CN102357094A - Pharmaceutical composition containing eighteen amino acids - Google Patents

Pharmaceutical composition containing eighteen amino acids Download PDF

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Publication number
CN102357094A
CN102357094A CN2011102379150A CN201110237915A CN102357094A CN 102357094 A CN102357094 A CN 102357094A CN 2011102379150 A CN2011102379150 A CN 2011102379150A CN 201110237915 A CN201110237915 A CN 201110237915A CN 102357094 A CN102357094 A CN 102357094A
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preparation
amount
value
amino acids
amino acid
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CN2011102379150A
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邓志明
邓志清
邓志平
徐广鑫
秦怀国
杨威
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FUJIAN TIANQUAN PHARMACEUTICAL Co Ltd
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FUJIAN TIANQUAN PHARMACEUTICAL Co Ltd
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Abstract

The invention relates to a pharmaceutical composition containing eighteen amino acids. A preparation method of the pharmaceutical composition containing eighteen amino acids comprises the following steps of feeding nitrogen gas having purity of 99.9% into a concentrating tank, pouring 750000ml of injection water into the concentrating tank, simultaneously, adding a prescription amount of sorbitol into the concentrating tank, stirring for 5 minutes until the sorbitol is dissolved fully and is mixed well, adding seventeen monomer amino acids into the mixed solution obtained by the previous step, stirring for 10 minutes until the seventeen monomer amino acids are dissolved fully, adding active carbon of which an addition amount is 0.05% of a final preparation amount into the mixture obtained by the previous step, stirring for 20 minutes, carrying out backflow for 15 minutes, cooling the concentrated solution obtained by the previous step, carrying out decarburization by a titanium bar filter until the concentrated solution is clear, filtering the clarified concentrated solution by the titanium bar filter, feeding the filtrate into a dilution tank, adding an appropriate amount of water into the dilution tank, adding NaHSO3 of which an addition amount is 0.05% of a preparation amount into the dilution tank, cooling, adding a prescription amount of tryptophan into the dilution tank, supplying injection water until the mixed solution in the dilution tank has a final prescription volume, stirring for 10 minutes, adjusting a pH value of the mixed solution in the dilution tank to a pH value of 3.8 to 4.3 by sodium hydroxide or hydrochloric acid, carrying out sampling, detecting total amino nigrogen content, tryptophan content and a pH value of the mixed solution, and adjusting the total amino nigrogen content, the tryptophan content and the pH value of the mixed solution so that the total amino nigrogen content, the tryptophan content and the pH value are in internal control ranges. The pharmaceutical composition containing eighteen amino acids overcomes the defect that adverse reactions can be produced in preparation adopting the prior art.

Description

18 seed amino acid pharmaceutical compositions
Technical field
The present invention relates to 18 seed amino acid pharmaceutical compositions and preparation method thereof.
Background technology
The pharmaceutical composition that contains 18 seed amino acids is to add the formulated sterile water solution of adjuvant by 18 seed amino acids, clinically is used for non-enteral nutrition agent.
Because it is aminoacid is very unstable in solution, very easily oxidized and produce the harmful material of a series of complicacies.From the sixties in 20th century Amino Acid Compound Injection put into production use, for guaranteeing the stability of product, must add sulphite compounds, like sodium sulfite, sodium pyrosulfite etc. with unique antioxidant properties.Because people did not understand the harm of this type material to human body at that time, thereby manufacturing enterprise is for guaranteeing the stability of product, and without stint adds in a large number usually.
At present, the most of Amino Acid Compound Injection of China manufacturer all adopts sulphite as antioxidant.Be prone to oxidized aminoacid such as L-tryptophan etc. owing to contain in the product, so antioxidant is playing a part key aspect its quality assurance.
Up to the present, in the quality standard of the many kinds of Amino Acid Compound Injection class medicine of national Bureau of Drugs Supervision approved list marketing, to the consumption of sulphite high reach 100mg/L, low is 30mg/L. and all unmatchful sulphite assay.Why the drug quality national standard does not do stricter control to the content of sulphite; Basic reason is the superior oxidation resistance that this material can not be substituted; Under present technical conditions, also can't produce the Amino Acid Compound Injection that does not contain sulphite.
Yet from the eighties in 20th century, along with the development of clinical pharmacy, pharmacology and medical science, people begin to recognize the toxic and side effects of sulfites material, are after having carried out comparatively deep research aspect the safety of sulphite.Simultaneously, the pharmaceutical control and administration of western developed country also steps up to collect the report of relevant clinical adverse when week.Modal clinically relevant side reaction is that sulphite is irritated, and symptom is a bronchospasm, stridulates dyspnea, pernicious laryngeal edema, hypotension, shock even death.
Research to the aspects such as pharmacology, molecular biology, toxicology and drug interaction of sulfites has also confirmed reality and the potential danger of sulfites as the infusion products antioxidant.
Sulfites has special drug interaction in Amino Acid Compound Injection.The Amino Acid Compound Injection that contains sulphite can cause the degraded of some vitamin, and the speed of degraded has substantial connection with the concentration of sulphite.As in the Amino Acid Compound Injection that contains the 500mg/L sodium sulfite, adding thiamine, room temperature storage is after 24 hours, almost all degradeds, and VB1 and folic acid are to understand obvious degradation after 24 hours in the vein total nutrient admixture of 100mg/L at sulfite concentration.When sulphite exists; The content of tryptophan approximately is reduced to 75% of normal value; People especially suspect the toxic action of 6 kinds of converted products of tryptophan to the human liver; Because test find to accept to contain the hepatocyte tissue of rat of the Amino Acid Compound Injection injection of sulphite variation has taken place, all fatty infiltrations of its liver enzyme, bilirubin and portal vein all have and increase.
The decline that the observed common indication of ability is blood plasma mesobilirubin and amino transaminase on human body.The influence of sulphite to multiple living matter also found in research.The irreversible reaction of the cystine linkage in sulphite and DNA (DNA), adenylic acid, vitaminK-3, uracil, cytosine and the protein possibly be the reason of sulphite side reaction, and the cross-linking reaction of chromosome and sulfinate also possibly be the major reason of its side reaction in addition.
To the mid-80, sulfites is familiar with the toxic and side effects of human body more fully.For this reason, it is limited one after another in medicine and Application in Food in countries in the world.Though various countries' pharmacopeia is variant to the type and the consumption of additives in the injection,, think that the consumption of additives is few more good more from security consideration.Permission daily intaking amount (ADI) like sulphite in foods is restricted to about 0.7mgSO2/kg body weight in western countries, and the people who is equivalent to 70 kg body weight takes in 80 milligrams of sodium sulfitees.
The national drug standards WS1-of State Food and Drug Administration (X-014)-2001Z-2002 contains 30 milligrams to being defined as in per 1000 milliliters of products of Amino Acid Compound Injection (18AA-II) Central Asia sulphates content, and international standard is also basic identical.Although standard Central Asia sulphates content is lower than the permission daily intaking amount, its toxic and side effects is eliminated fully, and therefore the preparation that does not contain sulphite of the thorough elimination of development sulphite toxic and side effects is very necessary.
Therefore explore and produce the Amino Acid Compound Injection that does not contain the sulfites antioxidant, be worth research.
Summary of the invention
In order to overcome the untoward reaction of the 18 seed amino acid pharmaceutical compositions that prepare in the prior art, the present invention provides a kind of 18 seed amino acid pharmaceutical compositions and preparation method thereof.
These article are compound preparation, and by 18 seed amino acids and the formulated sterile water solution of sorbitol, its component is that every 1000ml contains:
Figure BSA00000558910700041
These article 18 seed amino acid pharmaceutical compositions, its process for preparation is:
1, preparation:
In dense preparing tank, feed purity and be 99.9% nitrogen, and inject 750,000 ml waters for injection, add simultaneously recipe quantity sorbitol, stirred 5 minutes; To dissolving mixing fully; Add 17 kinds of single amino acid then, the EDTA-2NA that adds 0.005g again stirred 10 minutes, to dissolving fully.The active carbon that adds final amount of preparation 0.05% again; Stir 20min, backflow 15min (with producing the bacterial endotoxin that should detect concentrated wiring liquid the first time of a collection of supplementary material, answers<0.5EU/ml; As against regulation; Should increase the input amount of active carbon, restir refluxes up to specification until the endotoxin of concentrated wiring liquid), concentrated wiring liquid is cooled to about 45 ℃; Take off charcoal to clarification through titanium rod filter, concentrated wiring liquid is filtered to dilute preparing tank (dilute preparing tank should feed nitrogen in advance) through the titanium rod, add, add the NaHSO3 of amount of preparation 0.05% into proper amount of water for injection.Fluid temperature is reduced to about 45 ℃, add the tryptophan (1h receives before the preparation, with the dissolving earlier of a small amount of water for injection) of recipe quantity, the final volume of water to amount of preparation is penetrated in after-teeming.Stir 10min, regulate pH value to 3.8-4.3 with sodium hydroxide or hydrochloric acid, sampling detects total amino nitrogen, tryptophane and liquid PH value, is adjusted in content and the pH value internal control scope again.PH value 6.2~6.4; Amino nitrogen 0.538~0.541; Tryptophan 95.0~105.0%.Backflow 20min, fill after 1 μ m, 0.45 μ m, 0.2 μ m and 0.05 μ m folder filter filter.(annotating: join in the process rare, require fluid temperature is controlled at about 45 ℃).
2, fill, roll lid
The preceding medicinal liquid of fill is back to visible foreign matters and meets the transfusion requirement.Installed clean N 2 filter balls, opened N2 (in the pouring process towards nitrogen), mixed up loading amount to 250-255ml, inspection glass bottle, wash the cleanliness factor of film, plug up to specification after; Formal fill covers and washs film, beyond the Great Wall plug; Roll tight aluminium lid, bring up to vehicle of sterilization, by predetermined operation.
3, sterilization, lamp inspection
Produce legacy supreme time in the cleaning sterilization cabinet, the vehicle of sterilization that the medicinal liquid of waiting to sterilize is housed advanced in the cabinet from the Qianmen,, carry out moist heat sterilization.Sterilizing parameter: 110 ℃, 30min, 0.05Mpa.Sterilization method: 110 ℃ of intensification 10-20min-constant temperature, 30min (spray) 15min-60min that lowers the temperature, treat that in-cabinet temperature reduces to below 40 ℃, when interior chamber pressure is zero, pulls out vehicle of sterilization from the back door and further reduce to room temperature.Hang up the Status Flag board, carry out lamp inspection, what lamp inspection was qualified send packing by conveyer belt, and lamp inspection is underproof to be included into, and " defective work storehouse " is pending.
4, packing
The packing of every batch of product is assigned " batch packaging directive is single " by workshop and can be packed.Counting accurate (packing specification: 30 bottles/case) during packing.Print lot number by packaging directive, decals, vanning, input product description, joint sealing packing behind the quality certification.It is to be tested to be transferred to the warehouse for finished product Holding Area same day.Handle warehouse-in after the assay was approved.
The specific embodiment:
These article are compound preparation, and by 18 seed amino acids and the formulated sterile water solution of sorbitol, its component is that every 1000ml contains:
Figure BSA00000558910700051
Figure BSA00000558910700061
These article 18 seed amino acid pharmaceutical compositions, its process for preparation is:
1, preparation:
In dense preparing tank, feed purity and be 99.9% nitrogen, and inject 750,000 ml waters for injection, add simultaneously recipe quantity sorbitol, stirred 5 minutes; To dissolving mixing fully; Add 17 kinds of single amino acid then, the EDTA-2NA that adds 0.005g again stirred 10 minutes, to dissolving fully.The active carbon that adds final amount of preparation 0.05% again; Stir 20min, backflow 15min (with producing the bacterial endotoxin that should detect concentrated wiring liquid the first time of a collection of supplementary material, answers<0.5EU/ml; As against regulation; Should increase the input amount of active carbon, restir refluxes up to specification until the endotoxin of concentrated wiring liquid), concentrated wiring liquid is cooled to about 45 ℃; Take off charcoal to clarification through titanium rod filter, concentrated wiring liquid is filtered to dilute preparing tank (dilute preparing tank should feed nitrogen in advance) through the titanium rod, add, add the NaHSO3 of amount of preparation 0.05% into proper amount of water for injection.Fluid temperature is reduced to about 45 ℃, add the tryptophan (1h receives before the preparation, with the dissolving earlier of a small amount of water for injection) of recipe quantity, the final volume of water to amount of preparation is penetrated in after-teeming.Stir 10min, regulate pH value to 3.8-4.3 with sodium hydroxide or hydrochloric acid, sampling detects total amino nitrogen, tryptophane and liquid PH value, is adjusted in content and the pH value internal control scope again.PH value 6.2~6.4; Amino nitrogen 0.538~0.541; Tryptophan 95.0~105.0%.Backflow 20min, fill after 1 μ m, 0.45 μ m, 0.2 μ m and 0.05 μ m folder filter filter.(annotating: join in the process rare, require fluid temperature is controlled at about 45 ℃)
2, fill, roll lid
The preceding medicinal liquid of fill is back to visible foreign matters and meets the transfusion requirement.Installed clean N 2 filter balls, opened N2 (in the pouring process towards nitrogen), mixed up loading amount to 250-255ml, inspection glass bottle, wash the cleanliness factor of film, plug up to specification after; Formal fill covers and washs film, beyond the Great Wall plug; Roll tight aluminium lid, bring up to vehicle of sterilization, by predetermined operation.
3, sterilization, lamp inspection
Produce legacy supreme time in the cleaning sterilization cabinet, the vehicle of sterilization that the medicinal liquid of waiting to sterilize is housed advanced in the cabinet from the Qianmen,, carry out moist heat sterilization.Sterilizing parameter: 110 ℃, 30min, 0.05Mpa.Sterilization method: 110 ℃ of intensification 10-20min-constant temperature, 30min (spray) 15min-60min that lowers the temperature, treat that in-cabinet temperature reduces to below 40 ℃, when interior chamber pressure is zero, pulls out vehicle of sterilization from the back door and further reduce to room temperature.Hang up the Status Flag board, carry out lamp inspection, what lamp inspection was qualified send packing by conveyer belt, and lamp inspection is underproof to be included into, and " defective work storehouse " is pending.
4, packing
The packing of every batch of product is assigned " batch packaging directive is single " by workshop and can be packed.Counting accurate (packing specification: 30 bottles/case) during packing.Print lot number by packaging directive, decals, vanning, input product description, joint sealing packing behind the quality certification.It is to be tested to be transferred to the warehouse for finished product Holding Area same day.Handle warehouse-in after the assay was approved.
Above-described embodiment, the present invention specific embodiment a kind of more preferably just, common variation that those skilled in the art carries out in technical scheme scope of the present invention and replacement all should be included in protection scope of the present invention.

Claims (4)

1.18 the seed amino acid pharmaceutical composition is characterized in that: the active ingredient by following parts by weight is processed:
Its component is that every 1000ml contains:
Figure FSA00000558910600011
2. prepare the described 18 seed amino acid pharmaceutical compositions of claim 1, it is characterized in that: its process for preparation is:
In dense preparing tank, feed purity and be 99.9% nitrogen, and inject 750,000 ml waters for injection, add simultaneously recipe quantity sorbitol, stirred 5 minutes; To dissolving mixing fully, add 17 kinds of single amino acid then, the EDTA-2NA that adds 0.005g again stirred 10 minutes; To dissolving fully, add the active carbon of final amount of preparation 0.05% again, stir 20min; Backflow 15min lowers the temperature concentrated wiring liquid; Take off charcoal to clarification through titanium rod filter, concentrated wiring liquid is filtered to dilute preparing tank through the titanium rod, add into proper amount of water for injection; The NaHSO3 that adds amount of preparation 0.05% with the medicinal liquid cooling, adds the tryptophan of recipe quantity; The final volume of water to amount of preparation is penetrated in after-teeming, stirs 10min, regulates pH value to 3.8-4.3 with sodium hydroxide or hydrochloric acid; Sampling detects total amino nitrogen, tryptophane and liquid PH value, is adjusted in content and the pH value internal control scope again.
3. prepare the described 18 seed amino acid pharmaceutical compositions of claim 2, it is characterized in that: its process for preparation herb liquid temperature is controlled at 42 ℃~47 ℃.
4. according to claim 1 and 2 described 18 seed amino acid pharmaceutical compositions, it is characterized in that: add EDTA-2NA in its process for preparation herb liquid.
CN2011102379150A 2011-08-19 2011-08-19 Pharmaceutical composition containing eighteen amino acids Pending CN102357094A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113748115A (en) * 2019-03-04 2021-12-03 Tae生命科学有限责任公司 Boronated amino acid compositions for boron neutron capture therapy and methods thereof
CN115770217A (en) * 2022-12-29 2023-03-10 武汉久安药物研究院有限公司 Preparation method of antioxidant-free compound amino acid injection 18AA

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1615906A (en) * 2004-09-27 2005-05-18 俞锋 18 compound amino acid injection and its preparing method

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1615906A (en) * 2004-09-27 2005-05-18 俞锋 18 compound amino acid injection and its preparing method

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113748115A (en) * 2019-03-04 2021-12-03 Tae生命科学有限责任公司 Boronated amino acid compositions for boron neutron capture therapy and methods thereof
CN113748115B (en) * 2019-03-04 2024-02-23 Tae生命科学有限责任公司 Boronated amino acid compositions and methods for boron neutron capture therapy
CN115770217A (en) * 2022-12-29 2023-03-10 武汉久安药物研究院有限公司 Preparation method of antioxidant-free compound amino acid injection 18AA

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