CN103705446A - Polyene phosphatidyl choline injection, and preparation method thereof - Google Patents
Polyene phosphatidyl choline injection, and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the field of medicinal preparation, and specifically relates to a polyene phosphatidyl choline injection, and a preparation method thereof. The polyene phosphatidyl choline injection comprises polyene phosphatidyl choline, a solubilizer, an antiseptic, and a stabilizing agent; the solubilizer is selected from deoxycholic acid, deoxysodium cholate, dehydrocholic acid, sodium dehydrocholate, cholic acid, or sodium cholate; and the stabilizing agent is selected from amino acid, or a sodium salt thereof, or trometamol. Compared with a control group without the stabilizing agent, stability of the polyene phosphatidyl choline injection after high temperature sterilization and long-term storage is increased significantly, formula and preparation method are both simple, and the polyene phosphatidyl choline injection is convenient for industrialized production.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, in particular to a kind of stable Polyene Phosphatidylcholine injection liquid and preparation method thereof.
Background technology
Polyene phosphatidylcholine is a kind of lecithin in high purity extracting from soybean phospholipid, contain a large amount of unsaturated fatty acids, be mainly linoleic acid (accounting for 70%), linolenic acid and oleic acid, owing to being rich in multiple unsaturated fatty acid, therefore be called polyene phosphatidylcholine.Polyene phosphatidylcholine is " essential " phospholipid that can not synthesize in human body, is a kind of liver plasma membrane protective agent, can treat multiple acute and chronic hepatic disease.All there is liver plasma membrane and cell mitochondrial ultrastructure damage and accompany phospholipid loss and Cellular respiration and the synthetic deficiency of energy in various hepatopathys, take supplemented with exogenous phospholipid, unsaturated phospholipid is introduced in liver plasma membrane structure, substitute endogenous saturated phospholipid, can make membrane fluidity and transmembrane transport system activity strengthen, impaired membrane structure is therefore recovered.Polyene phosphatidylcholine is the comparatively sure hepatic of current curative effect.At present, this medicine has capsule and two kinds of dosage forms of injection.
Polyene Phosphatidylcholine injection liquid is phospholipid medicine, the same with other phospholipid, there is heat-labile feature, phospholipid hydrolysis in various degree all can occur in high temperature sterilize process and longer-term storage process, cause thus three large problems: 1) content of principal agent polyene phosphatidylcholine declines; 2) generation of toxicant LYSO-PHOSPHATIDYLCHOLINE LYSOPC; 3) hydrolysis of phospholipid causes product pH value to decline.
In fact, phospholipid hydrolysis generates LYSO-PHOSPHATIDYLCHOLINE LYSOPC and free fatty is the main cause that causes product pH value to decline, and therefore, controlling phospholipid hydrolysis is to control the fundamental means that product pH reduces.Yet the control that phospholipid is hydrolyzed in high temperature or longer-term storage process is the difficult problem extensively existing in phospholipid medicament research and development.
For improving the stability of polyene phosphatidylcholine, changing injection dosage form into freeze-dried powder dosage form is a kind of effective means that are generally considered.Existing numerous researcheres are attempted, such as following Chinese patent or patent application: CN201010264516.9, CN200510030631.9, CN200610009780.1, CN200510094998.7, CN200510021089.0, CN200510057457.7, CN200510037429.9, CN200610003436.1, CN200510021636.5 etc.Yet, to compare with injection dosage form, longer, production cost of production cycle of lyophilized formulations obviously increases, and need to additionally add freeze drying protectant; In addition, lyophilized formulations needs to redissolve with solvent before clinical use, complex operation, and easily cause liquid medicine contamination.
Therefore, develop a kind of Polyene Phosphatidylcholine injection liquid of good stability, for reducing production costs, simplify production operation, guaranteeing the higher practical value of the equal tool of clinical drug safety.There is researcher to be devoted to the exploitation of Polyene Phosphatidylcholine injection liquid, for example Chinese patent application CN200510105183.4 discloses a kind of infusion solutions that improves polyene phosphatidylcholine stability, and its polyene phosphatidylcholine by recipe quantity, nutrient, vitamin, cosolvent, antioxidant, isotonic agent, antiseptic, active carbon and water for injection form; Chinese patent CN200710050223.9 discloses the Polyene Phosphatidylcholine injection liquid that a kind of clarity is good, stability is strong, its polyene phosphatidylcholine by recipe quantity, benzyl alcohol, glycocholic acid or cholic acid or tween 80, ethanol or propylene glycol or glycerol, sodium hydroxide or sodium carbonate, 2,6 ditertiary butyl p cresol, tertiary butyl-4-hydroxy methoxybenzene and vitamin E form.But above-mentioned injection formula is more complicated, brought the problem of aspects such as cost, safety and Quality Control, therefore still needing to study new prescription solves the unsettled technical problem of polyene phosphatidylcholine.
Summary of the invention
Unexpectedly, when applicant finds to add aminoacid or its sodium salt or Tris in Polyene Phosphatidylcholine injection liquid, can significantly improve the stability of polyene phosphatidylcholine in high temperature sterilize and long term storage process.
One aspect of the present invention is to provide a kind of Polyene Phosphatidylcholine injection liquid, it comprises polyene phosphatidylcholine, solubilizing agent, antiseptic and stabilizing agent, wherein said solubilizing agent is selected from deoxycholic acid, sodium deoxycholate, dehydrocholic acid, sodium dehydrocholate, cholic acid or sodium cholate, and wherein said stabilizing agent is selected from aminoacid or its sodium salt or Tris.
Solubilizing agent of the present invention is preferably deoxycholic acid or sodium deoxycholate, more preferably deoxycholic acid.
Antiseptic of the present invention is preferably benzyl alcohol.
Aminoacid of the present invention comprises nonprotein amino acid and gal4 amino acid.Preferably, aminoacid is gal4 amino acid, comprises one or more in alanine, arginine, agedoite, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine or valine.More preferably, aminoacid of the present invention is glycine or arginine or their mixture.
Except said components, polyene phosphatidylcholine of the present invention also can comprise other pharmaceutically acceptable components.These components include but not limited to sodium chloride, sodium hydroxide, riboflavin, riboflavin sodium phosphate, vitamin E, Vitamin E acetate, vitamin C, sodium L-ascorbate-2-phosphate, BHA (butylated hydroxyarisol, tertiary butyl-4-hydroxy methoxybenzene, Butylated hydroxyanisole), BHT (2,6-di-tert-butyl-4-methy phenol, 2,6 ditertiary butyl p cresol), sodium sulfite, sodium sulfite, sodium pyrosulfite, EDTA (ethylenediaminetetraacetic acid), EDETATE SODIUM and Ethylenediaminetetraacetic Acid Calcium Salt.Optionally, can add one or more these components.
The content of each component of Polyene Phosphatidylcholine injection liquid of the present invention is restriction especially, and those skilled in the art can eligibly select according to the characteristic of quantity, each component etc.Should be appreciated that, selected certain content is preferred content, is not intended to illustrate that other content can not reach technique effect of the present invention.
In a preferred embodiment of the present invention, Polyene Phosphatidylcholine injection liquid comprises following component and content (weight portion): polyene phosphatidylcholine 220-275 part, solubilizing agent 120-200 part, antiseptic 30-60 part, stabilizing agent 1-40 part, wherein said solubilizing agent is selected from deoxycholic acid, sodium deoxycholate, dehydrocholic acid, sodium dehydrocholate, cholic acid or sodium cholate, and wherein said stabilizing agent refers to aminoacid or its sodium salt or Tris.Preferably, Polyene Phosphatidylcholine injection liquid comprises following component and content (weight portion): polyene phosphatidylcholine 220-275 part, deoxycholic acid or sodium deoxycholate 120-200 part, benzyl alcohol 30-60 part, aminoacid or Tris 1-40 part.More preferably, Polyene Phosphatidylcholine injection liquid comprises following component and content (weight portion): polyene phosphatidylcholine 220-275 part, deoxycholic acid 120-200 part, benzyl alcohol 30-60 part, glycine or arginine or Tris 1-40 part.
In another preferred embodiment of the present invention, Polyene Phosphatidylcholine injection liquid of the present invention comprises following component and content (weight portion): polyene phosphatidylcholine 220-250 part, solubilizing agent 125-175 part, antiseptic 40-50 part, stabilizing agent 10-30 part, wherein said solubilizing agent is selected from deoxycholic acid, sodium deoxycholate, dehydrocholic acid, sodium dehydrocholate, cholic acid or sodium cholate, and wherein said stabilizing agent refers to aminoacid or its sodium salt or Tris.Preferably, Polyene Phosphatidylcholine injection liquid comprises following component and content (weight portion): polyene phosphatidylcholine 220-250 part, deoxycholic acid or sodium deoxycholate 125-175 part, benzyl alcohol 40-50 part, aminoacid or Tris 10-30 part.More preferably, Polyene Phosphatidylcholine injection liquid comprises following component and content (weight portion): polyene phosphatidylcholine 220-250 part, deoxycholic acid 125-175 part, benzyl alcohol 40-50 part, glycine or arginine or Tris 10-30 part.
In the present invention again in another preferred embodiment, Polyene Phosphatidylcholine injection liquid of the present invention comprises following component and content (weight portion): polyene phosphatidylcholine 230-245 part, solubilizing agent 140-160 part, antiseptic 45-50 part, stabilizing agent 15-25 part, wherein said solubilizing agent is selected from deoxycholic acid, sodium deoxycholate, dehydrocholic acid, sodium dehydrocholate, cholic acid or sodium cholate, and wherein said stabilizing agent refers to aminoacid or its sodium salt or Tris.Preferably, Polyene Phosphatidylcholine injection liquid comprises following component and content (weight portion): polyene phosphatidylcholine 230-245 part, deoxycholic acid or sodium deoxycholate 140-160 part, benzyl alcohol 45-50 part, aminoacid or Tris 15-25 part.More preferably, Polyene Phosphatidylcholine injection liquid comprises following component and content (weight portion): polyene phosphatidylcholine 230-245 part, deoxycholic acid 140-160 part, benzyl alcohol 45-50 part, glycine or arginine or Tris 15-25 part.
In the present invention, go back in a preferred embodiment, Polyene Phosphatidylcholine injection liquid of the present invention comprises following component and content (weight portion): 232.5 parts of polyene phosphatidylcholine, solubilizing agent 140-160 part, antiseptic 45-50 part, stabilizing agent 15-25 part, wherein said solubilizing agent is selected from deoxycholic acid, sodium deoxycholate, dehydrocholic acid, sodium dehydrocholate, cholic acid or sodium cholate, and wherein said stabilizing agent refers to aminoacid or its sodium salt or Tris.Preferably, Polyene Phosphatidylcholine injection liquid comprises following component and content (weight portion): 232.5 parts of polyene phosphatidylcholine, deoxycholic acid or sodium deoxycholate 140-160 part, benzyl alcohol 45-50 part, aminoacid or Tris 15-25 part.More preferably, Polyene Phosphatidylcholine injection liquid comprises following component and content (weight portion): 232.5 parts of polyene phosphatidylcholine, deoxycholic acid 140-160 part, benzyl alcohol 45-50 part, glycine or arginine or Tris 15-25 part.
In yet another embodiment of the invention, Polyene Phosphatidylcholine injection liquid of the present invention is except comprising component mentioned above and content (weight portion), also comprise following component and content (weight portion): sodium chloride 6-25 part, preferably 8-20 part, more preferably 10-18 part; Riboflavin or riboflavin sodium phosphate (in riboflavin) 0.1-2 part, preferably 0.3-1 part, more preferably 0.35-0.6 part; Sodium hydroxide 11-30 part, preferably 11-25 part, more preferably 15-20 part.
Another aspect of the present invention provides a kind of preparation method of Polyene Phosphatidylcholine injection liquid, and it comprises the following steps:
(1) under nitrogen protection, in the water for injection of 60%～95% amount of preparation, add each component, stir, if desired suitably heating;
(2) to the activated carbon adsorption 15～30min that adds 0.01%～1% (by weight) in step (1) solution, carry out afterwards decarbonisation;
(3) if necessary, with sodium hydroxide solution or dilute hydrochloric acid solution, regulate pH to 7.5～9.5;
(4) add water to amount of preparation;
(5) filter, in nitrogen, cover lower embedding, sterilizing, inspection is qualified, obtains.
Wherein each component in step (1) can add simultaneously, also can first add a part, and then add remaining ingredient.In addition, the addition sequence of each component is restriction especially not, for example, can add at first polyene phosphatidylcholine, also can finally add polyene phosphatidylcholine.Part component also can add after the de-charcoal of step (2).
Wherein also can first sterilizing in step (5), then embedding under nitrogen covers, in step (5), also can not carry out sterilization steps in addition.
In addition, should be appreciated that, part steps in the method can be exchanged, for example can be prepared by the order of (1), (3), (4), (2), (5), but be not limited in this kind of exchange mode, those skilled in the art can desirably select as the case may be.
Polyene Phosphatidylcholine injection liquid of the present invention is compared with not adding contrasting of stabilizing agent, and high temperature sterilize and longer-term storage rear stability all significantly increase, and prescription and technique all simpler, be convenient to suitability for industrialized production.
They the invention is not restricted to particular methodology as herein described, scheme and reagent, because can change.In addition, term used herein is only for describing the object of particular, not to be intended to limit the scope of the invention.Unless clearly indication in literary composition, otherwise wording " comprises " and " comprising " is open rather than enclosed by being read as
The specific embodiment
Below in conjunction with specific embodiment, the present invention is conducted further description, yet in the present invention, these and other embodiment only do not limit the scope of the invention for illustrating.Equally, the invention is not restricted to any concrete preferred embodiment described herein.It should be appreciated by those skilled in the art that the replacement that is equal to that the technology of the present invention feature is done, or improve accordingly, within still belonging to protection scope of the present invention.
Embodiment 1
The preparation 5L Polyene Phosphatidylcholine injection liquid of take is example, under nitrogen protection, in the water for injection of 70% amount of preparation, add polyene phosphatidylcholine 232.5g, deoxycholic acid 150g, arginine 17.8g, sodium chloride 16g, benzyl alcohol 48.2g, sodium hydroxide 15g and riboflavin sodium phosphate 0.45g (in riboflavin), stir; Add 0.1% activated carbon adsorption 30min, de-charcoal; With sodium hydroxide solution or dilute hydrochloric acid solution, regulate pH to 9.0; Add water to amount of preparation; Filter, in nitrogen, cover lower subpackage embedding, 121 ℃ of sterilizing 12min, inspection is qualified, obtains.
Embodiment 2
The preparation 5L Polyene Phosphatidylcholine injection liquid of take is example, under nitrogen protection, in the water for injection of 70% amount of preparation, add polyene phosphatidylcholine 232.5g, deoxycholic acid 160g, arginine 19.6g, sodium chloride 18g, benzyl alcohol 50g, sodium hydroxide 16.3g and riboflavin sodium phosphate 0.60g (in riboflavin), stir; Add 0.1% activated carbon adsorption 30min, de-charcoal; With sodium hydroxide solution or dilute hydrochloric acid solution, regulate pH to 9.0; Add water to amount of preparation; Filter, in nitrogen, cover lower subpackage embedding, 121 ℃ of sterilizing 12min, inspection is qualified, obtains.
Embodiment 3
The preparation 5L Polyene Phosphatidylcholine injection liquid of take is example, under nitrogen protection, in the water for injection of 70% amount of preparation, add polyene phosphatidylcholine 232.5g, deoxycholic acid 140g, Tris 15g, sodium chloride 10g, benzyl alcohol 47.6g, sodium hydroxide 16.8g and riboflavin sodium phosphate 0.50g (in riboflavin), stir; Add 0.1% activated carbon adsorption 30min, de-charcoal; With sodium hydroxide solution or dilute hydrochloric acid solution, regulate pH to 9.0; Add water to amount of preparation; Filter, in nitrogen, cover lower subpackage embedding, 121 ℃ of sterilizing 12min, inspection is qualified, obtains.
Embodiment 4
The preparation 5L Polyene Phosphatidylcholine injection liquid of take is example, under nitrogen protection, in the water for injection of 70% amount of preparation, add polyene phosphatidylcholine 232.5g, deoxycholic acid 150g, glycine 25g, sodium chloride 16g, benzyl alcohol 45g, sodium hydroxide 20g and riboflavin sodium phosphate 0.35g (in riboflavin), stir; Add 0.1% activated carbon adsorption 30min, de-charcoal; With sodium hydroxide solution or dilute hydrochloric acid solution, regulate pH to 9.0; Add water to amount of preparation; Filter, in nitrogen, cover lower subpackage embedding, 121 ℃ of sterilizing 12min, inspection is qualified, obtains.
Embodiment 5
The preparation 5L Polyene Phosphatidylcholine injection liquid of take is example, under nitrogen protection, in the water for injection of 70% amount of preparation, add polyene phosphatidylcholine 232.5g, deoxycholic acid 140g, glycine 18.8g, sodium chloride 15g, benzyl alcohol 47.3g, sodium hydroxide 15.5g and riboflavin sodium phosphate 0.35g (in riboflavin), stir; Add 0.1% activated carbon adsorption 30min, de-charcoal; With sodium hydroxide solution or dilute hydrochloric acid solution, regulate pH to 9.0; Add water to amount of preparation; Filter, in nitrogen, cover lower subpackage embedding, 121 ℃ of sterilizing 12min, inspection is qualified, obtains.
Embodiment 6
The preparation 5L Polyene Phosphatidylcholine injection liquid of take is example, under nitrogen protection, in the water for injection of 70% amount of preparation, add polyene phosphatidylcholine 232.5g, deoxycholic acid 150g, Tris 15.6g, sodium chloride 16g, benzyl alcohol 48g, sodium hydroxide 16.3g and riboflavin sodium phosphate 0.45g (in riboflavin), stir; Add 0.1% activated carbon adsorption 30min, de-charcoal; With sodium hydroxide solution or dilute hydrochloric acid solution, regulate pH to 9.0; Add water to amount of preparation; Filter, in nitrogen, cover lower subpackage embedding, 121 ℃ of sterilizing 12min, inspection is qualified, obtains.
Embodiment 7
The preparation 5L Polyene Phosphatidylcholine injection liquid of take is example, under nitrogen protection, in the water for injection of 70% amount of preparation, add polyene phosphatidylcholine 220g, deoxycholic acid 120g, arginine 1g, sodium chloride 6g, benzyl alcohol 30g, sodium hydroxide 11g and riboflavin sodium phosphate 0.1g (in riboflavin), stir; Add 0.1% activated carbon adsorption 30min, de-charcoal; With sodium hydroxide solution or dilute hydrochloric acid solution, regulate pH to 9.0; Add water to amount of preparation; Filter, in nitrogen, cover lower subpackage embedding, 121 ℃ of sterilizing 12min, inspection is qualified, obtains.
Embodiment 8
The preparation 5L Polyene Phosphatidylcholine injection liquid of take is example, under nitrogen protection, in the water for injection of 70% amount of preparation, add polyene phosphatidylcholine 245g, deoxycholic acid 160g, Tris 25g, sodium chloride 18g, benzyl alcohol 50g, sodium hydroxide 20g and riboflavin sodium phosphate 0.60g (in riboflavin), stir; Add 0.1% activated carbon adsorption 30min, de-charcoal; With sodium hydroxide solution or dilute hydrochloric acid solution, regulate pH to 9.0; Add water to amount of preparation; Filter, in nitrogen, cover lower subpackage embedding, 121 ℃ of sterilizing 12min, inspection is qualified, obtains.
Embodiment 9:
The preparation 5L Polyene Phosphatidylcholine injection liquid of take is example, under nitrogen protection, in the water for injection of 70% amount of preparation, add polyene phosphatidylcholine 275g, deoxycholic acid 200g, arginine 40g, sodium chloride 25g, benzyl alcohol 60g, sodium hydroxide 30g and riboflavin sodium phosphate 2.0g (in riboflavin), stir; Add 0.1% activated carbon adsorption 30min, de-charcoal; With sodium hydroxide solution or dilute hydrochloric acid solution, regulate pH to 9.0; Add water to amount of preparation; Filter, in nitrogen, cover lower subpackage embedding, 121 ℃ of sterilizing 12min, inspection is qualified, obtains.
Control Example
The preparation 5L Polyene Phosphatidylcholine injection liquid of take is example, under nitrogen protection, in the water for injection of 70% amount of preparation, add polyene phosphatidylcholine 232.5g, deoxycholic acid 150g, sodium chloride 16g, benzyl alcohol 48.2g, sodium hydroxide 15g and riboflavin sodium phosphate 0.45g (in riboflavin), stir; Add 0.1% activated carbon adsorption 30min, de-charcoal; With sodium hydroxide solution or dilute hydrochloric acid solution, regulate pH to 9.0; Add water to amount of preparation; Filter, in nitrogen, cover lower subpackage embedding, 121 ℃ of sterilizing 12min, inspection is qualified, obtains.
The high-temperature heating stability of embodiment 10 Polyene Phosphatidylcholine injection liquids
According to the prescription in embodiment 1-9 and control Example and method, prepare 10 batches of Polyene Phosphatidylcholine injection liquids.By every batch of injection at 121 ℃ of sterilizing 12min, the relatively variation of polyene phosphatidylcholine (PPC) content, major impurity LYSO-PHOSPHATIDYLCHOLINE LYSOPC (LPC) content and pH before and after sterilizing, wherein PPC content and LPC content are all 100% calculating by PPC labelled amount 46.5mg/mL.
The long-time stability of embodiment 11 Polyene Phosphatidylcholine injection liquids
According to the prescription in embodiment 1-9 and control Example and method, prepare 10 batches of Polyene Phosphatidylcholine injection liquids.Every batch of injection is placed under 4 ℃ of conditions and is preserved, respectively at 0 month, March, June, JIUYUE, December sampling and measuring, the relatively variation of polyene phosphatidylcholine (PPC) content, major impurity lysophosphatide (LPC) content and pH value, wherein PPC content and LPC content are all 100% calculating by PPC labelled amount 46.5mg/mL.
Claims (10)
1. a Polyene Phosphatidylcholine injection liquid, it comprises polyene phosphatidylcholine, solubilizing agent, antiseptic and stabilizing agent, wherein said solubilizing agent is selected from deoxycholic acid, sodium deoxycholate, dehydrocholic acid, sodium dehydrocholate, cholic acid or sodium cholate, and wherein said stabilizing agent is selected from aminoacid or its sodium salt or Tris.
2. the Polyene Phosphatidylcholine injection liquid of claim 1, it comprises following component and content: polyene phosphatidylcholine 220-275 part, solubilizing agent 120-200 part, antiseptic 30-60 part, stabilizing agent 1-40 part, wherein content is weight portion.
3. the Polyene Phosphatidylcholine injection liquid of claim 2, it comprises following component and content: polyene phosphatidylcholine 220-250 part, solubilizing agent 125-175 part, antiseptic 40-50 part, stabilizing agent 10-30 part, wherein content is weight portion.
4. the Polyene Phosphatidylcholine injection liquid of claim 3, it comprises following component and content: polyene phosphatidylcholine 230-245 part, solubilizing agent 140-160 part, antiseptic 45-50 part, stabilizing agent 15-25 part, wherein content is weight portion.
5. the Polyene Phosphatidylcholine injection liquid of claim 4, it comprises following component and content: 232.5 parts of polyene phosphatidylcholine, solubilizing agent 140-160 part, antiseptic 45-50 part, stabilizing agent 15-25 part, wherein content is weight portion.
6. the Polyene Phosphatidylcholine injection liquid of any one in claim 1-5, it also comprises following component and content: sodium chloride 6-25 part, riboflavin or riboflavin sodium phosphate 0.1-2 part, sodium hydroxide 11-30 part, wherein content is weight portion, and wherein riboflavin phosphate sodium content is in riboflavin.
7. the Polyene Phosphatidylcholine injection liquid of any one in claim 1-6, wherein said solubilizing agent is selected from deoxycholic acid or sodium deoxycholate, and wherein said stabilizing agent is selected from gal4 amino acid or Tris, and wherein said antiseptic is selected from benzyl alcohol.
8. the Polyene Phosphatidylcholine injection liquid of claim 7, wherein said solubilizing agent is deoxycholic acid.
9. the Polyene Phosphatidylcholine injection liquid of claim 7, wherein said gal4 amino acid is selected from glycine or arginine or their mixture.
10. a method of preparing the Polyene Phosphatidylcholine injection liquid of any one in claim 1-9, it comprises the following steps:
(1) under nitrogen protection, in the water for injection of 60%～95% amount of preparation, add each component, stir, if desired suitably heating;
(2) to the activated carbon adsorption 15～30min that adds 0.01%～1% in step (1) solution, carry out afterwards decarbonisation, wherein active carbon content is weight portion;
(3) if necessary, with sodium hydroxide solution or dilute hydrochloric acid solution, regulate pH to 7.5～9.5;
(4) add water to amount of preparation;
(5) filter, in nitrogen, cover lower embedding, sterilizing, inspection is qualified, obtains.
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