CN109381460A - A kind of pharmaceutical composition and preparation method thereof containing 18 kinds of amino acid - Google Patents
A kind of pharmaceutical composition and preparation method thereof containing 18 kinds of amino acid Download PDFInfo
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- CN109381460A CN109381460A CN201710677077.6A CN201710677077A CN109381460A CN 109381460 A CN109381460 A CN 109381460A CN 201710677077 A CN201710677077 A CN 201710677077A CN 109381460 A CN109381460 A CN 109381460A
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Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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Abstract
The invention discloses a kind of pharmaceutical compositions and preparation method thereof containing 18 kinds of amino acid.The present invention provides a kind of pharmaceutical compositions containing 18 kinds of amino acid, and it includes tyrosine, leucine, isoleucine, phenylalanine, aspartic acid, valine, threonine, proline, methionine, glutamic acid, Lysine Acetate, arginine, alanine, glycine, histidine, serine, tryptophan, cysteine, pH adjusting agent and water.The pharmaceutical composition can be free of sulfites, therefore can thoroughly eliminate sulfites to the security risk of human body, keep clinical use safer；The validity period of the composition is longer.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of pharmaceutical composition and its preparation side containing 18 kinds of amino acid
Method.
Background technique
Amino Acid Compound Injection (18AA-IX) is to add sterile water solution made of auxiliaries as 18 kinds of amino acid, is faced
There is Hypoproteinemia, low nutrition state and amino acid supplementation perioperatively for acute and chronic potential renal insufficiency patient in bed.
State Food and Drug Administration standard WS1-XG-022-2011-2012 Amino Acid Compound Injection (18AA-
IX it) provides, 0.50g containing sodium hydrogensulfite in every liter of (18AA-IX) injection.
The moriamin-s (19AA) that No. NDA of U.S. FDA approval is 19018, trade name TrophAmine
Every 100 milliliters are designated in the specification (label) that on March 24th, 2004 newly modifies is less than 0.050g. containing sodium pyrosulfite
The moriamin-s (15AA) that No. NDA of U.S. FDA approval is 18676, trade name HepatAmine,
Every 100 milliliters, which are designated, in the specification (label) of modification in its on April 29th, 2004 is less than 0.10g. containing sodium hydrogensulfite
Since the partial amino-acid of amino acid solution easily aoxidizes, so all being needed in the preparation of Amino Acid Compound Injection
Antioxidant is added, it may be said that antioxidant is to prepare one of key component of such preparation
The antioxidant that tradition uses is sulphite substance；It is after the eighties research shows that sulfites in human body
With biggish side effect, degradation such as to thiamines, VB1, folic acid, tryptophan, to the irreversible reaction of DNA and nucleotide, because
This countries in the world limits its application in drug and food one after another.
Amino Acid Compound Injection is clinically widely used, and be clinically also reported out more adverse reaction, allergy
Reaction is exactly more typical serious adverse reaction relevant to sulfites, and clinical symptoms are bronchial spasm, asthma, breathing
Difficulty, nausea, laryngeal edema, low blood pressure, shock, in addition it is dead.
Micro sulphite can extend the prothrombin activating time, hinder the molten fine protein active of urokinase, and some patientss are several
Allergic reaction can occur in minute, especially influence liver function, cause transaminase raising or even necrosis of liver cells.Research is also sent out
Existing sulphite has an impact to a variety of living matters, such as with DNA (DNA), adenine flavin nucleotide, vitamin
Irreversible reaction occurs for the disulfide bond in K3, uracil, cytimidine and protein, this may be sulphite side reaction hair
Raw reason.
FDA understands added antioxygen on terrestrial reference early in the producer of formal demand pharmaceutical production in 1985 on medicine label
Agent content and its clinical side effects, to serve as warning.In addition, general headquarters are located at the public industry scientific center in the U.S. in Washington
(CSP) it proposes limitation sulphite dosage, and marks its content in drug in the description.
1988, respective specified was also made by Pharmaceutical Industries Association, country, France, it is desirable that sulfurous is put on medicine packing box
The warning statement of hydrochlorate.Careful attitude is increasingly held in clinical use to drug containing sulphite by western countries.
2015, national adverse reaction monitoring center in Amino Acid Compound Injection (18AA) specification Revision Suggestion,
Explicitly pointing out should describe in specification [adverse reaction] item: " allergic reaction: due to containing antioxidant sodium pyrosulfite or Asia
Sodium bisulfate, it is thus possible to allergic reaction (especially asthma patient) can be induced, show as fash, itch etc., serious person can occur
Anaphylactic shock, as occurred to be discontinued immediately ".In addition, this product antioxidant concentration should be indicated in specification corresponding contents.
No. 144 files in 2016 of CFDA are " about revision Amino Acid Compound Injection (18AA) and similar preparation explanation
The bulletin of book " in also proposed the requirement.
Up to the present, it does not retrieve and is related to the Chinese patent application of Amino Acid Compound Injection (18AA-IX).
Therefore the pharmaceutical composition for exploring 18 kinds of amino acid of the production without sulfites is worth research.
Summary of the invention
The technical problem to be solved by the present invention is to the pharmaceutical compositions of existing 18 kinds of amino acid to contain antioxidant,
The defects of to cause various adverse reactions, so, the present invention provides a kind of pharmaceutical composition containing 18 kinds of amino acid and its
Preparation method, the pharmaceutical composition can be free of sulfites antioxidant, therefore can thoroughly eliminate sulfites to human body
Security risk, keep clinical use safer, meanwhile, validity period is longer.
The present invention provides a kind of pharmaceutical compositions containing 18 kinds of amino acid, and it includes tyrosine, leucine, different bright ammonia
Acid, phenylalanine, aspartic acid, valine, threonine, proline, methionine, glutamic acid, Lysine Acetate, arginine,
Alanine, glycine, histidine, serine, tryptophan, cysteine, pH adjusting agent and water；
The tyrosine with the mass volume ratio of the, water is 0.475~0.525g/L；
The leucine with the mass volume ratio of the, water is 9.200~10.800g/L；
The isoleucine with the mass volume ratio of the, water is 6.900~8.100g/L；
The phenylalanine with the mass volume ratio of the, water is 4.750~5.250g/L；
The aspartic acid with the mass volume ratio of the, water is 0.230~0.270g/L；
The valine with the mass volume ratio of the, water is 6.900~8.100g/L；
The threonine with the mass volume ratio of the, water is 2.300~2.700g/L；
The proline with the mass volume ratio of the, water is 1.840~2.160g/L；
The methionine with the mass volume ratio of the, water is 4.600~5.400g/L；
The glutamic acid with the mass volume ratio of the, water is 0.230~0.270g/L；
The Lysine Acetate with the mass volume ratio of the, water is 6.440~7.560g/L；
The arginine with the mass volume ratio of the, water is 2.760~3.240g/L；
The alanine with the mass volume ratio of the, water is 2.760~3.240g/L；
The glycine with the mass volume ratio of the, water is 1.380~1.620g/L；
The histidine with the mass volume ratio of the, water is 2.300~2.700g/L；
The serine with the mass volume ratio of the, water is 0.920~1.080g/L；
The tryptophan with the mass volume ratio of the, water is 2.300~2.700g/L；
The cysteine with the mass volume ratio of the, water is 0.230~0.270g/L；
The content of dissolved oxygen is in 1.5mg/L or less in the pharmaceutical composition；The pH value of the pharmaceutical composition is
5.5~6.5 (such as 6.0).
The tyrosine with the mass volume ratio of the, water can be 0.50g/L.
The leucine with the mass volume ratio of the, water can be 10.00g/L.
The isoleucine with the mass volume ratio of the, water can be 7.50g/L.
The phenylalanine with the mass volume ratio of the, water can be 5.00g/L.
The aspartic acid with the mass volume ratio of the, water can be 0.25g/L.
The valine with the mass volume ratio of the, water can be 7.50g/L.
The threonine with the mass volume ratio of the, water can be 2.50g/L.
The proline with the mass volume ratio of the, water can be 2.0g/L.
The methionine with the mass volume ratio of the, water can be 5.0g/L.
The glutamic acid with the mass volume ratio of the, water can be 0.25g/L.
The Lysine Acetate with the mass volume ratio of the, water can be 7.00g/L.
The arginine with the mass volume ratio of the, water can be 3.00g/L.
The alanine with the mass volume ratio of the, water can be 3.00g/L.
The glycine with the mass volume ratio of the, water can be 1.50g/L.
The histidine with the mass volume ratio of the, water can be 2.50g/L.
The serine with the mass volume ratio of the, water can be 1.00g/L.
The tryptophan with the mass volume ratio of the, water can be 2.50g/L.
The cysteine with the mass volume ratio of the, water can be 0.25g/L.
The pH adjusting agent is used to adjust the pH value of the pharmaceutical composition, can be the pH value of this field routine
One of regulator, such as aqueous solution of citric acid, aqueous acetic acid, sodium citrate aqueous solution and sodium acetate aqueous solution or two
Kind.The concentration of the aqueous solution of citric acid can be 0.1mol/L.The concentration of the aqueous acetic acid can be 0.1mol/L.Institute
The concentration for the sodium citrate aqueous solution stated can be 0.1mol/L.The concentration of the sodium acetate aqueous solution can be 0.1mol/L.
The raw material of the pharmaceutical composition is not limited to Lysine Acetate by the Lysine Acetate, can also be it
Equivalent, such as acetic acid and lysine, in another example other suitable acid (in conjunction with above-mentioned pH adjusting agent) and lysine.Other
Amino acid is herewith.
Existence form of the Lysine Acetate in the pharmaceutical composition can be lysine.Other amino acid are same
This.
The water can be the water of this field routine, such as water for injection.The water for injection can be conventional for this field
Water for injection, such as water for injection as defined in " Chinese Pharmacopoeia version in 2015 " (purified water through distill resulting water).
The pharmaceutical composition can also contain antioxidant.The antioxidant can be the antioxidant of this field routine, example
Such as sodium hydrogensulfite and/or sodium pyrosulfite.
The pharmaceutical composition, which can be free of, antioxidant.The antioxidant can be the antioxidant of this field routine, example
Such as sodium hydrogensulfite and/or sodium pyrosulfite.
The pharmaceutical composition can also contain metal ion chelation agent.The metal ion chelation agent can be this field
(trace metal ion in its energy complex solution, is reduced because of metal ion catalysis amino acid oxygen conventional metal ion chelation agent
Change the generation of degradation reaction), such as natrium adetate.
The pharmaceutical composition, which can be free of, metal ion chelation agent.The metal ion chelation agent can be this field
(trace metal ion in its energy complex solution, is reduced because of metal ion catalysis amino acid oxygen conventional metal ion chelation agent
Change the generation of degradation reaction), such as natrium adetate.
The pharmaceutical composition can be by the tyrosine, the leucine, the isoleucine, the benzene
Alanine, the aspartic acid, the valine, the threonine, the proline, the methionine,
The glutamic acid, the Lysine Acetate, the arginine, the alanine, the glycine, the group
Propylhomoserin, the serine, the tryptophan, the cysteine, the pH adjusting agent and the water group
At.
In the pharmaceutical composition content of dissolved oxygen can also 1.3mg/L or less, 1.2mg/L or less, 1.1mg/L with
Under, 1.0mg/L or less, 0.8mg/L or less or 0.5mg/L or less.
The form of the pharmaceutical composition can be uniform solution, such as injection.The injection can be big infusion.
The pharmaceutical composition can be used for acute and chronic potential renal insufficiency patient and Hypoproteinemia, low nutrition state occurs
Or amino acid supplementation perioperatively.
The pharmaceutical composition can be made according to following preparation methods.
The pharmaceutical composition can be stored according to following storage methods.Realize that the mode of the storage can are as follows: will
The pharmaceutical composition is filling, tamponade, rolls lid, sterilizing, lamp inspection to get.The tamponade can be vacuum nitrogen filling tamponade.Institute
The sterilizing stated can for 121 DEG C moist heat sterilization 8 minutes.
The present invention also provides a kind of preparation methods of above-mentioned pharmaceutical composition containing 18 kinds of amino acid comprising following
Step:
In a nitrogen atmosphere, each component is mixed, obtains the pharmaceutical composition containing 18 kinds of amino acid；
Above-mentioned mixing is under dissolved oxygen content monitoring, when the dissolved oxygen content of the composition in discovery mixed process is big
In the pharmaceutical composition content of dissolved oxygen the upper limit (such as 1.5mg/L, 1.3mg/L, 1.2mg/L, 1.1mg/L,
1.0mg/L, 0.8mg/L or 0.5mg/L) when, then it carries out nitrogen displacement and (vacuumizes < refer to and pump portion gas, extract journey
Degree can be played by ear by those skilled in the art >, inflated with nitrogen；The time that the nitrogen displacement carries out can be by art technology
Personnel play by ear, can be when finding that dissolved oxygen content is greater than the upper limit of the content of dissolved oxygen in the pharmaceutical composition
It carves and carries out, can also be carried out finally；The number of the nitrogen displacement can be played by ear by those skilled in the art, so that institute
For composition in dissolved oxygen content be less than or equal to the pharmaceutical composition in dissolved oxygen content the upper limit < for example
1.5mg/L, 1.3mg/L, 1.2mg/L, 1.1mg/L, 1.0mg/L, 0.8mg/L or 0.5mg/L >).
In above-mentioned preparation method, the water can first pass through deoxygenation processing.The deoxygenation processing can be this field
Film process is filtered in conventional deoxygenation processing, such as deoxygenation.By in deoxygenation treated the water, dissolved oxygen content can be
0.000072mg/L。
In above-mentioned preparation method, the mixing can be the mixing of this field routine, example mixed process as mentioned
Using activated carbon adsorption (and active carbon removing) and/or refined filtration step.
Step included by above-mentioned preparation method can are as follows:
(1) in a nitrogen atmosphere, by water described in part and, the tyrosine, the leucine, described different bright
Propylhomoserin, the valine, the aspartic acid, the phenylalanine and the methionine mixing, obtain medical fluid
1；
(2) in a nitrogen atmosphere, by the medical fluid 1 and the threonine, the proline, the paddy ammonia
Sour, described Lysine Acetate, the arginine, the alanine, the glycine, the histidine and the institute
The serine mixing stated, obtains medical fluid 2；
(3) in a nitrogen atmosphere, the medical fluid 2 is mixed with active carbon, then removes active carbon, obtain medical fluid 3；
(4) in a nitrogen atmosphere, the medical fluid 3 is mixed with the tryptophan, obtains medical fluid 4；
(5) in a nitrogen atmosphere, after the medical fluid 4 being mixed with the cysteine, the pH value tune is added
Agent is saved, pH value 5.5~6.5 is made, the remaining water is then added, obtains medical fluid 5；
(6) in a nitrogen atmosphere, the medical fluid 5 is subjected to refined filtration, obtains the pharmaceutical composition containing 18 kinds of amino acid i.e.
It can；
Above-mentioned step (one or more of steps 1 and 2 as escribed above, 3,4,5 and 6, in another example all steps, also
Such as only step 6, then for example, at least step 6) is under dissolved oxygen content monitoring, when the composition (example of discovery institute's monitoring step
Such as above-mentioned one or more of medical fluid 1,2,3,4 and 5) in dissolved oxygen content be greater than in the pharmaceutical composition and dissolve
The upper limit (such as 1.5mg/L, 1.3mg/L, 1.2mg/L, 1.1mg/L, 1.0mg/L, 0.8mg/L or 0.5mg/ of the content of oxygen
When L), then carries out nitrogen displacement and (vacuumize < refer to and pump portion gas, extraction degree can regard feelings by those skilled in the art
Depending on shape >, inflated with nitrogen；The time that the nitrogen displacement carries out can be played by ear by those skilled in the art, can found
Dissolved oxygen content carries out at once when being greater than the upper limit of the content of dissolved oxygen in the pharmaceutical composition, can also carry out finally；
The number of the nitrogen displacement can be played by ear by those skilled in the art, so that the dissolved oxygen in targeted composition
Content is less than or equal to the upper limit < such as 1.5mg/L, 1.3mg/L, 1.2mg/ of the content of dissolved oxygen in the pharmaceutical composition
L, 1.1mg/L, 1.0mg/L, 0.8mg/L or 0.5mg/L >).
In above-mentioned each step, " in a nitrogen atmosphere " can be the nitrogen atmosphere of this field routine, such as
Under nitrogen stream protection." nitrogen atmosphere " can be realized by the method for this field routine, such as nitrogen displacement.
In above-mentioned each step, the result of " mixing " can be the mixing resultant of this field routine, such as dissolve
Form uniform solution or suspension.
In above-mentioned step (1), the amount of " part " in " water described in part " can be the amount of this field routine, such as
Be enough the amount of Dissolved Amino Acids, can by those skilled in the art regard concrete condition determine, such as full dose 70%.
In above-mentioned step (1), " water described in part " can be handled by the method for this field routine, such as: in nitrogen
Under gas atmosphere, by the water of heat preservation.The nitrogen atmosphere is same as above.The temperature of the heat preservation can be 70 DEG C~80 DEG C,
The time of the heat preservation can be 15min.
In above-mentioned step (1), the water can first pass through deoxygenation processing.The deoxygenation processing can be normal for this field
The deoxygenation of rule is handled, such as film process is filtered in deoxygenation.By in deoxygenation treated the water, dissolved oxygen content can be
0.000072mg/L。
In above-mentioned step (1), temperature when the described mixing can be the temperature of this field routine, such as 70 DEG C~80
℃。
In above-mentioned step (2), the medical fluid 1 can be the medical fluid 1 of this field ordinary temperature, such as be cooled to 40
~45 DEG C of medical fluid 1.
In above-mentioned step (2), temperature when the described mixing can be the temperature of this field routine, such as 40 DEG C~45
℃。
In above-mentioned step (3), the active carbon can be the active carbon of this field routine, such as " Chinese Pharmacopoeia
Version in 2015 " as defined in active carbon (injection).The mass volume ratio of the active carbon and the pharmaceutical composition can
For the mass volume ratio of this field routine, such as 0.5g/L.The active carbon can first be moistened with the water-wet when in use.
In above-mentioned step (3), what the time that the medical fluid 2 is mixed with the active carbon can be conventional for this field
Time, such as until adsorbing completely, in another example 15min.
In above-mentioned step (3), " removing " can be the removing mode of this field routine, such as be filtered to remove.
The filtering can be the filter type of this field routine, such as titanium core filter returns filter.The aperture of the titanium core filter
It can be the aperture of this field routine, such as 3 μm.The time for returning filter can be the time of this field routine, such as 30min.
In above-mentioned step (3), temperature when the described mixing can be the temperature of this field routine, such as 40 DEG C~45
℃。
In above-mentioned step (4), temperature when the described mixing can be the temperature of this field routine, such as 40 DEG C~45
℃。
In above-mentioned step (5), " the remaining water " refers to that " water " subtracts in step (1)
Water after " water described in part ", for example, full dose 30%.
In above-mentioned step (5), the water can first pass through deoxygenation processing.The deoxygenation processing can be normal for this field
The deoxygenation of rule is handled, such as film process is filtered in deoxygenation.By in deoxygenation treated the water, dissolved oxygen content can be
0.000072mg/L。
In above-mentioned step (5), temperature when the described mixing can be the temperature of this field routine, such as 40 DEG C~45
℃。
In above-mentioned step (6), the refined filtration can be the refined filtration of this field routine, such as use miillpore filter mistake
Filter.The aperture of the miillpore filter can be the aperture of this field routine, such as 0.45 μm and/or 0.22 μm.When described micro-
When the number of hole filter membrane is two, the aperture of the miillpore filter can be followed successively by 0.45 μm and 0.22 μm.
In above-mentioned step (6), temperature when the described mixing can be the temperature of this field routine, such as 40 DEG C~45
℃。
When above-mentioned dissolution Monitoring Oxygen Ventilation, as composition (1,2,3,4 and of medical fluid as escribed above for not finding institute's monitoring step
One or more of 5) dissolved oxygen content in be greater than the content of dissolved oxygen in the pharmaceutical composition the upper limit (such as
1.5mg/L, 1.3mg/L, 1.2mg/L, 1.1mg/L, 1.0mg/L, 0.8mg/L or 0.5mg/L) when, then it is set without nitrogen
It changes.
A kind of preparation method storing above-mentioned pharmaceutical composition in a reservoir comprising following step:
(1) according to the preparation method of the above-mentioned pharmaceutical composition containing 18 kinds of amino acid, the medicine containing 18 kinds of amino acid is made
Compositions；
(2) pharmaceutical composition containing 18 kinds of amino acid is stored according to following methods to get the pharmaceutical composition in container
Object.
In above-mentioned step (2), realize that the mode of the storage can are as follows: the pharmaceutical composition is filling, pressure
Plug, roll lid, sterilizing, lamp inspection to get.The tamponade can be vacuum nitrogen filling tamponade.The sterilizing damp and hot can go out for 121 DEG C
Bacterium 8 minutes.
A kind of storage method of above-mentioned pharmaceutical composition comprising following step: the pharmaceutical composition is stored
In a reservoir, in the container there are gas, the percent by volume of oxygen is below 1.5% in the gas.
The gas and the volume of a container than can be this field routine volume ratio (after i.e. routinely filling, in
The volume ratio retained in container), such as 0.06~0.20, in another example 0.08~0.12, also such as 0.10.
The volume of a container can be 100ml~500ml, and can be 200ml~250ml.
When the volume of a container is 100ml, the gas and the volume of a container ratio can for 0.06~
0.12。
When the volume of a container is 200ml~250ml, the gas can be with the volume of a container ratio
0.08~0.12.
When the volume of a container is 500ml, the gas and the volume of a container ratio can for 0.10~
0.20。
The percent by volume of oxygen can be 1.0% hereinafter, can also be below 0.5% in the gas.
The container can be infusion bottle.When the pharmaceutical composition is filled in the container, it can pass through following
Step: lid, sterilizing, lamp inspection are rolled in tamponade.The tamponade can be vacuum nitrogen filling tamponade.The sterilizing can be damp and hot for 121 DEG C
Sterilizing 8 minutes.
In addition to glycine, amino acid used in the present invention is L-configuration amino acid.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can any combination to get the present invention it is each preferably
Example.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is that: Amino Acid Compound Injection of the invention can be by molten in control injection
The content of headspace oxygen in oxygen and injection hold-up vessel is solved, and in the item without pyrosulfite or sulfites antioxidant
It under part, can be stabilized, and then thoroughly solve pyrosulfite or sulfites antioxidant to the danger of human body
Evil.Meanwhile preparation method is simple, and it is easy to operate, it is suitable for industrialized production.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
The selection of product specification.
In following embodiments and effect example, if not otherwise specified, the water for injection being related to is before use, by removing
Oxygen filters film process, and the dissolved oxygen content in water for injection is made to be reduced to 10ppm or less.The 10ppm refers to that dissolved oxygen contains
Amount is ten a ten thousandths (i.e. 0.000072mg/L) of the dissolved oxygen content during room temperature is lauched.The room temperature be lauched in dissolution
Oxygen content is generally 7.2mg/L.
The preparation of 1 Amino Acid Compound Injection 18AA of embodiment
Each component and dosage are as shown in the table in Amino Acid Compound Injection 18AA:
| Tyrosine | 0.50g | Glutamic acid | 0.25g |
| Leucine | 10.00g | Lysine Acetate | 7.00g |
| Isoleucine | 7.50g | Arginine | 3.00g |
| Phenylalanine | 5.00g | Alanine | 3.00g |
| Aspartic acid | 0.25g | Glycine | 1.50g |
| Valine | 7.50g | Histidine | 2.50g |
| Threonine | 2.50g | Serine | 1.00g |
| Proline | 2.00g | Tryptophan | 2.50g |
| Methionine | 5.00g | Cysteine | 0.25g |
| The acetum of 0.1mol/L | In right amount | Water for injection | In right amount |
Total amount is 1000ml.
Preparation method:
(1) each former, auxiliary material is weighed by prescription；
(2) water for injection for taking full dose 70% maintains water temperature at 70 DEG C, carries out nitrogen replacement operator 3 times to reaction kettle, protects
Temperature is passed through nitrogen.
(3) under nitrogen stream protection, monitor dissolved oxygen in 1.5mg/L hereinafter, be added the tyrosine of recipe quantity, leucine,
Isoleucine, valine, aspartic acid, phenylalanine and methionine.Stirring is extremely dissolved.
(4) under nitrogen stream protection, 40 DEG C are cooled to, threonine, proline, glutamic acid, the acetic acid that recipe quantity is added rely
Propylhomoserin, arginine, alanine, glycine, histidine and serine, stirring to dissolution.0.05% active carbon (w/v, with suitable is added
Measure water for injection wetting), 40 DEG C of absorption 15min.Solution returns filter 30min by titanium core filter (3 μm of aperture).
(5) under nitrogen stream protection, dissolved oxygen is monitored in 1.5mg/L hereinafter, the tryptophan of recipe quantity is added, dissolution is complete
Afterwards, it is added the cysteine of recipe quantity, after dissolution completely, the acetum of 0.1mol/L is added, make pH value 6.0, constant volume.
(6) under nitrogen stream protection, medical fluid is filtered by 0.45 μm, 0.22 μm of polyether sulfone micropore filter element, must be dissolved
Oxygen is in 1.5mg/L medical fluid below.
(7) under nitrogen stream protection, medical fluid is filling into 200ml infusion bottle, wherein volume of air is 20ml.It vacuumizes
Nitrogen charging tamponade, controls headspace oxygen 1.5% hereinafter, roll lid, in 121 DEG C moist heat sterilization 8 minutes, lamp inspection to get.
The preparation of 2 Amino Acid Compound Injection 18AA of embodiment
Each component and dosage are as shown in the table in Amino Acid Compound Injection 18AA:
| Tyrosine | 0.475g | Glutamic acid | 0.230g |
| Leucine | 9.200g | Lysine Acetate | 6.440g |
| Isoleucine | 6.900g | Arginine | 2.760g |
| Phenylalanine | 4.750g | Alanine | 2.760g |
| Aspartic acid | 0.230g | Glycine | 1.380g |
| Valine | 6.900g | Histidine | 2.300g |
| Threonine | 2.300g | Serine | 0.920g |
| Proline | 1.840g | Tryptophan | 2.300g |
| Methionine | 4.600g | Cysteine | 0.230g |
| The sodium acetate solution of 0.1mol/L | In right amount | Water for injection | In right amount |
Total amount is 1000ml.
Preparation method:
(1) each former, auxiliary material is weighed by prescription；
(2) water for injection for taking full dose 70% maintains water temperature at 80 DEG C, carries out nitrogen replacement operator 3 times to reaction kettle, protects
Temperature is passed through nitrogen.
(3) under nitrogen stream protection, monitor dissolved oxygen in 1.3mg/L hereinafter, be added the tyrosine of recipe quantity, leucine,
Isoleucine, valine, aspartic acid, phenylalanine and methionine.Stirring is extremely dissolved.
(4) under nitrogen stream protection, 45 DEG C are cooled to, threonine, proline, glutamic acid, the acetic acid that recipe quantity is added rely
Propylhomoserin, arginine, alanine, glycine, histidine and serine, stirring to dissolution.0.05% active carbon (w/v, with suitable is added
Measure water for injection wetting), 45 DEG C of absorption 15min.Solution returns filter 30min by titanium core filter (3 μm of aperture).
(5) under nitrogen stream protection, dissolved oxygen is monitored in 1.3mg/L hereinafter, the tryptophan of recipe quantity is added, dissolution is complete
Afterwards, it is added the cysteine of recipe quantity, after dissolution completely, the sodium acetate solution of 0.1mol/L is added, make pH value 6.5, constant volume.
(6) under nitrogen stream protection, medical fluid is filtered by 0.45 μm, 0.22 μm of polyether sulfone micropore filter element, must be dissolved
Oxygen is in 1.3mg/L medical fluid below.
(7) under nitrogen stream protection, medical fluid is filling into 100ml infusion bottle, wherein volume of air is 6ml.It vacuumizes
Nitrogen charging tamponade, controls headspace oxygen 1.5% hereinafter, roll lid, in 121 DEG C moist heat sterilization 8 minutes, lamp inspection to get.
The preparation of 3 Amino Acid Compound Injection 18AA of embodiment
Each component and dosage are as shown in the table in Amino Acid Compound Injection 18AA:
Total amount is 1000ml.
Preparation method:
(1) each former, auxiliary material is weighed by prescription；
(2) water for injection for taking full dose 70% maintains water temperature at 70 DEG C, carries out nitrogen replacement operator 3 times to reaction kettle, protects
Temperature is passed through nitrogen.
(3) under nitrogen stream protection, monitor dissolved oxygen in 0.5mg/L hereinafter, be added the tyrosine of recipe quantity, leucine,
Isoleucine, valine, aspartic acid, phenylalanine and methionine.Stirring is extremely dissolved.
(4) under nitrogen stream protection, 40 DEG C are cooled to, threonine, proline, glutamic acid, the acetic acid that recipe quantity is added rely
Propylhomoserin, arginine, alanine, glycine, histidine and serine, stirring to dissolution.0.05% active carbon (w/v, with suitable is added
Measure water for injection wetting), 40 DEG C of absorption 15min.Solution returns filter 30min by titanium core filter (3 μm of aperture).
(5) under nitrogen stream protection, dissolved oxygen is monitored in 0.5mg/L hereinafter, the tryptophan of recipe quantity is added, dissolution is complete
Afterwards, it is added the cysteine of recipe quantity, after dissolution completely, the citric acid soln of 0.1mol/L is added, make pH value 5.5, constant volume.
(6) under nitrogen stream protection, medical fluid is filtered by 0.45 μm, 0.22 μm of polyether sulfone micropore filter element, must be dissolved
Oxygen is in 0.5mg/L medical fluid below.
(7) under nitrogen stream protection, medical fluid is filling into 100ml infusion bottle, wherein volume of air is 12ml.It vacuumizes
Nitrogen charging tamponade, controls headspace oxygen 0.5% hereinafter, roll lid, in 121 DEG C moist heat sterilization 8 minutes, lamp inspection to get.
The preparation of 4 Amino Acid Compound Injection 18AA of embodiment
Each component and dosage are as shown in the table in Amino Acid Compound Injection 18AA:
| Tyrosine | 0.50g | Glutamic acid | 0.25g |
| Leucine | 10.00g | Lysine Acetate | 7.00g |
| Isoleucine | 7.50g | Arginine | 3.00g |
| Phenylalanine | 5.00g | Alanine | 3.00g |
| Aspartic acid | 0.25g | Glycine | 1.50g |
| Valine | 7.50g | Histidine | 2.50g |
| Threonine | 2.50g | Serine | 1.00g |
| Proline | 2.00g | Tryptophan | 2.50g |
| Methionine | 5.00g | Cysteine | 0.25g |
| The liquor sodii citratis of 0.1mol/L | In right amount | Water for injection | In right amount |
Total amount is 1000ml.
Preparation method:
(1) each former, auxiliary material is weighed by prescription；
(2) water for injection for taking full dose 70% maintains water temperature at 70 DEG C, carries out nitrogen replacement operator 3 times to reaction kettle, protects
Temperature is passed through nitrogen.
(3) under nitrogen stream protection, monitor dissolved oxygen in 1.0mg/L hereinafter, be added the tyrosine of recipe quantity, leucine,
Isoleucine, valine, aspartic acid, phenylalanine and methionine.Stirring is extremely dissolved.
(4) under nitrogen stream protection, 40 DEG C are cooled to, threonine, proline, glutamic acid, the acetic acid that recipe quantity is added rely
Propylhomoserin, arginine, alanine, glycine, histidine and serine, stirring to dissolution.0.05% active carbon (w/v, with suitable is added
Measure water for injection wetting), 40 DEG C of absorption 15min.Solution returns filter 30min by titanium core filter (3 μm of aperture).
(5) under nitrogen stream protection, dissolved oxygen is monitored in 1.0mg/L hereinafter, the tryptophan of recipe quantity is added, dissolution is complete
Afterwards, the cysteine of recipe quantity is added, the liquor sodii citratis of 0.1mol/L is added after dissolution completely, make pH value 5.5, determine
Hold.
(6) under nitrogen stream protection, medical fluid is filtered by 0.45 μm, 0.22 μm of polyether sulfone micropore filter element, must be dissolved
Oxygen is in 1.0mg/L medical fluid below.
(7) under nitrogen stream protection, medical fluid is filling into 250ml infusion bottle, wherein volume of air is 30ml.It vacuumizes
Nitrogen charging tamponade, controls headspace oxygen 1.0% hereinafter, roll lid, in 121 DEG C moist heat sterilization 8 minutes, lamp inspection to get.
The preparation of 5 Amino Acid Compound Injection 18AA of embodiment
Each component and dosage are as shown in the table in Amino Acid Compound Injection 18AA:
| Tyrosine | 0.50g | Glutamic acid | 0.25g |
| Leucine | 10.00g | Lysine Acetate | 7.00g |
| Isoleucine | 7.50g | Arginine | 3.00g |
| Phenylalanine | 5.00g | Alanine | 3.00g |
| Aspartic acid | 0.25g | Glycine | 1.50g |
| Valine | 7.50g | Histidine | 2.50g |
| Threonine | 2.50g | Serine | 1.00g |
| Proline | 2.00g | Tryptophan | 2.50g |
| Methionine | 5.00g | Cysteine | 0.25g |
| The liquor sodii citratis of 0.1mol/L | In right amount | Water for injection | In right amount |
Total amount is 1000ml.
Preparation method:
(1) each former, auxiliary material is weighed by prescription；
(2) water for injection for taking full dose 70% maintains water temperature at 70 DEG C, carries out nitrogen replacement operator 3 times to reaction kettle, protects
Temperature is passed through nitrogen.
(3) under nitrogen stream protection, monitor dissolved oxygen in 0.8mg/L hereinafter, be added the tyrosine of recipe quantity, leucine,
Isoleucine, valine, aspartic acid, phenylalanine and methionine.Stirring is extremely dissolved.
(4) under nitrogen stream protection, 40 DEG C are cooled to, threonine, proline, glutamic acid, the acetic acid that recipe quantity is added rely
Propylhomoserin, arginine, alanine, glycine, histidine and serine, stirring to dissolution.0.05% active carbon (w/v, with suitable is added
Measure water for injection wetting), 40 DEG C of absorption 15min.Solution returns filter 30min by titanium core filter (3 μm of aperture).
(5) under nitrogen stream protection, dissolved oxygen is monitored in 0.8mg/L hereinafter, the tryptophan of recipe quantity is added, dissolution is complete
Afterwards, the cysteine of recipe quantity is added, the liquor sodii citratis of 0.1mol/L is added after dissolution completely, make pH value 5.5, determine
Hold.
(6) under nitrogen stream protection, medical fluid is filtered by 0.45 μm, 0.22 μm of polyether sulfone micropore filter element, must be dissolved
Oxygen is in 0.8mg/L medical fluid below.
(7) under nitrogen stream protection, medical fluid is filling into 500ml infusion bottle, wherein volume of air is 50ml.It vacuumizes
Nitrogen charging tamponade, controls headspace oxygen 1.0% hereinafter, roll lid, in 121 DEG C moist heat sterilization 8 minutes, lamp inspection to get.
The preparation of 6 Amino Acid Compound Injection 18AA of embodiment
Each component and dosage are as shown in the table in Amino Acid Compound Injection 18AA:
| Tyrosine | 0.50g | Glutamic acid | 0.25g |
| Leucine | 10.00g | Lysine Acetate | 7.00g |
| Isoleucine | 7.50g | Arginine | 3.00g |
| Phenylalanine | 5.00g | Alanine | 3.00g |
| Aspartic acid | 0.25g | Glycine | 1.50g |
| Valine | 7.50g | Histidine | 2.50g |
| Threonine | 2.50g | Serine | 1.00g |
| Proline | 2.00g | Tryptophan | 2.50g |
| Methionine | 5.00g | Cysteine | 0.25g |
| The liquor sodii citratis of 0.1mol/L | In right amount | Water for injection | In right amount |
Total amount is 1000ml.
Preparation method:
(1) each former, auxiliary material is weighed by prescription；
(2) water for injection for taking full dose 70% maintains water temperature at 70 DEG C, carries out nitrogen replacement operator 3 times to reaction kettle, protects
Temperature is passed through nitrogen.
(3) under nitrogen stream protection, monitor dissolved oxygen in 1.2mg/L hereinafter, be added the tyrosine of recipe quantity, leucine,
Isoleucine, valine, aspartic acid, phenylalanine and methionine.Stirring is extremely dissolved.
(4) under nitrogen stream protection, 40 DEG C are cooled to, threonine, proline, glutamic acid, the acetic acid that recipe quantity is added rely
Propylhomoserin, arginine, alanine, glycine, histidine and serine, stirring to dissolution.0.05% active carbon (w/v, with suitable is added
Measure water for injection wetting), 40 DEG C of absorption 15min.Solution returns filter 30min by titanium core filter (3 μm of aperture).
(5) under nitrogen stream protection, dissolved oxygen is monitored in 1.2mg/L hereinafter, the tryptophan of recipe quantity is added, dissolution is complete
Afterwards, the cysteine of recipe quantity is added, the liquor sodii citratis of 0.1mol/L is added after dissolution completely, make pH value 5.5, determine
Hold.
(6) under nitrogen stream protection, medical fluid is filtered by 0.45 μm, 0.22 μm of polyether sulfone micropore filter element, must be dissolved
Oxygen is in 1.2mg/L medical fluid below.
(7) under nitrogen stream protection, medical fluid is filling into 500ml infusion bottle, wherein volume of air is 100ml.It takes out true
Empty nitrogen charging tamponade, controls headspace oxygen 1.0% hereinafter, roll lid, in 121 DEG C moist heat sterilization 8 minutes, lamp inspection to get.
1 remaining oxygen of effect example: the test of dissolved oxygen and headspace oxygen limit
Referring to the prescription and preparation process of embodiment 1, (but only whole process is passed through nitrogen during preparation, without nitrogen
Displacement, not vacuum nitrogen filling tamponade, used water for injection filter film process without deoxygenation), prepare amino acid note
Liquid (18AA-IX) sample is penetrated, the limit of dissolved oxygen and headspace oxygen is shown in Table 1 in sample:
The limit of dissolved oxygen and headspace oxygen in 1 sample of table
| Test group | Ck | 1 | 2 | 3 | 4 | 5 | 6 |
| Dissolved oxygen (mg/L) | 7.2 | 3.0 | 3.2 | 3.4 | 3.6 | 3.8 | 4.0 |
| Headspace oxygen (%) | 20.6 | 2.8 | 3.2 | 3.6 | 4.0 | 4.4 | 4.8 |
Nitrogen is passed through in process for preparation merely, the dissolved oxygen of sample can only control between 3.0~4.0mg/L, headspace oxygen
It can only control between 2.8~4.8%.
Blank control (ck): not nitrogen charging (dissolved oxygen when nitrogen charging in solution is not 7.2mg/L, headspace oxygen 20.6%).
Every group 30 bottles are tested, the sample of test is placed in 60 DEG C of insulating boxs, is maintained the circulation of air, was taken in the 0th, 5,10 day
Sample checks that its character, light transmittance, cysteine indicate content etc., determines test effect with the 10th day inspection result, as a result sees
Table 2.
The test situation table of the limit of dissolved oxygen and headspace oxygen in 2 sample of table
Test result shows: the sample without nitrogen charging control is unstable during storage；If only in the mistake of configuration
Nitrogen is passed through in journey to control the dissolved oxygen and headspace oxygen in medical fluid, dissolved oxygen can only be controlled in 3.0mg/L, and headspace oxygen control exists
2.8%, and the sample that the two combines is still unqualified, needs to improve.
2 remaining oxygen of effect example: the test of dissolved oxygen and headspace oxygen limit
Referring to the prescription and preparation process of embodiment 1, (but only whole process is passed through nitrogen during preparation, without nitrogen
Displacement, used water for injection filter film process without deoxygenation), Amino Acid Compound Injection (18AA-IX) sample is prepared,
The limit of dissolved oxygen and headspace oxygen is shown in Table 3 in sample:
The limit of dissolved oxygen and headspace oxygen in 3 sample of table
| Test group | Ck | 1 | 2 | 3 | 4 | 5 | 6 |
| Dissolved oxygen (mg/L) | 7.2 | 2.9 | 3.1 | 3.3 | 3.5 | 3.7 | 3.9 |
| Headspace oxygen (%) | 20.6 | 0.7 | 0.9 | 1.1 | 1.3 | 1.5 | 1.7 |
Nitrogen is passed through in process for preparation merely, is vacuumized simultaneously when filling, the dissolved oxygen of sample can only be controlled 2.9
Between~3.9mg/L, headspace oxygen be can control between 0.7~1.7%.
Blank control (ck): not nitrogen charging (dissolved oxygen when nitrogen charging in solution is not 7.2mg/L, headspace oxygen 20.6%).
Every group 30 bottles are tested, the sample of test is placed in 60 DEG C of insulating boxs, is maintained the circulation of air, was taken in the 0th, 5,10 day
Sample checks that its character, light transmittance, cysteine indicate content etc., determines test effect with the 10th day inspection result, as a result sees
Table 4.
The test situation table of the limit of dissolved oxygen and headspace oxygen in 4 sample of table
Test result shows: the sample without nitrogen charging control is unstable during storage；If only in preparation
Whole process is passed through nitrogen in the process, changes the Novel filling machine for being able to carry out and vacuumizing and synchronizes when filling and is vacuumized, dissolved oxygen
It can only control in 2.9mg/L, headspace oxygen is controlled 0.7%, and the sample that the two combines is still unqualified, than simple nitrogen charging
Sample is obviously improved, and is appointed and so is needed to improve.
3 remaining oxygen of effect example: the test of dissolved oxygen and headspace oxygen limit
The prescription and preparation process (but used water for injection filters film process without deoxygenation) of reference embodiment 1,
Amino Acid Compound Injection (18AA-IX) sample is prepared, vacuum pump is added on preparing tank, vacuumizes and fills during preparation
Nitrogen carries out simultaneously, continues to vacuumize when filling, and the limit of dissolved oxygen and headspace oxygen is shown in Table 5 in sample:
The limit of dissolved oxygen and headspace oxygen in 5 sample of table
| Test group | Ck | 1 | 2 | 3 | 4 |
| Dissolved oxygen (mg/L) | 7.2 | 1.1 | 1.3 | 1.5 | 1.7 |
| Headspace oxygen (%) | 20.6 | 0.5 | 1.0 | 1.5 | 1.7 |
It vacuumizes during preparation and is carried out simultaneously with nitrogen charging and (dissolution Monitoring Oxygen Ventilation is carried out, beyond carrying out after the monitoring upper limit
Nitrogen displacement), continue to vacuumize when filling, the dissolved oxygen of sample can only control between 1.1~1.7mg/L, headspace oxygen
It can control between 0.5~1.7%.
Blank control (ck): not nitrogen charging (dissolved oxygen when nitrogen charging in solution is not 7.2mg/L, headspace oxygen 20.6%).
Every group 30 bottles are tested, the sample of test is placed in 60 DEG C of insulating boxs, is maintained the circulation of air, was taken in the 0th, 5,10 day
Sample checks that its character, light transmittance, cysteine indicate content etc., determines test effect with the 10th day inspection result, as a result sees
Table 6.
The test situation table of the limit of dissolved oxygen and headspace oxygen in 6 sample of table
Test result shows: the sample without nitrogen charging control is unstable during storage；It is vacuumized during preparation
It is carried out simultaneously with nitrogen charging, continues to vacuumize when filling, dissolved oxygen control is in 1.5mg/L hereinafter, headspace oxygen control is 1.5%
Hereinafter, sample passes.But may there is underproof sample to generate, so having done further improvement to working condition.
4 remaining oxygen of effect example: the test of dissolved oxygen and headspace oxygen limit
By the prescription and preparation process of embodiment 1, Amino Acid Compound Injection (18AA-IX) sample is prepared, in injection
Install deoxygenation filter membrane in water dispenser additional, the water for injection after deoxygenation is added in preparing tank, and vacuum pump is added on preparing tank, is matched
It vacuumizes during system and is carried out simultaneously with nitrogen charging, continue to vacuumize when filling, the limit of dissolved oxygen and headspace oxygen in sample
Degree is shown in Table 7:
The limit of dissolved oxygen and headspace oxygen in 7 sample of table
| Test group | Ck | 1 | 2 | 3 | 4 |
| Dissolved oxygen (mg/L) | 7.2 | 0.8 | 1.0 | 1.2 | 1.5 |
| Headspace oxygen (%) | 20.6 | 0.5 | 1.0 | 1.5 | 1.5 |
It vacuumizes during preparation and is carried out simultaneously with nitrogen charging, continue to vacuumize when filling, the dissolved oxygen energy of sample
Between 0.8~1.5mg/L, headspace oxygen be can control between 0.5~1.5% for control.
Blank control (ck): not nitrogen charging (dissolved oxygen when nitrogen charging in solution is not 7.2mg/L, headspace oxygen 20.6%).
Every group 30 bottles are tested, the sample of test is placed in 60 DEG C of insulating boxs, is maintained the circulation of air, was taken in the 0th, 5,10 day
Sample checks that its character, light transmittance, cysteine indicate content etc., determines test effect with the 10th day inspection result, as a result sees
Table 8.
The test situation table of the limit of dissolved oxygen and headspace oxygen in 8 sample of table
Test result shows: final sample dissolved oxygen can be controlled all in 1.5mg/L hereinafter, headspace oxygen control exists
1.5% hereinafter, sample is all qualified.When dissolved oxygen is controlled in 1.5mg/L or less, with the reduction of headspace oxygen, cysteine
Degradation amount significantly reduce；When headspace oxygen control is below 1.5%, with the reduction of dissolved oxygen, the degradation amount of cysteine
It significantly reduces；It is considered that: while controlling the dissolved oxygen in container and headspace oxygen and have stronger protective effect to amino acid.
The stability comparative test of 5 sample of effect example and the commercially available similar product containing sodium hydrogensulfite
By 1 sample prescription of embodiment and preparation process, a kind of injection of pharmaceutical composition containing 18 kinds of amino acid is prepared
(18AA-IX) different samples:
Test group 1: dissolved oxygen is 1.0mg/L in container, and sodium hydrogensulfite is not added in headspace oxygen 1.0%
Test group 2: referring to national drug standards WS1- XG-022-2011-2012 provides 0.50g/L containing sodium hydrogensulfite,
It is identical as presently commercially available similar product.
For the stability for examining or check prepared sample, we use accelerated test method, the sample of test are placed in 60 DEG C
In insulating box, its oxidation rate is improved.If being able to maintain stabilization under acceleration conditions, under 5~25 DEG C and dark conditions
Stability will be more preferable.Every group 40 bottles of production, every batch of respectively takes 10 bottles, is respectively put into be placed in 60 DEG C of insulating boxs and place, and keeps
Air circulation.10 bottles are respectively taken in the 5th day, 10 days, 30 days, by State Food and Drug Administration national drug standards WS1-
XG-022-2011-2012, the appearance character of test sample, light transmittance and pH value the results are shown in Table 9, table 10, table 11, table 12.
9 sample of table testing result at 0 day
10 sample of table testing result at 5 days
Compared with 0 day result, the content of cysteine can the degree that is oxidized of response sample, the content of cysteine gets over
Height, the degree for illustrating that sample is oxidized is smaller, and the stability of sample is better.The result shows that: two groups of test sample position 5 days property
Shape, light transmittance, cysteine indicate content there are no significant difference.
11 sample of table testing result at 10 days
Compared with 0 day and 5 days results, two groups of test sample positions, 10 days characters, light transmittance, cysteine indicate content table
Reveal nuance, the accelerated test of experimental group 1,2 products obtained therefrom quality is all qualified.
12 sample of table testing result at 30 days
With 0 day, 5 days, result compares within 10 days, two groups of test sample positions, 30 days characters, light transmittance, cysteine expression contain
Scale reveals nuance, and the accelerated test of experimental group 1,2 products obtained therefrom quality is all qualified.
It can be seen that the sample that sodium hydrogensulfite is not added in the case where can be effectively controlled dissolved oxygen and headspace oxygen from experimental result
Character, light transmittance, cysteine indicate the effect identical with the product containing sodium hydrogensulfite such as content, comply fully with similar medicine
The requirement of product national standard.
The detection of 6 sample quality of effect example
For the quality for examining or check product of the present invention, our 0 month after product is made, January, 2 months, March, June, by state
Family food and medicine Surveillance Authority national drug standards WS1- XG-022-2011-2012 " Amino Acid Compound Injection (18AA-
IX standard) " is tested.
Testing result shows: dissolved oxygen control is controlled in 1.0mg/L, headspace oxygen 1.0%, and the sample of sodium hydrogensulfite is not added
The indices of product are qualified, and product is qualified.Specific testing result is shown in Table 13, table 14.
A kind of injection quality measurements of the pharmaceutical composition containing 18 kinds of amino acid of table 13
A kind of injection quality measurements of the pharmaceutical composition containing 18 kinds of amino acid of table 14
In terms of above-mentioned testing result, invention formulation presses State Food and Drug Administration's standard WS1-XG-022-
2011-2012 is examined, and as a result meets regulation.Each index of sample shows sample matter without significant change in 6 months accelerated tests
Amount is stablized.Product of the present invention has good stability, and has also reacted the technical scheme is that feasible, effectively.
Claims (10)
1. a kind of pharmaceutical composition containing 18 kinds of amino acid, which is characterized in that it includes tyrosine, leucine, isoleucine, benzene
Alanine, aspartic acid, valine, threonine, proline, methionine, glutamic acid, Lysine Acetate, arginine, the third ammonia
Acid, glycine, histidine, serine, tryptophan, cysteine, pH adjusting agent and water；
The tyrosine with the mass volume ratio of the, water is 0.475~0.525g/L；
The leucine with the mass volume ratio of the, water is 9.200~10.800g/L；
The isoleucine with the mass volume ratio of the, water is 6.900~8.100g/L；
The phenylalanine with the mass volume ratio of the, water is 4.750~5.250g/L；
The aspartic acid with the mass volume ratio of the, water is 0.230~0.270g/L；
The valine with the mass volume ratio of the, water is 6.900~8.100g/L；
The threonine with the mass volume ratio of the, water is 2.300~2.700g/L；
The proline with the mass volume ratio of the, water is 1.840~2.160g/L；
The methionine with the mass volume ratio of the, water is 4.600~5.400g/L；
The glutamic acid with the mass volume ratio of the, water is 0.230~0.270g/L；
The Lysine Acetate with the mass volume ratio of the, water is 6.440~7.560g/L；
The arginine with the mass volume ratio of the, water is 2.760~3.240g/L；
The alanine with the mass volume ratio of the, water is 2.760~3.240g/L；
The glycine with the mass volume ratio of the, water is 1.380~1.620g/L；
The histidine with the mass volume ratio of the, water is 2.300~2.700g/L；
The serine with the mass volume ratio of the, water is 0.920~1.080g/L；
The tryptophan with the mass volume ratio of the, water is 2.300~2.700g/L；
The cysteine with the mass volume ratio of the, water is 0.230~0.270g/L；
The content of dissolved oxygen is in 1.5mg/L or less in the pharmaceutical composition；The pH value of the pharmaceutical composition be 5.5~
6.5。
2. pharmaceutical composition as described in claim 1, which is characterized in that the tyrosine, the mass body with, the water
Product is than being 0.50g/L；
It and/or the leucine, with the mass volume ratio of the, water is 10.00g/L；
It and/or the isoleucine, with the mass volume ratio of the, water is 7.50g/L；
It and/or the phenylalanine, with the mass volume ratio of the, water is 5.00g/L；
It and/or the aspartic acid, with the mass volume ratio of the, water is 0.25g/L；
It and/or the valine, with the mass volume ratio of the, water is 7.50g/L；
It and/or the threonine, with the mass volume ratio of the, water is 2.50g/L；
It and/or the proline, with the mass volume ratio of the, water is 2.0g/L；
It and/or the methionine, with the mass volume ratio of the, water is 5.0g/L；
It and/or the glutamic acid, with the mass volume ratio of the, water is 0.25g/L；
It and/or the Lysine Acetate, with the mass volume ratio of the, water is 7.00g/L；
It and/or the arginine, with the mass volume ratio of the, water is 3.00g/L；
It and/or the alanine, with the mass volume ratio of the, water is 3.00g/L；
It and/or the glycine, with the mass volume ratio of the, water is 1.50g/L；
It and/or the histidine, with the mass volume ratio of the, water is 2.50g/L；
It and/or the serine, with the mass volume ratio of the, water is 1.00g/L；
It and/or the tryptophan, with the mass volume ratio of the, water is 2.50g/L；
It and/or the cysteine, with the mass volume ratio of the, water is 0.25g/L；
And/or the pH value of the pharmaceutical composition is 6.0；
And/or the pH adjusting agent is aqueous solution of citric acid, aqueous acetic acid, sodium citrate aqueous solution and sodium acetate water
One or both of solution；
And/or the water is water for injection；
And/or the pharmaceutical composition also contains antioxidant；
And/or the pharmaceutical composition also contains metal ion chelation agent；
And/or in the pharmaceutical composition dissolved oxygen content in 1.3mg/L or less；
And/or the form of the pharmaceutical composition is uniform solution；
And/or there is Hypoproteinemia, low nutrition state for acute and chronic potential renal insufficiency patient in the pharmaceutical composition
Or amino acid supplementation perioperatively.
3. pharmaceutical composition as claimed in claim 2, which is characterized in that the concentration of the aqueous solution of citric acid is
0.1mol/L；
And/or the concentration of the aqueous acetic acid is 0.1mol/L；
And/or the concentration of the sodium citrate aqueous solution is 0.1mol/L；
And/or the concentration of the sodium acetate aqueous solution is 0.1mol/L；
And/or the antioxidant is sodium hydrogensulfite and/or sodium pyrosulfite；
And/or the metal ion chelation agent is natrium adetate；
And/or in the pharmaceutical composition dissolved oxygen content in 1.2mg/L or less；
And/or the form of the pharmaceutical composition is injection.
4. pharmaceutical composition as claimed in claim 3, which is characterized in that the content of dissolved oxygen exists in the pharmaceutical composition
1.1mg/L following；
And/or the injection is big infusion.
5. pharmaceutical composition as described in claim 1, which is characterized in that the content of dissolved oxygen exists in the pharmaceutical composition
1.0mg/L following；
And/or the pharmaceutical composition does not contain antioxidant.
6. pharmaceutical composition as described in claim 1, which is characterized in that the content of dissolved oxygen exists in the pharmaceutical composition
0.8mg/L or less；
And/or the pharmaceutical composition does not contain metal ion chelation agent.
7. pharmaceutical composition as described in claim 1, which is characterized in that the content of dissolved oxygen exists in the pharmaceutical composition
0.5mg/L or less；
And/or the pharmaceutical composition is by the tyrosine, the leucine, the isoleucine, the benzene
Alanine, the aspartic acid, the valine, the threonine, the proline, the methionine,
The glutamic acid, the Lysine Acetate, the arginine, the alanine, the glycine, the group
Propylhomoserin, the serine, the tryptophan, the cysteine, the pH adjusting agent and the water group
At.
8. a kind of preparation method of such as pharmaceutical composition according to any one of claims 1 to 7, which is characterized in that it includes
Following step: in a nitrogen atmosphere, each component is mixed, obtains the pharmaceutical composition containing 18 kinds of amino acid；
Above-mentioned mixing is under dissolved oxygen content monitoring, when the dissolved oxygen content of the composition in discovery mixed process is greater than institute
In the pharmaceutical composition stated when the upper limit of the content of dissolved oxygen, then nitrogen displacement is carried out.
9. a kind of storage method of such as pharmaceutical composition according to any one of claims 1 to 7, which is characterized in that it includes
Following step: in a reservoir by the described pharmaceutical composition storage, there are gas in the container, oxygen in the gas
Percent by volume below 1.5%.
10. a kind of preparation method of the pharmaceutical composition of storage in a reservoir, which is characterized in that it includes the following steps:
(1) pharmaceutical composition containing 18 kinds of amino acid is made in preparation method according to claim 8；
(2) pharmaceutical composition containing 18 kinds of amino acid is stored according to the method for claim 9 to get being stored in
Pharmaceutical composition in container.
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| CN112999148A (en) * | 2021-02-26 | 2021-06-22 | 北京诺康达医药科技股份有限公司 | Compound amino acid composition and preparation method thereof |
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| US20060079565A1 (en) * | 2003-05-30 | 2006-04-13 | Takashi Abe | Amino acid composition and supplementary liquid containing the same |
| JP2008255033A (en) * | 2007-04-03 | 2008-10-23 | Meiji Milk Prod Co Ltd | Amino acid composition and food/drink |
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| US20060079565A1 (en) * | 2003-05-30 | 2006-04-13 | Takashi Abe | Amino acid composition and supplementary liquid containing the same |
| JP2008255033A (en) * | 2007-04-03 | 2008-10-23 | Meiji Milk Prod Co Ltd | Amino acid composition and food/drink |
| CN101439031A (en) * | 2008-12-29 | 2009-05-27 | 郑飞雄 | Pharmaceutical composition containing 18 kinds of amino acid |
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| CN112999148A (en) * | 2021-02-26 | 2021-06-22 | 北京诺康达医药科技股份有限公司 | Compound amino acid composition and preparation method thereof |
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| CN109381460B (en) | 2023-09-01 |
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