Prescription 254 | Prescription 255 | Prescription 256 | Prescription 257 | Prescription 258 | Prescription 259 | |
| Ribavirin | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| RH40 | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| Propylene glycol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The ribavirin, TPGS, the RH40 that take recipe quantity form oil phase; Measure the propylene glycol of recipe quantity and water for injection as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, glycerol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace propylene glycol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 50:with TPGS solubilising without the preparation (fixing TPGS:RH40=1:3 (m/m), polyol is selected not commensurability glycerol) of ribavirin injection that plays phenomenon covered with clouds
Prescription:
| Prescription 260 | Prescription 261 | Prescription 262 | Prescription 263 | Prescription 264 | Prescription 265 | |
| Ribavirin | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| RH40 | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg |
| Glycerol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The ribavirin, TPGS, the RH40 that take recipe quantity form oil phase; Measure the glycerol of recipe quantity and water for injection as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace glycerol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 51: with TPGS solubilising without preparation (fixing the TPGS:(F68+RH40)=1:1 (m/m) of ribavirin injection that plays phenomenon covered with clouds, polyol is selected not commensurability propylene glycol)
Prescription:
| Prescription 266 | Prescription 267 | Prescription 268 | Prescription 269 | Prescription 270 | Prescription 271 | |
| Ribavirin | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg |
| RH40 | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg |
| Propylene glycol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The ribavirin, TPGS, the RH40 that take recipe quantity form oil phase; Measure F68, propylene glycol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, glycerol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace propylene glycol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 52:with TPGS solubilising without preparation (fixing the TPGS:(F68+RH40)=1:3 (m/m) of ribavirin injection that plays phenomenon covered with clouds, polyol is selected not commensurability glycerol)
Prescription:
| Prescription 272 | Prescription 273 | Prescription 274 | Prescription 275 | Prescription 276 | Prescription 277 | |
| Ribavirin | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg | 60 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg |
| RH40 | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg |
| Glycerol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The ribavirin, TPGS, the RH40 that take recipe quantity form oil phase; Measure F68, glycerol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace glycerol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 53:the preparation of the independent cucurbitacin injection with TPGS solubilising
Prescription 278:
Cucurbitacin 6 mg
TPGS 600 mg
Water for injection 28 mL
30 mL
Technique:
The cucurbitacin, the TPGS that take recipe quantity form oil phase; Measure the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After material in oil phase dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, half preparation is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: gained preparation is colourless transparent solution.
After sterilizing, observe: preparation becomes muddy, and the bottle end has jelly to separate out, illustrate that the certain existence of TPGS significantly plays phenomenon covered with clouds.
embodiment 54: with TPGS solubilising without the preparation (fixing TPGS:F68=1:1 (m/m), polyol is selected not commensurability propylene glycol) of cucurbitacin injection that plays phenomenon covered with clouds
Prescription:
| Prescription 279 | Prescription 280 | Prescription 281 | Prescription 282 | Prescription 283 | Prescription 284 | |
| Cucurbitacin | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| Propylene glycol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The cucurbitacin, the TPGS that take recipe quantity form oil phase; Measure F68, propylene glycol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, glycerol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace propylene glycol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 55:with TPGS solubilising without the preparation (fixing TPGS:F68=1:3 (m/m), polyol is selected not commensurability glycerol) of cucurbitacin injection that plays phenomenon covered with clouds
Prescription:
| Prescription 285 | Prescription 286 | Prescription 287 | Prescription 288 | Prescription 289 | Prescription 290 | |
| Cucurbitacin | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg |
| Glycerol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The cucurbitacin, the TPGS that take recipe quantity form oil phase; Measure F68, glycerol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace glycerol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 56: with TPGS solubilising without the preparation (fixing TPGS:RH40=1:1 (m/m), polyol is selected not commensurability propylene glycol) of cucurbitacin injection that plays phenomenon covered with clouds
Prescription:
| Prescription 291 | Prescription 292 | Prescription 293 | Prescription 294 | Prescription 295 | Prescription 296 | |
| Cucurbitacin | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| RH40 | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| Propylene glycol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The cucurbitacin, TPGS, the RH40 that take recipe quantity form oil phase; Measure the propylene glycol of recipe quantity and water for injection as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, glycerol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace propylene glycol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 57:with TPGS solubilising without the preparation (fixing TPGS:RH40=1:3 (m/m), polyol is selected not commensurability glycerol) of cucurbitacin injection that plays phenomenon covered with clouds
Prescription:
| Prescription 297 | Prescription 298 | Prescription 299 | Prescription 300 | Prescription 301 | Prescription 302 | |
| Cucurbitacin | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| RH40 | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg | 1800 mg |
| Glycerol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The cucurbitacin, TPGS, the RH40 that take recipe quantity form oil phase; Measure the glycerol of recipe quantity and water for injection as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace glycerol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 58: with TPGS solubilising without preparation (fixing the TPGS:(F68+RH40)=1:1 (m/m) of cucurbitacin injection that plays phenomenon covered with clouds, polyol is selected not commensurability propylene glycol)
Prescription:
| Prescription 303 | Prescription 304 | Prescription 305 | Prescription 306 | Prescription 307 | Prescription 308 | |
| Cucurbitacin | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg |
| RH40 | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg | 300 mg |
| Propylene glycol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The cucurbitacin, TPGS, the RH40 that take recipe quantity form oil phase; Measure F68, propylene glycol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, glycerol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace propylene glycol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
embodiment 59:with TPGS solubilising without preparation (fixing the TPGS:(F68+RH40)=1:3 (m/m) of cucurbitacin injection that plays phenomenon covered with clouds, polyol is selected not commensurability glycerol)
Prescription:
| Prescription 309 | Prescription 310 | Prescription 311 | Prescription 312 | Prescription 313 | Prescription 314 | |
| Cucurbitacin | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg | 6 mg |
| TPGS | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg | 600 mg |
| F68 | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg |
| RH40 | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg | 900 mg |
| Glycerol | 1800 mg | 2400 mg | 3000 mg | 3600 mg | 4800 mg | 6000 mg |
| Water for injection | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml | Add to 30ml |
Technique:
The cucurbitacin, TPGS, the RH40 that take recipe quantity form oil phase; Measure F68, glycerol and the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃.After biphase middle material dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, aluminium lid sealing, the half preparation of each prescription is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Before sterilizing, observe preparation state: above-mentioned six prescription gained preparations are colourless transparent solution.
After sterilizing, observe at once preparation state: be colourless transparent solution, preparation has had no phenomenon covered with clouds.
Use xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, the PEG600 of same amount to replace glycerol to obtain consistent experimental result, can eliminate the phenomenon covered with clouds that rises of TPGS.
Claims (8)
1. can eliminate TPGS and rise the compositions of phenomenon covered with clouds, comprise insoluble drug, TPGS, poloxalkol and/or polyoxyethylene castor oil, polyol and water, wherein insoluble drug: TPGS: poloxalkol: the weight ratio of polyol is 0.001-2:1:0.5-5:2-20, surplus is water.
2. the compositions that can eliminate TPGS as claimed in claim 1 and rise phenomenon covered with clouds, is characterized in that: insoluble drug comprises ubiquinone
10, fat-soluble A, D, E, K; Nimodipine, ginsenoside, Alprostadil, adenosine cyclophosphate, acyclovir, paclitaxel, Docetaxel, hydroxy camptothecin, ribavirin, cucurbitacin, at interior poorly water-soluble, can be used the medicine of TPGS increase-volume.
3. the TPGS of elimination as claimed in claim 1 plays the compositions of phenomenon covered with clouds, it is characterized in that: the poloxalkol in compositions is EOn-POm-EOn.
4. polyoxyethylene (hydrogenation) Oleum Ricini in compositions as claimed in claim 1, is characterized in that: can be a kind of or several mixture in the poly-hydrogen-oxygen ester 35 of polyoxyl 40 hydrogenated castor oil RH40, Oleum Ricini, the poly-hydrogen-oxygen ester 35 of Oleum Ricini.
5. the TPGS of elimination as claimed in claim 1 plays the compositions of phenomenon covered with clouds, it is characterized in that: when compositions is made up of insoluble drug, TPGS, polyoxyethylene castor oil, polyol and water, wherein insoluble drug: TPGS: polyoxyethylene castor oil: the weight ratio of polyol is 0.001-2:1:0.5-5:2-20, surplus is water.
6. the TPGS of elimination as claimed in claim 1 plays the compositions of phenomenon covered with clouds, it is characterized in that: polyol is a kind of or several mixture in glucose, xylose, fructose, sucrose, maltose, lactose, galactose, trehalose, mannitol, xylitol, sorbitol, maltol, propylene glycol, glycerol, PEG200, PEG300, PEG400, PEG600, PEG1000, PEG2000, PEG4000, PEG6000 etc.
7. described eliminated TPGS plays the compositions of phenomenon covered with clouds as claimed in claim 1, it is characterized in that: water is the one in purified water, distilled water, water for injection, sterilizing purified water, sterilized water for injection.
8. described eliminated TPGS plays the compositions of phenomenon covered with clouds as claimed in claim 1, it is characterized in that: the ubiquinone that takes recipe quantity
10, TPGS forms oil phase; Measure the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃, after material in oil phase dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, sealing, half preparation is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210456014.5A CN103800913B (en) | 2012-11-14 | 2012-11-14 | TPGS can be eliminated and play the compositions of phenomenon covered with clouds and the application in pharmaceutical preparation thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210456014.5A CN103800913B (en) | 2012-11-14 | 2012-11-14 | TPGS can be eliminated and play the compositions of phenomenon covered with clouds and the application in pharmaceutical preparation thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103800913A true CN103800913A (en) | 2014-05-21 |
| CN103800913B CN103800913B (en) | 2016-02-10 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210456014.5A Expired - Fee Related CN103800913B (en) | 2012-11-14 | 2012-11-14 | TPGS can be eliminated and play the compositions of phenomenon covered with clouds and the application in pharmaceutical preparation thereof |
Country Status (1)
| Country | Link |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017194965A1 (en) * | 2016-05-13 | 2017-11-16 | Phytoceutical Limited | Micelles of d-alpha-tocopheryl polyethylene glycol 1000 succinate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1698753A (en) * | 2005-05-12 | 2005-11-23 | 沈阳药科大学 | Garlicin and garlic oil emulsion capable of filtering and eliminating bacteria and preparation process thereof |
| CN1698620A (en) * | 2005-06-03 | 2005-11-23 | 沈阳药科大学 | Cucurbitacin emulsion capable of filtering out and eliminating bacteria and preparation method thereof |
| CN1706377A (en) * | 2005-05-27 | 2005-12-14 | 沈阳药科大学 | Norcantharidin emulsion capable of being sterilized through filtering and its prepn process |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1698753A (en) * | 2005-05-12 | 2005-11-23 | 沈阳药科大学 | Garlicin and garlic oil emulsion capable of filtering and eliminating bacteria and preparation process thereof |
| CN1706377A (en) * | 2005-05-27 | 2005-12-14 | 沈阳药科大学 | Norcantharidin emulsion capable of being sterilized through filtering and its prepn process |
| CN1698620A (en) * | 2005-06-03 | 2005-11-23 | 沈阳药科大学 | Cucurbitacin emulsion capable of filtering out and eliminating bacteria and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017194965A1 (en) * | 2016-05-13 | 2017-11-16 | Phytoceutical Limited | Micelles of d-alpha-tocopheryl polyethylene glycol 1000 succinate |
| EP4275706A3 (en) * | 2016-05-13 | 2024-02-28 | Phytoceutical Limited | Micelles of d-alpha-tocopheryl polyethylene glycol 1000 succinate |
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| CN103800913B (en) | 2016-02-10 |
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