CN106943347B - The amplification production method of Rui Jiade loose parenteral solutions - Google Patents
The amplification production method of Rui Jiade loose parenteral solutions Download PDFInfo
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- CN106943347B CN106943347B CN201710248627.2A CN201710248627A CN106943347B CN 106943347 B CN106943347 B CN 106943347B CN 201710248627 A CN201710248627 A CN 201710248627A CN 106943347 B CN106943347 B CN 106943347B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Abstract
The invention discloses a kind of amplification production methods of Rui Jiade loose parenteral solutions, include the following steps：（1）Mass content is prepared to be 15%~35% aqueous solution of propylene glycol and be heated to 60 ~ 75 DEG C, or it is 15%~35% aqueous solution of propylene glycol dissolving in 60 ~ 75 DEG C of water for injection to be added mass content is made by propylene glycol, it adds Rui Jiadesong and maintains mixed dissolution at 60 ~ 75 DEG C, then sequentially add and dissolving phosphoric acid disodium hydrogen, sodium dihydrogen phosphate and natrium adetate, mix to it is complete it is molten after add water for injection constant volume and obtain liquid；（2）Be filtered after the completion of drug solution preparing it is filling, then sterilize to get.Inventive process avoids liquids in the longer problem of exposed ambient time, the high liquid of mass is prepared using correct charging sequence, and realize that the kind amplifies the transfer of production from laboratory lab scale to workshop, improving the sterile horizontal preparation process simultaneously of product, there is mild condition, quick, at low cost, liquid property easy to operate to stablize, quality standard is high, is suitable for industrialized production.
Description
Technical field
The invention belongs to biomedicine field, the preparation side of especially a kind of Rui Jiade loose parenteral solutions and its amplification production
Method.
Background technology
Rui Jiadesong is also known as class and adds adenosine, trade name：LEXISCAN, injection common name：REGADENOSON, molecular formula：
C15H18N8O5·H2O, molecular weight：408.37 structural formula is：
Rui Jiade loose parenteral solutions are listed in the U.S. for 2008 for the first time by Astellas company, every year with 100% after listing
Amplitude increases, and has reached average annual 500000000 dollars of steady sales volume at present.
Single-photon emission computed tomography (MPI) is that generally acknowledged diagnosis of coronary heart disease and coronary heart disease risk are layered accurate non-invasive
Image technology is divided into two kinds of tranquillization and load.Load MPI is tried again after need to reaching load criterion injection myocardial perfusion imaging agent
It tests, two kinds of the mitogenetic reason of cardiac load and drug, for being unable to sufficient movement and because of non-cardiac reason or due to limited by physiologic factor
The patient that can not be moved, drug load are a kind of effective alternatives.The annual load MPI in the U.S. checks about 10,000,000, medicine
Object load accounts for 50%.Domestic common drug load includes adenosine and Dipyridamole, both drugs are non-to all adenosine receptors
Selective binding can cause many adverse reactions, such as activate adenosine A 1 receptor that can often cause atrioventricular block, pectoralgia, activate
A2b receptors cause peripheral blood vessel expansion, bronchoconstriction etc..In order to reduce above-mentioned adverse reaction, Abroad in Recent Years has developed more
A selectivity A2a receptor stimulating agents, Rui Jiadesong are the currently the only kinds listed.The medicine Clinical practice is more convenient, adopts
With fixed dosage bolus in ection, i.e. injectable radioactivity myocardial perfusion imaging agent, tolerance compare adenosine in 30 seconds after administration
More preferably, and diagnosis of coronary heart disease and adenosine test have good consistency.
It is domestic before Rui Jiade pinales not go public also, belong to 3.1 kind new medicines, prescription information, patent are given in FDA specifications
CN104224706A《A kind of Rui Jiade loose parenteral solutions and preparation method thereof》The method for preparing Rui Jiade loose parenteral solutions is provided, is adopted
With disodium hydrogen phosphate aqueous solution and biphosphate sodium water solution is first prepared respectively, the phosphate-buffered body of PH7.4 is obtained after mixing
Then propylene glycol and natrium adetate mixed aqueous solution are prepared by system, finally weigh a certain amount of Rui Jiadesong and be dissolved to inside water, will
This Rui Jiadesong aqueous solution is added to the propylene glycol and natrium adetate mixed aqueous solution that front is prepared, and adds the phosphorus of PH7.4
Hydrochlorate buffer system stirs constant volume.Liquid carries out aseptic filtration by the filter core that moist heat sterilization is crossed, and obtains sterile Rui Jiadesong notes
Penetrate liquid.And in practical operation, it is found that Rui Jiadesong is almost insoluble in water (25 DEG C), so the operation in above-mentioned patent is difficult to reality
Existing, aseptic parenteral solution is in addition prepared by the way of aseptic filtration can improve surviving microorganisms contamination probability, while study discovery
Rui Jiadesong (API) is more sensitive to oxygen under aqueous solution state, and the chemical changes such as dissociation, hydrolysis, oxidation can occur for API,
Rui Jiadesong (API) is also more sensitive to different auxiliary materials, realizes and finds that the addition sequence of auxiliary material can influence Rui Jiadesong (API)
Stability.
Invention content
The purpose of the present invention is on the basis of existing technology, match liquid and preparation for existing Rui Jiade loose parenteral solutions
Technique is not fully applicable in actual production, and the liquid that the different supplementary material addition sequences found in experiment make contains
Amount a variety of practical problems such as different with impurity are provided and a kind of easy use and can rapidly be prepared in the industrial production of amplification
Go out that content is high, impurity is few, liquid is stable and the method for the Rui Jiade loose parenteral solutions uniform, quality standard is high.
The purpose of the present invention can be achieved by the following measures：
A kind of amplification production method of Rui Jiade loose parenteral solutions comprising following steps：
(1) it prepares mass content to be 15%~35% aqueous solution of propylene glycol and be heated to 60~75 DEG C, or by propylene glycol
It is 15%~35% aqueous solution of propylene glycol dissolving in 60~75 DEG C of water for injection to be added, mass content is made, and adds Rui Jiade
Pine maintains mixed dissolution at 60~75 DEG C, then sequentially adds simultaneously dissolving phosphoric acid disodium hydrogen, sodium dihydrogen phosphate and edetic acid(EDTA) two
Sodium, mix to it is complete it is molten after add water for injection constant volume and obtain liquid；
(2) be filtered after the completion of drug solution preparing it is filling, then sterilize to get；Wherein per in 1ml Rui Jiade loose parenteral solutions
Contain：0.07~0.09mg of Rui Jiadesong, 8~9mg of disodium hydrogen phosphate, 4~5mg of sodium dihydrogen phosphate, 130~170mg of propylene glycol,
0.5~1.5mg of natrium adetate, pH value are 6.3~7.7.
In a kind of preferred embodiment, contain in every 1ml Rui Jiade loose parenteral solutions：0.075~0.085mg of Rui Jiadesong, phosphorus
Sour 8.5~9.5mg of disodium hydrogen, 4.5~5mg of sodium dihydrogen phosphate, 140~160mg of propylene glycol, 0.7~1.2mg of natrium adetate,
Its pH value is 6.3~7.7.
In a kind of preferred scheme, contain in every 1ml Rui Jiade loose parenteral solutions：0.08mg Rui Jiadesong, 8.7mg phosphorus
Sour disodium hydrogen, 4.7mg sodium dihydrogen phosphates, 150mg propylene glycol, 1mg natrium adetates and water for injection, pH value are：6.3~7.7.
Rui Jiadesong in the present invention uses anhydrous or with the crystallization water Rui Jiadesong, such as a hydration Rui Jiadesong, two
It is hydrated Rui Jiadesong, the disodium hydrogen phosphate uses anhydrous or with the crystallization water disodium hydrogen phosphate, such as two hypophosphite monohydrate hydrogen two
Sodium, seven hypophosphite monohydrate disodium hydrogens and disodium hydrogen phosphate dodecahydrate；The sodium dihydrogen phosphate uses anhydrous or with the crystallization water phosphorus
Acid dihydride sodium, such as two hypophosphite monohydrate sodium dihydrogens；It is auspicious to add in the content calculation of step (2) and every 1ml Rui Jiade loose parenteral solutions
The content of moral pine, disodium hydrogen phosphate and sodium dihydrogen phosphate is pressed nodeless mesh water and is calculated.Propylene glycol in the present invention is 1,2- the third two
Alcohol.
In step (1), 65~70 DEG C are heated to after preparing aqueous solution of propylene glycol, or propylene glycol is added 65~70 DEG C
Water for injection in dissolved.
Practical to find, Rui Jiadesong is almost insoluble in water (25 DEG C), still insoluble improving the amount of dissolving water.
The solubility of Rui Jiadesong can be promoted to a certain extent by improving water temperature, however at 60 DEG C hereinafter, API is difficult still molten in water
Solution, and with the increase of water volume, have improved solubility and less, only temperature reaches 60 DEG C or more and can just be completely dissolved.But temperature
Impurity content can be seriously affected when spending high again.By taking API in water solubility experiment as an example：API 8.4mg add water 1ml stirrings not
It is molten, it is still insoluble to continue to add water to 10m, 20ml；40 DEG C of stirring 40min, 2/3API dissolvings of water-bath；It is increased to 60 DEG C of about 36min
Quan Rong；API 8.4mg add 75 DEG C of stirring 15min of water 20ml entirely molten；8.4mg adds 90 DEG C of stirring 8min of water 20ml entirely molten；Respectively
Sample detection and the API comparison that 60 DEG C, 75 DEG C and 90 DEG C are dissolved, the 60 DEG C and 75 DEG C sample sizes dissolved and related substance
Essentially unchanged, the apparent impurity of sample of 90 DEG C of dissolvings increases.
It finds that propylene glycol hydrotropy and can delay API to hydrolyze in research, increases API stability in the solution.However API exists
It is different that situation is dissolved in various concentration aqueous solution of propylene glycol, can only improve API's within the scope of specific PG concentration
Dissolving, propylene glycol can restrict the dissolving of API instead when beyond the range.For being dissolved at 65 DEG C：API is 10% the third
32min is entirely molten in glycol；18min is entirely molten in 20% propylene glycol；11min is entirely molten in 30% propylene glycol；35min in 40% propylene glycol
Quan Rong；38min is entirely molten in 60% propylene glycol；43min is entirely molten in 80% propylene glycol.It can be seen that API is at 65 DEG C, it is dense 20~30%
Solution rate is most fast in the propylene glycol of degree, after reduce the solution rate of API instead with PG concentration increase.
The concentration and temperature of the aqueous solution of propylene glycol used in the application it can be seen from above-mentioned actual experiment and binding analysis
Degree has particular requirement.Therefore in step (1), the preferred mass content of aqueous solution of propylene glycol is 20~30%, prepares propylene glycol
It is heated to 65~70 DEG C after aqueous solution, or propylene glycol is added in 65~70 DEG C of water for injection and is dissolved.Rui Jiadesong
Solution temperature be 65~70 DEG C；The preparation of aqueous solution of propylene glycol or Rui Jiadesong be dissolved under stirring or ultrasound condition into
Row.
In step (1), after Rui Jiadesong dissolvings, simultaneously dissolving phosphoric acid disodium hydrogen, sodium dihydrogen phosphate are sequentially added and according to ground
Acid disodium adds a kind of lower material wherein being often added after a kind of material fully dissolves.Inventor has found in actual production, auspicious
The addition sequence of Jia Desong and auxiliary material can not only seriously affect the speed of production, can also influence the stability and matter of Rui Jiadesong
Amount.It when using unfavorable addition sequence, can greatly extend manufacture cycle, liquid content, uniformity are allotted in reduction, and are carried
High impurity content.Only it could realize that the synchronous high-efficiency of speed of production and quality carries under the specified conditions required by the application
It rises.
For only investigating auxiliary material order of addition, transformation propylene glycol, natrium adetate and phosphatic charging sequence can be with
It was found that natrium adetate be dissolved in water-propylene glycol solution the time required to much larger than natrium adetate be directly dissolved in water when
Between, but natrium adetate is dissolved in aqueous solution of propylene glycol and phosphatic mixed solution neutralizes the time being directly dissolved in water
It is almost the same.It is verified below using three kinds of different auxiliary material addition sequences, a：Recipe quantity propylene glycol is weighed, 35% prescription is added
Measure 65 DEG C of water for injection stirring and dissolvings, add natrium adetate stirring it is complete it is molten after, then add disodium hydrogen phosphate and sodium dihydrogen phosphate, 65 DEG C
Stirring needs 25min, it is 7.07 that constant volume, which surveys PH, to complete molten altogether；b：In volumetric flask plus 35% recipe quantity, 65 DEG C of waters for injection, add according to
Ground acid disodium stirring is complete molten, then adds disodium hydrogen phosphate and sodium dihydrogen phosphate, then 65 DEG C of propylene glycol is added to stir evenly, and needs altogether
3.5min, it is 7.09 that constant volume, which surveys PH,；c：Recipe quantity propylene glycol is weighed, adds 35% recipe quantity, 65 DEG C of water for injection stirring and dissolvings, adds
Disodium hydrogen phosphate and sodium dihydrogen phosphate, then add natrium adetate, 65 DEG C of stirrings need 4min, constant volume to survey PH and be to complete molten altogether
7.10.From verification result it can be found that matching liquid sequence according to b and c, dissolution time ratio a shortens very much, thus auxiliary material sequentially with
B sequences or c sequences are advisable.
On the basis of combining auxiliary material sequence, the influence of API addition sequences is further investigated.Natrium adetate is in prescription
As chelating agent, find that solution rate of the natrium adetate in pure water is more than the solution rate in buffer solution by step (3).
In view of practical condition, natrium adetate addition sequence need to be investigated, in addition API addition sequences, which also influence to allot liquid, contains
Amount, impurity and uniformity；Specifically provide following three kinds of sequences：
a：API and 30% aqueous solution of propylene glycol (propylene glycol and 35% recipe quantity water) add after 65 DEG C of heating stirrings dissolve
Enter recipe quantity disodium hydrogen phosphate, sodium dihydrogen phosphate, natrium adetate, constant volume after 65 DEG C of stirring and dissolvings；
b：Natrium adetate and 65% recipe quantity water, after 65 DEG C of stirring and dissolvings plus disodium hydrogen phosphate, sodium dihydrogen phosphate and third
Glycol after stirring evenly, then adds API constant volumes；
c：Natrium adetate, 35% recipe quantity water, after 65 DEG C of stirring and dissolvings, be added disodium hydrogen phosphate, sodium dihydrogen phosphate and
Propylene glycol stirring and dissolving, then add constant volume after API.
Its verification result is as follows：
Method a：18min is needed with liquid process, 99% or more content, impurity 4, total miscellaneous 0.90%, maximum single miscellaneous 0.4%；
Method b：32min is needed with liquid process, 99% or more content, impurity 4, total miscellaneous 0.95%, maximum single miscellaneous 0.4%；
Method c：47min is needed with liquid process, content 97~98%, impurity 5, total miscellaneous 1.45%, maximum single miscellaneous 0.8%；
Liquid preparation time is most short in method a, liquid content highest, impurity number and size are also minimum.It was found from test result
Be the dissolution time being added in the less a schemes of water needed for API and natrium adetate instead all it is minimum.From this conclusion
Also demonstrate the API used in this method in 20~30% aqueous solution of propylene glycol the most diffluent conclusion at 65 DEG C.
In conjunction with the characteristics of API, using concentrated compounding method come preparating liquid when the amplification of the application production, concentrated compounding ratio is 50%~
80%, preferably 50%~65%.Under normal circumstances whole dissolvings of the lower alignment type of the ratio of concentrated compounding with liquid it is more secure and
The easier transfer in production, but concentrated compounding ratio is lower higher to the quality of liquid and the time challenge of integrated liquid-distributing, then
Influence actual operability.The concentrated compounding method of the application needs to use specific concentrated compounding ratio, has investigated four kinds of concentrated compoundings below
Ratio：
30% concentrated compounding：It weighs in recipe quantity propylene glycol to 10L beakers, 65 DEG C of water for injection 1.5L is added and water-bath maintains 65
It DEG C stirs evenly；Add API stirrings complete molten；Continue plus disodium hydrogen phosphate, sodium dihydrogen phosphate, natrium adetate are to complete molten, is settled to
10L, stirring 0.55h solids are still difficult to complete molten when concentrated compounding, only dilute just entirely molten after constant volume, and sample detection liquid is uniform
Property it is bad, per ml liquids in 10 μm and 10 μm or more of particle >=1300.
50% concentrated compounding：Operation takes 0.32h with 30% concentrated compounding altogether, and solid can be complete molten when concentrated compounding, and liquid homogeneity is good, often
10 μm and 10 μm or more of particle≤300 in ml liquids.
65% concentrated compounding：Operation only mends after adding API with 30% concentrated compounding and injects water to 65%, take altogether
0.38h, can be complete molten when concentrated compounding, and liquid homogeneity is good, per ml liquids in 10 μm and 10 μm or more of particle≤250.
80% concentrated compounding：Operation takes 0.25h with 65% concentrated compounding altogether, and when concentrated compounding can be complete molten, and liquid homogeneity is good, per ml medicines
10 μm and 10 μm or more of particle≤250 in liquid.
50%, in 65% and 80% concentrated compounding, the molten time is almost the same entirely for API, phosphate and natrium adetate, and liquid contains
It measures, is suitable in relation to substance, pH value and particulate matter.
In conjunction with above the investigation as a result, the application is in step (1), water for injection used in aqueous solution of propylene glycol is prepared
Account for the 25%~45% of total injection water, preferably 25%~35%, further preferred 25%~30%.
The pH value that the liquid of completion is prepared in the application is 6.3~7.7.It is practical to the PH of different volumes liquid to be examined
It examines, to verify stability action of the phosphate buffer to liquid PH value, and in view of amplification preparating liquid in production
The test to phosphate buffer to pH value durability is measured, discovery is small to 1L in preparation, slow to phosphate in 100L liquids greatly
It is highly stable to adjusting pH value to rush system, the enlarge-effect of general acid-base accommodation pH value routine does not occur, in addition prescription
In the addition of API, natrium adetate and propylene glycol the liquid PH value under the recipe quantity is not influenced substantially, the pH value of liquid
Depending on phosphate buffer pH value.Verification method is as follows：1L, 50L and 100L phosphate-buffered body are prepared according to recipe quantity
System, test pH value is respectively 7.07,7.06 and 7.10.Other supplementary materials are added according to recipe quantity, retest liquid PH value point
It Wei 7.09,7.05 and 7.12, it is seen that the pH value of phosphate buffer is basically the pH value after being made into liquid, i.e. prescription
In the addition of API, natrium adetate and propylene glycol liquid PH value is not influenced substantially, the pH value of liquid depends on phosphate
Buffer system pH value, and equal proportion is amplified on liquid PH value without influence, therefore liquid PH value does not have risk when amplifying production, notes
It is 6.3~7.7 to penetrate liquid regulation PH, so adjusting pH value without additional.
The Injection Process of the application uses terminal sterilization, specifically, in step (2), is obtained after the completion of filling
Product 15~60min of sterilizing at 115~126 DEG C in moist heat sterilization cabinet.In actual production, terminal sterilization sterile product
Sterility assurance level is surviving microorganisms contamination probability≤10-6, nonterminal sterilizing sterile product sterility assurance level at least answer
Reach the contamination probability under 95% confidence limit<0.1%.It can be seen that there are microbial contaminations for nonterminal sterilizing sterile product
Probability is far above terminal sterilization sterile product.For the angle of quality assurance, terminal sterilization is far high to sterile controlled level
It sterilizes in nonterminal, only can just consider that nonterminal sterilizes under the premise of product is not suitable for terminal sterilization.Rui Jiadesong is noted
It penetrates liquid and carries out moist heat sterilization condition investigation, 15min, 30min and 60min and unpasteurized injection are sterilized separately at 121 DEG C
It is compared, mainly investigates character, content, in relation to substance, pH value and sterile (microbial limit).As a result, it has been found that at 121 DEG C
Sterilizing can reach sterility requirements, and character, content and related substance, pH value before sterilization after it is substantially unchanged, only with going out
The extension of bacterium time, other single impurity and total miscellaneous content slightly increase.Patent 104224706A《A kind of Rui Jiadesong injections
Liquid and preparation method thereof》In mention Rui Jiadesong and sterilize under hot pressing condition and can cause the notable degradation of API, thus use degerming
Filter type prepares aseptic parenteral solution；This method can actually greatly improve the contamination probability of microorganism
The present invention be directed to existing Rui Jiade loose parenteral solutions with liquid and preparation process in actual production not fully
Applicable angle optimizes it, and changes the quality that existing preparation process improves injection.By matching liquid process
The order of addition of middle supplementary material, which is investigated to provide, optimal matches liquid technique：35% recipe quantity water adds propylene glycol, is made into 30% propylene glycol
Aqueous solution after API stirring and dissolvings, sequentially adds disodium hydrogen phosphate, sodium dihydrogen phosphate, natrium adetate stirring and dissolving and fixed
Hold, make content height, impurity is few, liquid is stable and uniformly high liquid.In addition it is terminal sterilization to change aseptic filtration, is avoided
The culture medium analoging filling of producing line, and the sterility barrier for improving product is horizontal, and investigate out for production amplification demand suitable
In 50~65% concentrated compounding ratio of production, the liquid PH value of verification phosphate buffer adjustment is not as medicine liquid volume increases
There is enlarge-effect greatly.
Inventive process avoids liquids in the longer problem of exposed ambient time, is prepared using correct charging sequence
The high liquid of mass, and realize the kind amplify from laboratory lab scale to workshop production transfer, improve product without
There is the horizontal preparation process simultaneously of bacterium mild condition, quick, at low cost, liquid property easy to operate to stablize, and quality standard is high,
Suitable for industrialized production.
Specific implementation mode
Embodiment one：
60 DEG C of water for injection 122.5L are added to be pre-dissolved in bucket in 200L, is pre-dissolved outside bucket and uses heating mantle, maintain temperature within the barrel
60 DEG C, be added 52.5kg1,2- propylene glycol stirring and dissolvings, add 28.01g without hydration Rui Jiadesong stirring and dissolvings；It weighs
3.045kg Anhydrous Disodium Phosphate, 1.645kg anhydrous sodium dihydrogen phosphate and natrium adetate 350.02g are stirred to whole dissolvings.
Liquid in bucket will be pre-dissolved to be transferred in Agitation Tank, heating mantle is used outside Agitation Tank, it is same to maintain temperature 60 C in tank；Add 60 DEG C of notes
It penetrates and is settled to 350L with water, stir 0.2h, take 0.42h with liquid, it is 99.98% that taking liquid, which is detected content, related substance：
Total miscellaneous 0.87%, maximum single miscellaneous 0.39%.Liquid is cooled to room temperature to be filtered in workshop, uses cillin bottle line afterwards
The progress of FLC3080 bottle placers is filling, and in filling 5ml liquids to 6R cillin bottles, filling speed is 200/min, rolls lid and seals
6.55 Wan Zhiruijiade loose parenteral solutions, take to roll lid sample and be put at 121 DEG C of moist heat sterilization cabinet ADV09.09-12/2 and sterilize
15min, sampling carry out sample detection, character after putting to room temperature：Colourless clear liquid；PH：7.02；Content：100.09%；It is related
Substance：Total miscellaneous 0.86%, maximum single miscellaneous 0.40%；It is sterile：≤10-6, meet regulation, particulate matter：10 μm in per ml liquids
And 10 μm or more of particle is 282.
Embodiment two：
65 DEG C of water for injection 122.5L are added to be pre-dissolved in bucket in 200L, is pre-dissolved outside bucket and uses heating mantle, maintain temperature within the barrel
65 DEG C, 52.5kg1 is added, 2- propylene glycol stirring and dissolvings add a hydration Rui Jiadesong stirring and dissolvings of 29.43g；It weighs
Bis- hypophosphite monohydrate disodium hydrogens of 3.818kg, mono- hypophosphite monohydrate sodium dihydrogens of 1.892g and natrium adetate 350.25g are stirred to all molten
Solution.Liquid in bucket will be pre-dissolved to be transferred in Agitation Tank, heating mantle is used outside Agitation Tank, it is same to maintain 65 DEG C of temperature in tank；Add 65
DEG C water for injection is settled to 350L, stirs 0.2h, takes 0.38h with liquid, it is 100.06% that taking liquid, which is detected content, related
Substance：Total miscellaneous 0.92%, maximum single miscellaneous 0.43%.Liquid is cooled to room temperature to be filtered in workshop, uses cillin bottle line afterwards
The progress of FLC3080 bottle placers is filling, and in filling 5ml liquids to 6R cillin bottles, filling speed is 200/min, rolls lid and seals
6.68 Wan Zhiruijiade loose parenteral solutions, take to roll lid sample and be put at 121 DEG C of moist heat sterilization cabinet ADV09.09-12/2 and sterilize
30min, sampling carry out sample detection, character after putting to room temperature：Colourless clear liquid；PH：7.08；Content：100.12%；It is related
Substance：Total miscellaneous 0.91%, maximum single miscellaneous 0.41%,；It is sterile：≤10-6, meet regulation, particulate matter：10 μm in per ml liquids
And 10 μm or more of particle is 265.
Embodiment three：
75 DEG C of water for injection 122.5L are added to be pre-dissolved in bucket in 200L, is pre-dissolved outside bucket and uses heating mantle, maintain temperature within the barrel
75 DEG C, 52.5kg1 is added, 2- propylene glycol stirring and dissolvings add the two hydration Rui Jiadesong stirring and dissolvings of 30.73g；It weighs
Bis- hypophosphite monohydrate disodium hydrogens of 3.812kg, mono- hypophosphite monohydrate sodium dihydrogens of 1.895g and natrium adetate 350.05g are stirred to all molten
Solution.Liquid in bucket will be pre-dissolved to be transferred in Agitation Tank, heating mantle is used outside Agitation Tank, it is same to maintain 75 DEG C of temperature in tank；Add 75
DEG C water for injection is settled to 350L, stirs 0.2h, takes 0.45h with liquid, it is 100.01% that taking liquid, which is detected content, related
Substance：Total miscellaneous 0.88%, maximum single miscellaneous 0.37%.Liquid is cooled to room temperature to be filtered in workshop, uses cillin bottle line afterwards
The progress of FLC3080 bottle placers is filling, and in filling 5ml liquids to 6R cillin bottles, filling speed is 200/min, rolls lid and seals
6.63 Wan Zhiruijiade loose parenteral solutions take sample to be put at 121 DEG C of moist heat sterilization cabinet ADV09.09-12/2 the 60min that sterilizes, take
Sample carries out sample detection after putting to room temperature, sampling carries out sample detection, character after putting to room temperature：Colourless clear liquid；PH：
7.05；Content：100.09%；Related substance：Total miscellaneous 0.93%, maximum single miscellaneous 0.39%,；It is sterile：≤10-6, meet regulation, no
Dissolubility particle：10 μm and 10 μm or more of particle is 274 in per ml liquids.
Comparative example one：
It weighs natrium adetate 350.25g to 200L to be pre-dissolved in bucket, is pre-dissolved outside bucket and uses heating mantle, maintain temperature within the barrel 65
DEG C, 65 DEG C of water for injection 52.5L stirring and dissolvings are added；Weigh bis- hypophosphite monohydrate disodium hydrogens of 3.818kg, mono- hypophosphite monohydrates of 1.892g
The 1,2-PD of sodium dihydrogen and 52.5kg are also added and are pre-dissolved in bucket, and a hydration Rui Jiade of 29.43g is added after stirring and dissolving
Pine is stirred for being completely dissolved.Liquid in bucket will be pre-dissolved to be transferred in Agitation Tank, heating mantle is used outside Agitation Tank, it is same to maintain
65 DEG C of temperature in tank；Add 65 DEG C of waters for injection to be settled to 350L, stir 0.58h, takes 1.2h with liquid, taking liquid, which is detected, to be contained
Amount is 97.65%, related substance：Total miscellaneous 1.52%, maximum single miscellaneous 0.83%.Liquid is cooled to room temperature to carry out in workshop
Filter, is produced using sterile working, in filling 5ml liquids to 6R cillin bottles, is rolled lid and is sealed to obtain 6.54 Wan Zhiruijiadesong notes
Liquid is penetrated, sampling carries out sample detection, character after putting to room temperature：Colourless clear liquid；PH：7.08；Content：97.74%；Related object
Matter：Total miscellaneous 1.50%, maximum single miscellaneous 0.81%；It is sterile：<10-3, but > 10-4, particulate matter：In per ml liquids 10 μm and
10 μm or more of particle is 1453.
Comparative example two：
Water for injection 10L is taken, propylene glycol 1.5kg is added, stirs evenly.EDTA-2Na 100g are added, dissolve and are stirred
Uniformly.16g injections Rui Jiadesong (based on pure without crystallization water bulk pharmaceutical chemicals) is weighed, is dissolved in 65 DEG C of waters for injection, then
Rui Jiadesong solution is added into the aqueous solution for injection of propylene glycol and EDTA-2Na under stirring, adds pH7.4 phosphate
Buffer system 400ml, stirs.Water for injection is added to total volume 200L.By above-mentioned prepared 200L it is auspicious plus
It is pre- that moral loose parenteral solution (wherein containing propylene glycol, EDTA-2Na and pH7.4 phosphate buffers) first passes through 0.45 μm of sand stick
Filtration, then by the filtration of 0.22 μm of polyether sulfone filter core to get to sterile Rui Jiade loose parenteral solutions.
Sampling carries out sample detection, character after putting to room temperature：Colourless clear liquid；PH：7.08；Content：99.00%；Have
Close substance：Total miscellaneous 1.20%, maximum single miscellaneous 0.81%；It is sterile：<10-3, particulate matter：In per ml liquids 10 μm and 10 μm with
On particle be 1000.
Claims (8)
1. a kind of amplification production method of Rui Jiade loose parenteral solutions, it is characterised in that include the following steps：
（1）Mass content is prepared to be 15%~35% aqueous solution of propylene glycol and be heated to 60 ~ 75 DEG C, or propylene glycol is added 60 ~
It is 15%~35% aqueous solution of propylene glycol that mass content, which is made, in dissolving in 75 DEG C of water for injection, adds Rui Jiadesong and maintains 60
Then mixed dissolution at ~ 75 DEG C sequentially adds simultaneously dissolving phosphoric acid disodium hydrogen, sodium dihydrogen phosphate and natrium adetate, mixes to complete
Water for injection constant volume is added after molten obtains liquid；Rui Jiadesong liquids are wherein prepared using concentrated compounding method, concentrated compounding ratio is 50%~
80%；
（2）Be filtered after the completion of drug solution preparing it is filling, then in moist heat sterilization cabinet at 115~126 DEG C sterilizing 15 ~
60min to get；Contain in wherein every 1ml Rui Jiade loose parenteral solutions：0.07~0.09mg of Rui Jiadesong, disodium hydrogen phosphate 8~
9mg, 4~5mg of sodium dihydrogen phosphate, 130~170mg of propylene glycol, 0.5~1.5mg of natrium adetate, pH value are 6.3 ~ 7.7.
2. according to the method described in claim 1, it is characterized in that in step（1）In, the quality of the aqueous solution of propylene glycol contains
Amount is 20~30%.
3. according to the method described in claim 1, it is characterized in that in step（1）In, it is heated to after preparing aqueous solution of propylene glycol
65 ~ 70 DEG C, or propylene glycol is added in 65 ~ 70 DEG C of water for injection and is dissolved, the propylene glycol is 1,2-PD.
4. according to the method described in claim 1, it is characterized in that in step（1）In, it prepares used in aqueous solution of propylene glycol
Water for injection accounts for the 25%~45% of total injection water.
5. according to the method described in claim 1, it is characterized in that in step（1）In, the solution temperature of Rui Jiadesong is 65 ~ 70
℃；The preparation of aqueous solution of propylene glycol or being dissolved under stirring or ultrasound condition for Rui Jiadesong carry out.
6. according to the method described in claim 1, it is characterized in that in step（1）In, after Rui Jiadesong dissolvings, sequentially add simultaneously
Dissolving phosphoric acid disodium hydrogen, sodium dihydrogen phosphate and natrium adetate, wherein be often added after a kind of material fully dissolves add it is next
Kind material.
7. according to the method described in claim 1, it is characterized in that in step（1）In, the Rui Jiadesong uses anhydrous or band
The Rui Jiadesong of the crystallization water, the disodium hydrogen phosphate use anhydrous or with the crystallization water disodium hydrogen phosphate；The sodium dihydrogen phosphate
Using sodium dihydrogen phosphate anhydrous or with the crystallization water；In step（2）In, Rui Jiadesong, disodium hydrogen phosphate and sodium dihydrogen phosphate
Content is pressed nodeless mesh water and is calculated.
8. according to the method described in claim 1, it is characterized in that preparing Rui Jiadesong liquids, concentrated compounding ratio using concentrated compounding method
It is 50%~65%.
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