CN109381457B - Pharmaceutical composition containing 14 amino acids and preparation method thereof - Google Patents
Pharmaceutical composition containing 14 amino acids and preparation method thereof Download PDFInfo
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- CN109381457B CN109381457B CN201710675915.6A CN201710675915A CN109381457B CN 109381457 B CN109381457 B CN 109381457B CN 201710675915 A CN201710675915 A CN 201710675915A CN 109381457 B CN109381457 B CN 109381457B
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/401—Proline; Derivatives thereof, e.g. captopril
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4172—Imidazole-alkanecarboxylic acids, e.g. histidine
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- A—HUMAN NECESSITIES
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D81/00—Containers, packaging elements, or packages, for contents presenting particular transport or storage problems, or adapted to be used for non-packaging purposes after removal of contents
- B65D81/18—Containers, packaging elements, or packages, for contents presenting particular transport or storage problems, or adapted to be used for non-packaging purposes after removal of contents providing specific environment for contents, e.g. temperature above or below ambient
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Abstract
The invention discloses a pharmaceutical composition containing 14 amino acids and a preparation method thereof. The invention provides a pharmaceutical composition containing 14 amino acids, which comprises isoleucine, leucine, lysine acetate, methionine, phenylalanine, threonine, tryptophan, valine, alanine, arginine, histidine, proline, serine, glycine, a pH value regulator and water. The pharmaceutical composition can not contain sulfite, so that potential safety hazard of sulfite to human body can be thoroughly eliminated, and clinical use is safer; the composition has longer shelf life.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a pharmaceutical composition containing 14 amino acids and a preparation method thereof.
Background
The compound amino acid injection (14 AA) is a sterilized aqueous solution prepared by adding auxiliary materials into 14 amino acids, and is clinically used for (1) improving the nutritional status of patients before and after operation; (2) protein digestion and absorption disorders, mild malnutrition due to insufficient protein intake or excessive consumption, and the like.
The compound amino acid injection (14 AA) of the sixth volume of the medicine standard (two parts) of the Ministry of health provides that each liter of the 14AA injection contains 0.500g of sodium bisulphite.
The new modified specification (label) for the compound amino acid injection (19 AA) of the type sold under the trade name Trophamine, no. 19018, 3.24.2004, approved by the FDA in the United states, shows less than 0.050g of sodium metabisulfite per 100 ml.
The U.S. FDA approved complex amino acid injection (15 AA) under the trade name HepatAmine, which was identified in the modified Specification (label) at 4/29/2004, contained less than 0.10g sodium bisulfite per 100 ml.
Because the amino acid solution is extremely easy to oxidize, an antioxidant is required to be added in the preparation of the compound amino acid injection, so that the antioxidant is one of key components for preparing the preparation.
The antioxidant used conventionally is a sulfite substance; research after 80 s shows that sulfite has great side effects in human body, such as degradation of thiamine, VB1, folic acid and tryptophan, irreversible reaction on DNA and nucleotide, so that the application of sulfite in medicines and foods is limited in various countries around the world.
The compound amino acid injection is widely applied clinically, and more adverse reactions are reported clinically, the allergic reaction is a common serious adverse reaction related to sulfite, and clinical symptoms are bronchospasm, asthma, dyspnea, nausea, laryngeal edema, hypotension, shock and even death.
The trace sulfite can prolong the time of activating prothrombin, prevent urokinase fibrinolytic activity, and can cause anaphylactic reaction in a few minutes of patients, especially influence liver function, cause transaminase to rise and even liver cell necrosis. Studies have also found that sulphite has an effect on various living substances, such as irreversible reactions with deoxyribonucleic acid (DNA), adenine dinucleotide, vitamin K3, uracil, cytosine and disulphide bonds in proteins, which may be responsible for sulphite side reactions.
The FDA has formally required the drug manufacturer to clearly mark the content of antioxidants added and their clinical side effects on drug labels to play a warning role as early as 1985. In addition, headquarters were set up in the United states public service science Center (CSP) of Washington to limit the dosage of sulfite used and its content in the medicine is marked in the specification.
In 1988, the national pharmaceutical industry association of france made a corresponding regulation, requiring a warning statement that sulfite be marked on pharmaceutical packaging boxes. The western world has been increasingly careful about the clinical use of sulfite-containing drugs.
In 2015, the national adverse reaction monitoring center explicitly points out that the adverse reaction monitoring center is described in the specification [ adverse reaction ] in the revised opinion of the compound amino acid injection (18 AA): "allergic reaction: because of the presence of sodium metabisulfite or sodium bisulphite, allergic reactions (especially in asthmatic patients) may be induced, manifested as rash, itching, etc., and severe allergic shock may occur, if immediate withdrawal should occur. In addition, the antioxidant concentration of the product should be indicated in the corresponding content of the specification.
This requirement is also set forth in the publication of the specification for revising compound amino acid injection (18 AA) and similar preparations in the 2016 No. 144 of CFDA.
Up to now, no published chinese patent application has been searched for an injection (14 AA) containing compound amino acids.
It is therefore worth studying to explore the production of pharmaceutical compositions containing 14 amino acids and free of sulfite antioxidants.
Disclosure of Invention
The invention aims to overcome the defects that the prior compound amino acid injection (14 AA) contains sulfite antioxidants which possibly induce anaphylactic reaction (especially asthma patients), and the serious patients can generate anaphylactic shock and the like, and provides a pharmaceutical composition containing 14 amino acids and a preparation method thereof. The compound amino acid injection (14 AA) can exist stably under the condition of not containing sulfite antioxidants, so that the harm of the sulfite antioxidants to human bodies is thoroughly solved, and the validity period is longer. Meanwhile, the preparation method is simple, easy to operate and suitable for industrial production.
The invention provides a pharmaceutical composition containing 14 amino acids, which comprises isoleucine, leucine, lysine acetate, methionine, phenylalanine, threonine, tryptophan, valine, alanine, arginine, histidine, proline, serine, glycine, a pH value regulator and water;
The mass volume ratio of the isoleucine to the water is 5.31-6.49g/L;
the mass volume ratio of the leucine to the water is 6.93-8.47g/L;
the mass volume ratio of the lysine acetate to the water is 7.83-9.57g/L;
the mass volume ratio of the methionine to the water is 4.05-4.95g/L;
the mass volume ratio of the phenylalanine to the water is 4.32-5.28g/L;
the mass volume ratio of threonine to water is 3.06-3.74g/L;
the mass volume ratio of the tryptophan to the water is 1.17-1.43g/L;
the mass volume ratio of valine to water is 5.04-6.16g/L;
the mass volume ratio of the alanine to the water is 5.40-6.60g/L;
the mass volume ratio of the arginine to the water is 7.28-8.91g/L;
the mass volume ratio of the histidine to the water is 2.16-2.64g/L;
the mass volume ratio of the proline to the water is 8.55-10.45g/L;
the mass volume ratio of serine to water is 4.50-5.50g/L;
the mass volume ratio of the glycine to the water is 10.71-13.09g/L;
The content of dissolved oxygen in the pharmaceutical composition is below 1.0 mg/L; the pH of the pharmaceutical composition is 5.5-6.5 (e.g., 6.0).
The mass-to-volume ratio of the isoleucine to the water can be 5.9g/L.
The mass-to-volume ratio of the leucine to the water can be 7.7g/L.
The mass volume ratio of the lysine acetate to the water can be 8.7g/L.
The mass-to-volume ratio of methionine to water can be 4.5g/L.
The mass-volume ratio of the phenylalanine to the water can be 4.8g/L.
The mass-volume ratio of threonine to water can be 3.4g/L.
The mass-volume ratio of tryptophan to water can be 1.3g/L.
The mass volume ratio of valine to water can be 5.6g/L.
The mass-volume ratio of the alanine to the water can be 6.0g/L.
The mass-volume ratio of the arginine to the water can be 8.1g/L.
The mass-volume ratio of the histidine to the water can be 2.4g/L.
The mass volume ratio of the proline to the water can be 9.5g/L.
The mass-volume ratio of serine to water can be 5.0g/L.
The mass volume ratio of the glycine to the water can be 11.9g/L.
The pH adjuster is used to adjust the pH of the pharmaceutical composition, and may be any pH adjuster commonly used in the art, such as glacial acetic acid (without water, the volume of which may be 0.35% of the total volume of the pharmaceutical composition), aqueous citric acid, aqueous acetic acid, aqueous sodium citrate, or aqueous sodium acetate. The concentration of the aqueous solution of citric acid can be 0.1mol/L. The concentration of the aqueous acetic acid solution may be 0.1mol/L. The concentration of the sodium citrate aqueous solution can be 0.1mol/L. The concentration of the sodium acetate aqueous solution can be 0.1mol/L.
The water may be water conventional in the art, such as water for injection. The water for injection may be water for injection conventional in the art, for example, water for injection (water obtained by distilling purified water) prescribed in the "chinese pharmacopoeia 2015 edition". The pharmaceutical composition may further comprise an antioxidant. The antioxidant may be an antioxidant conventional in the art, such as sodium bisulfite and/or sodium metabisulfite.
The lysine acetate does not limit the raw materials of the pharmaceutical composition to lysine acetate, but may be equivalents thereof, such as acetic acid and lysine, and other suitable acids (in combination with the pH regulator described above) and lysine.
The lysine acetate may be present in the pharmaceutical composition in the form of lysine.
The pharmaceutical composition may be free of antioxidants. The antioxidant may be an antioxidant conventional in the art, such as sodium bisulfite and/or sodium metabisulfite.
The pharmaceutical composition may further comprise a metal ion chelating agent. The metal ion chelating agent may be a conventional metal ion chelating agent in the art (which is capable of complexing trace metal ions in solution to reduce the occurrence of oxidative degradation reactions of amino acids due to metal ions), such as disodium edetate.
The pharmaceutical composition may be free of metal ion chelators. The metal ion chelating agent may be a conventional metal ion chelating agent in the art (which is capable of complexing trace metal ions in solution to reduce the occurrence of oxidative degradation reactions of amino acids due to metal ions), such as disodium edetate.
The pharmaceutical composition may consist of the isoleucine, the leucine, the lysine acetate, the methionine, the phenylalanine, the threonine, the tryptophan, the valine, the alanine, the arginine, the histidine, the proline, the serine, the glycine, the pH adjustor, and the water.
The content of dissolved oxygen in the pharmaceutical composition can be less than 0.8mg/L or less than 0.5 mg/L.
The pharmaceutical composition may be in the form of a homogeneous solution, such as an injection. The injection can be a large infusion.
The pharmaceutical composition can be used for parenteral support of patients with acute and chronic renal insufficiency; severe renal failure due to major surgery, trauma or sepsis, and acute and chronic renal failure.
The pharmaceutical composition can be prepared according to the following preparation method.
The pharmaceutical composition may be stored according to the following storage method. The storage mode can be as follows: and (3) filling the pharmaceutical composition, pressing, capping, sterilizing and performing light inspection to obtain the pharmaceutical composition. The pressure plug can be a vacuum pumping nitrogen charging pressure plug. The sterilization can be a wet heat sterilization at 121 ℃ for 10 minutes.
The invention also provides a preparation method of the pharmaceutical composition containing 14 amino acids, which comprises the following steps:
mixing the components under nitrogen atmosphere to obtain a pharmaceutical composition containing 14 amino acids;
the above mixing is under monitoring of dissolved oxygen content, and when the dissolved oxygen content of the composition during mixing is found to be greater than the upper limit of the content of dissolved oxygen in the pharmaceutical composition (e.g., 1.0mg/L, 0.8mg/L, or 0.5 mg/L), then nitrogen substitution is performed (i.e., vacuum < means evacuation of a portion of the gas, the degree of extraction may be determined by the person skilled in the art), nitrogen is filled, the nitrogen substitution may be performed for a period of time determined by the person skilled in the art, and may be performed immediately upon finding that the dissolved oxygen content is greater than the upper limit of the content of dissolved oxygen in the pharmaceutical composition, or may be performed at the end, the number of times of nitrogen substitution may be determined by the person skilled in the art, such that the content of dissolved oxygen in the composition concerned is less than or equal to the upper limit of the content of dissolved oxygen in the pharmaceutical composition < e.g., 1.0mg/L, 0.8mg/L, or 0.5 mg/L.
In the above preparation method, the water may be subjected to an oxygen removal treatment. The deoxygenation treatment may be a deoxygenation treatment conventional in the art, such as a deoxygenation filtration membrane treatment. The content of dissolved oxygen in the deoxidized water can be 0.000072mg/L.
In the above preparation methods, the mixing may be conventional in the art, for example, the mixing process employs activated carbon adsorption (and activated carbon removal) and/or fine filtration steps.
The preparation method comprises the following steps:
(1) Mixing part of the water with the isoleucine, the leucine, the methionine, the valine and the phenylalanine in a nitrogen atmosphere to obtain a liquid medicine 1;
(2) Mixing the liquid medicine 1 with the lysine acetate, the threonine, the arginine, the histidine, the alanine, the glycine, the proline and the serine in a nitrogen atmosphere, adding the pH value regulator to enable the pH value to be 5.5-6.5 (for example, 6.0), and then adding the rest of the water to obtain liquid medicine 2;
(3) Mixing the liquid medicine 2 with active carbon in nitrogen atmosphere, and then removing the active carbon to obtain liquid medicine 3;
(4) Mixing the liquid medicine 3 with the tryptophan, the activated carbon and the rest water in a nitrogen atmosphere, and finely filtering to obtain a pharmaceutical composition containing 14 amino acids;
the above steps (e.g., one or more of steps 1, 2, 3 and 4, e.g., all of steps 1, 2, 3 and 4, e.g., only step 4, and at least step 4) are monitored for dissolved oxygen content, and when the concentration of dissolved oxygen in the composition of the monitored steps (e.g., one or more of the above-mentioned medical solutions 1, 2 and 3) is found to be greater than the upper limit of dissolved oxygen content in the pharmaceutical composition (e.g., 1.0mg/L, 0.8mg/L, or 0.5 mg/L), then a nitrogen substitution (i.e., evacuation < refers to the withdrawal of a portion of the gas, the withdrawal being made by those skilled in the art, as the case may be), and charging of nitrogen, as the case may be, is made by those skilled in the art, and when the concentration of dissolved oxygen in the composition of the monitored steps (e.g., one or more than the upper limit of dissolved oxygen content in the pharmaceutical composition) is found to be made last, the number of nitrogen substitution may be determined by those skilled in the art, such that the concentration of dissolved oxygen in the composition is less than or equal to the upper limit of dissolved oxygen content of 1.0mg/L, 0.5mg/L, or less than the upper limit of the oxygen content of the composition, as the case of the drug composition.
In each of the above steps, the "under nitrogen atmosphere" may be a nitrogen atmosphere conventional in the art, for example, under nitrogen flow protection. The "nitrogen atmosphere" may be achieved by methods conventional in the art, such as nitrogen substitution.
In each of the above steps, the result of the "mixing" may be a conventional mixing result in the art, such as dissolution to form a homogeneous solution or suspension.
In step (1) above, the amount of "part" in the "part of the water" may be an amount conventional in the art, for example an amount sufficient to solubilize the amino acids, which may be determined by the person skilled in the art as the case may be, for example 80% of the total amount.
In the above step (1), the "part of the water" may be water heated under a nitrogen atmosphere and then incubated. The nitrogen atmosphere is as described above. The temperature of the heating may be 95 ℃. The heating time may be 15 minutes. The temperature of the heat preservation can be 70-75 ℃.
In the step (1), the water may be subjected to an oxygen removal treatment. The deoxygenation treatment may be a deoxygenation treatment conventional in the art, such as a deoxygenation filtration membrane treatment. The content of dissolved oxygen in the deoxidized water can be 0.000072mg/L.
In the step (1), the temperature at the time of the mixing may be a temperature of 70℃to 75℃which is conventional in the art.
In the step (2), the liquid medicine 1 may be a liquid medicine 1 having a temperature which is conventional in the art, for example, a liquid medicine 1 having been cooled to 40 to 50 ℃.
In the above step (2), the temperature at the time of the mixing may be a temperature of 40 to 50℃which is conventional in the art.
In the step (3), the activated carbon may be activated carbon conventional in the art, for example, activated carbon specified in "chinese pharmacopoeia 2015 edition", and activated carbon for injection, for example. The mass to volume ratio of the activated carbon to the pharmaceutical composition may be 0.0003g/ml. The activated carbon may be first wetted with the water when in use.
In the above step (3), the time of mixing with the activated carbon may be a time conventional in the art, for example, to complete adsorption, for example, 30 minutes.
In the step (3) described above, the "removal" may be a removal means conventional in the art, such as filtration removal. The filtration may be in a manner conventional in the art, such as titanium core (i.e., titanium rod) back filtration. The pore size of the titanium core filter may be conventional in the art, for example 3 μm. The time for the back-filtering may be a time conventional in the art, for example, 5 minutes.
In the above step (3), the temperature at the time of the mixing may be a temperature conventional in the art, for example, 40 ℃.
In the above step (4), the "remaining water" means water obtained by subtracting the "part of the water" in the step (1), for example, 20% of the total amount.
In the step (4), the water may be subjected to an oxygen removal treatment. The deoxygenation treatment may be a deoxygenation treatment conventional in the art, such as a deoxygenation filtration membrane treatment. The content of dissolved oxygen in the deoxidized water can be 0.000072mg/L.
In the step (4), the activated carbon may be activated carbon conventional in the art, for example, activated carbon specified in "chinese pharmacopoeia 2015 edition", and activated carbon for injection, for example. The mass volume ratio of the active carbon to the pharmaceutical composition can be 0.0001g/ml. The activated carbon may be first wetted with the water when in use.
In the above step (4), the temperature at the time of the mixing may be a temperature conventional in the art, for example, 40 ℃.
In the step (4), the fine filtration may be conventional in the art, for example, filtration using a microporous filter membrane. The pore size of the microporous filter membrane may be conventional in the art, for example 0.45 μm and/or 0.22 μm. When the number of the microporous filter membranes is two, the pore diameters of the microporous filter membranes can be 0.45 mu m and 0.22 mu m in sequence.
In the case of the above-mentioned dissolved oxygen monitoring, when the dissolved oxygen content in the composition of the monitored step (e.g., one or more of the above-mentioned medicinal liquids 1, 2, 3, 4 and 5) is not found to be greater than the upper limit (e.g., 1.0mg/L, 0.8mg/L, or 0.5 mg/L) of the dissolved oxygen content in the pharmaceutical composition, no nitrogen substitution is performed.
A method of preparing the above pharmaceutical composition stored in a container comprising the steps of:
(1) According to the preparation method of the pharmaceutical composition containing 14 amino acids, the pharmaceutical composition containing 14 amino acids is prepared;
(2) The pharmaceutical composition containing 14 amino acids is stored according to the following method to obtain the pharmaceutical composition in the container.
In the step (2), the storage may be implemented by: and (3) filling the pharmaceutical composition, pressing, capping, sterilizing and performing light inspection to obtain the pharmaceutical composition. The pressure plug can be a vacuum pumping nitrogen charging pressure plug. The sterilization can be a wet heat sterilization at 121 ℃ for 10 minutes.
A method of storing the pharmaceutical composition described above, comprising the steps of: the pharmaceutical composition is stored in a container, wherein a gas is present in the container, and the volume percentage of oxygen in the gas is below 1.0%.
The volume ratio of the gas to the container can be 0.06-0.20, 0.08-0.12, or 0.10.
The volume of the container can be 100 ml-500 ml, and can be 200 ml-250 ml.
When the volume of the container is 100ml, the volume ratio of the gas to the container may be 0.06-0.12.
When the volume of the container is 200 ml-250 ml, the volume ratio of the gas to the container can be 0.08-0.12.
When the volume of the container is 500ml, the volume ratio of the gas to the container may be 0.10 to 0.20.
The volume percentage of oxygen in the gas can be below 0.5%.
The container can be an infusion bottle. The pharmaceutical composition may be filled into the container by the steps of: pressing the plug, rolling the cover, sterilizing and checking the lamp. The pressure plug can be a vacuum pumping nitrogen charging pressure plug. The sterilization can be a wet heat sterilization at 121 ℃ for 10 minutes.
The amino acid used in the present invention is an L-form amino acid except glycine.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: under the condition of no pyrosulfite or sulfite antioxidant, the compound amino acid injection can exist stably by controlling the content of dissolved oxygen in the injection and the content of headspace oxygen in an injection storage container, so that the harm of the pyrosulfite or sulfite antioxidant to human bodies is thoroughly solved, and the effective period is longer. Meanwhile, the preparation method is simple, easy to operate and suitable for industrial production.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
In the following examples and effect examples, as not specifically described, the water for injection was subjected to an oxygen-scavenging filtration membrane treatment before use, so that the dissolved oxygen content in the water for injection was reduced to 10ppm or less. The 10ppm refers to the dissolved oxygen content being one ten thousandth of the dissolved oxygen content in water at normal temperature (namely 0.000072 mg/L). The content of dissolved oxygen in the water at normal temperature is generally 7.2mg/L.
Example 1 preparation of Compound amino acid injection 14 AA:
the components and the amounts of the components in the compound amino acid injection 14AA are shown in the following table:
the preparation method of the compound amino acid injection 14AA comprises the following steps:
1. weighing each raw material and auxiliary materials according to the prescription;
2. about 80% of the prescribed amount of water for injection is added to the compounding tank, heated to 95 ℃ or higher, and kept for 15min. Continuously stirring, cooling simultaneously under the protection of nitrogen, and introducing nitrogen at the temperature.
3. When the temperature of water for injection is reduced to 70 ℃, monitoring that the dissolved oxygen is below 1mg/L, adding leucine, isoleucine, phenylalanine, valine and methionine with corresponding amounts in the table; stirring until the mixture is dissolved;
4. cooling to 40deg.C under nitrogen protection, adding threonine, lysine acetate, arginine, histidine, alanine, glycine, proline and serine in the corresponding amounts, and stirring to dissolve completely; after complete dissolution, the pH was adjusted by adding glacial acetic acid solution in an amount of about 0.35% (v/v) of the total. The pH of the solution should be 6.0 after the addition is completed.
5. Adding 0.03% of medicinal active carbon (active carbon mass/solution volume, wetting with proper amount of water for injection) under the protection of nitrogen, and stirring at 40deg.C for 30min; back filtering for about 5min by a titanium rod, then conveying the solution into another clean liquid preparation tank, and stirring under the protection of nitrogen;
6. Monitoring that dissolved oxygen is below 1 mg/L; adding tryptophan with a prescription amount, stirring and dissolving, adding 0.01% of medicinal active carbon (w/v, wetting with proper amount of water for injection), adding water for injection to 1000mL, and stirring at 40 ℃ for 15min;
7. filtering the liquid medicine by a microporous filter membrane with the thickness of 0.45 mu m and a microporous filter membrane with the thickness of 0.22 mu m in sequence under the protection of nitrogen to obtain the liquid medicine with the dissolved oxygen below 1 mg/L;
8. filling the liquid medicine into glass infusion bottles under the protection of nitrogen, carrying out vacuum pumping and nitrogen filling on each bottle with the volume of air being 20mL, controlling the residual oxygen in the headspace of the container to be less than 1.0%, pressing a plug, rolling a cover, sterilizing at 121 ℃ for 10 minutes, and carrying out lamp inspection to obtain the liquid medicine.
Example 2 preparation of Compound amino acid injection 14 AA:
the components and the amounts of the components in the compound amino acid injection 14AA are shown in the following table:
the preparation method of the compound amino acid injection 14AA comprises the following steps:
1. weighing each raw material and auxiliary materials according to the prescription;
2. about 80% of the prescribed amount of water for injection is added to the compounding tank, heated to 95 ℃ or higher, and kept for 15min. Continuously stirring, cooling simultaneously under the protection of nitrogen, and introducing nitrogen at the temperature.
3. When the temperature of water for injection is reduced to 70 ℃, monitoring that the dissolved oxygen is below 1.0mg/L, adding leucine, isoleucine, phenylalanine, valine and methionine with the corresponding amounts in the table; stirring until the mixture is dissolved;
4. Cooling to 40deg.C under nitrogen protection, adding threonine, lysine acetate, arginine, histidine, alanine, glycine, proline and serine in the corresponding amounts, and stirring to dissolve completely; after complete dissolution, the pH was adjusted by adding glacial acetic acid solution in an amount of about 0.35% (v/v) of the total. The pH of the solution should be 6.0 after the addition is completed.
5. Adding 0.03% of medicinal active carbon (active carbon mass/solution volume, wetting with proper amount of water for injection) under the protection of nitrogen, and stirring at 40deg.C for 30min; back filtering for about 5min by a titanium rod, then conveying the solution into another clean liquid preparation tank, and stirring under the protection of nitrogen;
6. monitoring that dissolved oxygen is below 10 mg/L; adding tryptophan with a prescription amount, stirring and dissolving, adding 0.01% of medicinal active carbon (w/v, wetting with proper amount of water for injection), adding water for injection to 1000mL, and stirring at 40 ℃ for 15min;
7. filtering the liquid medicine by a microporous filter membrane with the thickness of 0.45 mu m and a microporous filter membrane with the thickness of 0.22 mu m under the protection of nitrogen to obtain the liquid medicine with the dissolved oxygen below 1.0 mg/L;
8. filling the liquid medicine into glass infusion bottles under the protection of nitrogen, vacuumizing and filling nitrogen into each bottle with 100mL, wherein the volume of air is 6mL, controlling the residual oxygen in the headspace of the container to be less than 1.0%, pressing a plug, rolling a cover, sterilizing at 121 ℃ for 10 minutes, and performing lamp inspection to obtain the liquid medicine.
Example 3 preparation of Compound amino acid injection 14 AA:
the components and the amounts of the components in the compound amino acid injection 14AA are shown in the following table:
the preparation method of the compound amino acid injection 14AA comprises the following steps:
1. weighing each raw material and auxiliary materials according to the prescription;
2. about 80% of the prescribed amount of water for injection is added to the compounding tank, heated to 95 ℃ or higher, and kept for 15min. Continuously stirring, cooling simultaneously under the protection of nitrogen, and introducing nitrogen at the temperature.
3. When the temperature of water for injection is reduced to 70 ℃, monitoring that the dissolved oxygen is below 1.0mg/L, adding leucine, isoleucine, phenylalanine, valine and methionine with the corresponding amounts in the table; stirring until the mixture is dissolved;
4. cooling to 50deg.C under nitrogen protection, adding threonine, lysine acetate, arginine, histidine, alanine, glycine, proline and serine in the corresponding amounts, and stirring to dissolve completely; after complete dissolution, the pH was adjusted by adding glacial acetic acid solution in an amount of about 0.35% (v/v) of the total. The pH of the solution should be 6.0 after the addition is completed.
5. Adding 0.03% of medicinal active carbon (active carbon mass/solution volume, wetting with proper amount of water for injection) under the protection of nitrogen, and stirring at 40deg.C for 30min; back filtering for about 5min by a titanium rod, then conveying the solution into another clean liquid preparation tank, and stirring under the protection of nitrogen;
6. Monitoring that dissolved oxygen is below 1.0 mg/L; adding tryptophan with a prescription amount, stirring and dissolving, adding 0.01% of medicinal active carbon (w/v, wetting with proper amount of water for injection), adding water for injection to 1000mL, and stirring at 40 ℃ for 15min;
7. filtering the liquid medicine by a microporous filter membrane with the thickness of 0.45 mu m and a microporous filter membrane with the thickness of 0.22 mu m under the protection of nitrogen to obtain the liquid medicine with the dissolved oxygen below 1.0 mg/L;
8. filling the liquid medicine into glass infusion bottles under the protection of nitrogen, vacuumizing and filling nitrogen into each bottle with 100mL, wherein the air volume is 12mL, controlling the residual oxygen in the headspace of the container to be less than 1.0%, pressing a plug, rolling a cover, sterilizing at 121 ℃ for 10 minutes, and performing lamp inspection to obtain the liquid medicine.
Example 4 preparation of Compound amino acid injection 14 AA:
the components and the amounts of the components in the compound amino acid injection 14AA are shown in the following table:
the preparation method of the compound amino acid injection 14AA comprises the following steps:
1. weighing each raw material and auxiliary materials according to the prescription;
2. about 80% of the prescribed amount of water for injection is added to the compounding tank, heated to 95 ℃ or higher, and kept for 15min. Continuously stirring, cooling simultaneously under the protection of nitrogen, and introducing nitrogen at the temperature.
3. When the temperature of water for injection is reduced to 5 ℃, monitoring that the dissolved oxygen is below 1.0mg/L, adding leucine, isoleucine, phenylalanine, valine and methionine with the corresponding amounts in the table; stirring until the mixture is dissolved;
4. Cooling to 50deg.C under nitrogen protection, adding threonine, lysine acetate, arginine, histidine, alanine, glycine, proline and serine in the corresponding amounts, and stirring to dissolve completely; after the dissolution is completed, adding glacial acetic acid solution to adjust the pH value, and after the addition is completed, the pH value of the solution is 5.5.
5. Adding 0.03% of medicinal active carbon (active carbon mass/solution volume, wetting with proper amount of water for injection) under the protection of nitrogen, and stirring at 40deg.C for 30min; back filtering for about 5min by a titanium rod, then conveying the solution into another clean liquid preparation tank, and stirring under the protection of nitrogen;
6. monitoring that dissolved oxygen is below 1.0 mg/L; adding tryptophan with a prescription amount, stirring and dissolving, adding 0.01% of medicinal active carbon (w/v, wetting with proper amount of water for injection), adding water for injection to 1000mL, and stirring at 40 ℃ for 15min;
7. filtering the liquid medicine by a microporous filter membrane with the thickness of 0.45 mu m and a microporous filter membrane with the thickness of 0.22 mu m under the protection of nitrogen to obtain the liquid medicine with the dissolved oxygen below 1.0 mg/L;
8. filling the liquid medicine into glass infusion bottles under the protection of nitrogen, wherein each bottle is 200mL, vacuumizing and filling nitrogen, the volume of air is 16mL, controlling the residual oxygen in the headspace of the container to be below 0.5%, pressing a plug, rolling a cover, sterilizing at 121 ℃ for 10 minutes, and performing lamp inspection to obtain the liquid medicine.
Example 5 preparation of Compound amino acid injection 14 AA:
the components and the amounts of the components in the compound amino acid injection 14AA are shown in the following table:
| component (A) | Dosage of |
| Isoleucine (C) 6 H 13 NO 2 ) | 5.9g |
| Leucine (C) 6 H 13 NO 2 ) | 7.7g |
| Lysine acetate (C) 6 H 14 N 2 O 2 ·C 2 H 4 O 2 ) | 8.7g |
| Methionine (C) 5 H 11 NO 2 S) | 4.5g |
| Phenylalanine (C) 9 H 11 NO 2 ) | 4.8g |
| Threonine (C) 4 H 9 NO 3 ) | 3.4g |
| Tryptophan (C) 11 H 12 N 2 O 2 ) | 1.3g |
| Valine (C) 5 H 11 NO 2 ) | 5.6g |
| Alanine (C) 3 H 7 NO 2 ) | 6.0g |
| Arginine (C) 6 H 14 N 4 O 2 ) | 8.1g |
| Histidine (C) 6 H 9 N 3 O 2 ) | 2.4g |
| Proline (C) 5 H 9 NO 2 ) | 9.5g |
| Serine (C) 3 H 7 NO 3 ) | 5.0g |
| Glycine (C) 2 H 6 NO 2 ) | 11.9g |
| Glacial acetic acid | Proper amount of |
| Water for injection | Proper amount of |
| Total amount of | 1000mL |
The preparation method of the compound amino acid injection 14AA comprises the following steps:
1. weighing each raw material and auxiliary materials according to the prescription;
2. about 80% of the prescribed amount of water for injection is added to the compounding tank, heated to 95 ℃ or higher, and kept for 15min. Continuously stirring, cooling simultaneously under the protection of nitrogen, and introducing nitrogen at the temperature.
3. When the temperature of water for injection is reduced to 70 ℃, monitoring that the dissolved oxygen is below 0.8mg/L, adding leucine, isoleucine, phenylalanine, valine and methionine with the corresponding amounts in the table; stirring until the mixture is dissolved;
4. cooling to 50deg.C under nitrogen protection, adding threonine, lysine acetate, arginine, histidine, alanine, glycine, proline and serine in the corresponding amounts, and stirring to dissolve completely; after the dissolution is completed, adding glacial acetic acid solution to adjust the pH value, and after the addition is completed, the pH value of the solution is 6.5.
5. Adding 0.03% of medicinal active carbon (active carbon mass/solution volume, wetting with proper amount of water for injection) under the protection of nitrogen, and stirring at 40deg.C for 30min; back filtering for about 5min by a titanium rod, then conveying the solution into another clean liquid preparation tank, and stirring under the protection of nitrogen;
6. monitoring that dissolved oxygen is below 0.8 mg/L; adding tryptophan with a prescription amount, stirring and dissolving, adding 0.01% of medicinal active carbon (w/v, wetting with proper amount of water for injection), adding water for injection to 1000mL, and stirring at 40 ℃ for 15min;
7. filtering the liquid medicine by a microporous filter membrane with the thickness of 0.45 mu m and a microporous filter membrane with the thickness of 0.22 mu m under the protection of nitrogen to obtain the liquid medicine with the dissolved oxygen below 0.8 mg/L;
8. filling the liquid medicine into glass infusion bottles under the protection of nitrogen, carrying out vacuum pumping and nitrogen filling on each bottle with the volume of air being 30mL, controlling the residual oxygen in the headspace of the container to be below 0.5%, pressing a plug, rolling a cover, sterilizing at 121 ℃ for 10 minutes, and carrying out lamp inspection to obtain the liquid medicine.
Example 6 preparation of Compound amino acid injection 14 AA:
the components and the amounts of the components in the compound amino acid injection 14AA are shown in the following table:
the preparation method of the compound amino acid injection 14AA comprises the following steps:
1. weighing each raw material and auxiliary materials according to the prescription;
2. about 80% of the prescribed amount of water for injection is added to the compounding tank, heated to 95 ℃ or higher, and kept for 15min. Continuously stirring, cooling simultaneously under the protection of nitrogen, and introducing nitrogen at the temperature.
3. When the temperature of water for injection is reduced to 75 ℃, monitoring that the dissolved oxygen is below 0.5mg/L, adding leucine, isoleucine, phenylalanine, valine and methionine with the corresponding amounts in the table; stirring until the mixture is dissolved;
4. cooling to 50deg.C under nitrogen protection, adding threonine, lysine acetate, arginine, histidine, alanine, glycine, proline and serine in the corresponding amounts, and stirring to dissolve completely; after complete dissolution, the pH was adjusted by adding glacial acetic acid solution in an amount of about 0.35% (v/v) of the total. The pH of the solution should be 6.0 after the addition is completed.
5. Adding 0.03% of medicinal active carbon (active carbon mass/solution volume, wetting with proper amount of water for injection) under the protection of nitrogen, and stirring at 40deg.C for 30min; back filtering for about 5min by a titanium rod, then conveying the solution into another clean liquid preparation tank, and stirring under the protection of nitrogen;
6. monitoring that dissolved oxygen is below 0.5 mg/L; adding tryptophan with a prescription amount, stirring and dissolving, adding 0.01% of medicinal active carbon (w/v, wetting with proper amount of water for injection), adding water for injection to 1000mL, and stirring at 40 ℃ for 15min;
7. filtering the liquid medicine by a microporous filter membrane with the thickness of 0.45 mu m and a microporous filter membrane with the thickness of 0.22 mu m under the protection of nitrogen to obtain the liquid medicine with the dissolved oxygen below 0.5 mg/L;
8. Filling the liquid medicine into glass infusion bottles under the protection of nitrogen, vacuumizing and filling nitrogen into 500mL of each bottle, controlling the volume of air to be 50mL, controlling the residual oxygen in the headspace of the container to be less than 1.0%, pressing a plug, rolling a cover, sterilizing at 121 ℃ for 10 minutes, and performing lamp inspection to obtain the liquid medicine.
Example 7 preparation of Compound amino acid injection 14 AA:
the components and the amounts of the components in the compound amino acid injection 14AA are shown in the following table:
the preparation method of the compound amino acid injection 14AA comprises the following steps:
1. weighing each raw material and auxiliary materials according to the prescription;
2. about 80% of the prescribed amount of water for injection is added to the compounding tank, heated to 95 ℃ or higher, and kept for 15min. Continuously stirring, cooling simultaneously under the protection of nitrogen, and introducing nitrogen at the temperature.
3. When the temperature of water for injection is reduced to 70 ℃, monitoring that the dissolved oxygen is below 1.0mg/L, adding leucine, isoleucine, phenylalanine, valine and methionine with the corresponding amounts in the table; stirring until the mixture is dissolved;
4. cooling to 50deg.C under nitrogen protection, adding threonine, lysine acetate, arginine, histidine, alanine, glycine, proline and serine in the corresponding amounts, and stirring to dissolve completely; after complete dissolution, the pH was adjusted by adding glacial acetic acid solution in an amount of about 0.35% (v/v) of the total. The pH of the solution should be 6.0 after the addition is completed.
5. Adding 0.03% of medicinal active carbon (active carbon mass/solution volume, wetting with proper amount of water for injection) under the protection of nitrogen, and stirring at 40deg.C for 30min; back filtering for about 5min by a titanium rod, then conveying the solution into another clean liquid preparation tank, and stirring under the protection of nitrogen;
6. monitoring that dissolved oxygen is below 1.0 mg/L; adding tryptophan with a prescription amount, stirring and dissolving, adding 0.01% of medicinal active carbon (w/v, wetting with proper amount of water for injection), adding water for injection to 1000mL, and stirring at 40 ℃ for 15min;
7. filtering the liquid medicine by a microporous filter membrane with the thickness of 0.45 mu m and a microporous filter membrane with the thickness of 0.22 mu m under the protection of nitrogen to obtain the liquid medicine with the dissolved oxygen below 1.0 mg/L;
8. filling the liquid medicine into glass infusion bottles under the protection of nitrogen, vacuumizing and filling nitrogen into 500mL of each bottle, controlling the volume of air to be 100mL, controlling the residual oxygen in the headspace of the container to be less than 1.0%, pressing a plug, rolling a cover, sterilizing at 121 ℃ for 10 minutes, and performing lamp inspection to obtain the liquid medicine.
Effect example 1 test of dissolved oxygen and headspace oxygen limitation
Referring to the prescription and preparation process of example 1 (but only introducing nitrogen in the whole process, not performing nitrogen replacement, not vacuumizing and filling nitrogen to press the plug, the used water for injection is not subjected to deoxygenation filtering membrane treatment), compound amino acid injection (14 AA) is prepared, and the difference is only that the dissolved oxygen in the compound amino acid injection (14 AA) and the content of the headspace oxygen in the glass infusion bottle during storage are controlled to be different, as shown in Table 1. In addition, the blank control ck refers to the compound amino acid injection 14AA prepared according to a preparation method conventional in the art, namely, the dissolved oxygen in the compound amino acid injection 14AA and the content of the headspace oxygen in the glass infusion bottle during storage are not additionally controlled.
Table 1 content of dissolved oxygen and headspace oxygen in the samples
| Numbering device | ck | 1 | 2 | 3 | 4 | 5 | 6 |
| Dissolved oxygen (mg/L) | 7.5 | 3.0 | 3.2 | 3.4 | 3.6 | 3.8 | 4.0 |
| Headspace oxygen (%) | 20.2 | 2.8 | 3.2 | 3.6 | 4.0 | 4.4 | 4.8 |
Blank (ck): the dissolved oxygen and the headspace oxygen were not controlled (dissolved oxygen in the solution was 7.5mg/L, headspace oxygen was 20.2%).
Test group (1-6): each group of 30 bottles, the samples of the test group were placed in a 60 ℃ incubator, kept air circulation, and were sampled and inspected for properties, transmittance, pH value, etc. on days 0, 5, 10, and the test effect was determined from the inspection results on day 10, and the results are shown in Table 2.
Table 2 table of test conditions for limitation of dissolved oxygen and headspace oxygen in samples
The test results show that: samples that were not nitrogen-filled were unstable during storage; by controlling the nitrogen filling, the dissolved oxygen is controlled at 3.0mg/L, the headspace oxygen is controlled at 2.8%, and the combined sample is still unqualified and needs improvement.
Effect example 2 residual oxygen amount: test of dissolved oxygen and headspace oxygen limitation
Referring to the prescription and preparation process of example 1 (but nitrogen is only fully introduced during the preparation process, nitrogen replacement is not performed, the used water for injection is not subjected to deoxygenation filtration membrane treatment), a compound amino acid injection (14 AA) sample is prepared, nitrogen is fully introduced during the preparation process, and the novel filling machine capable of performing vacuum pumping synchronously performs vacuum pumping during filling, wherein the limits of dissolved oxygen and headspace oxygen in the sample are shown in table 3:
TABLE 3 limitation of dissolved oxygen and headspace oxygen in samples
| Test group | Ck | 1 | 2 | 3 | 4 | 5 | 6 |
| Dissolved oxygen (mg/L) | 7.5 | 2.9 | 3.1 | 3.3 | 3.5 | 3.7 | 3.9 |
| Headspace oxygen (%) | 20.2 | 0.7 | 0.9 | 1.1 | 1.3 | 1.5 | 1.7 |
In the preparation process, nitrogen is simply introduced, and vacuum pumping is performed at the same time when filling, the dissolved oxygen of the sample can only be controlled between 2.9 and 3.9mg/L, and the headspace oxygen can be controlled between 0.7 and 1.7 percent.
Blank (ck): and the nitrogen is not filled (the dissolved oxygen in the solution is 7.5mg/L and the headspace oxygen is 20.2 percent when the nitrogen is not filled).
Each group of 30 bottles was tested, the test samples were placed in a 60℃incubator, kept air-circulated, and the samples were sampled and examined for their properties, tryptophan marker content, etc. on days 0,5, 10, and the test results were determined on day 10, with the results shown in Table 4.
Table 4 table of test conditions for limits of dissolved oxygen and headspace oxygen in samples
The test results show that: samples that were not nitrogen-filled were unstable during storage; in the preparation process, nitrogen is introduced in the whole process, the novel vacuumizing filling machine is used for vacuumizing synchronously during filling, the dissolved oxygen can only be controlled at 2.9mg/L, the headspace oxygen is controlled at 0.7%, the sample combined with the dissolved oxygen and the headspace oxygen is still unqualified, and the sample is obviously improved compared with the sample filled with nitrogen only, and the improvement is still needed.
Effect example 3 residual oxygen amount: test of dissolved oxygen and headspace oxygen limitation
Referring to the prescription and preparation process of example 1 (but the water for injection is not treated by an deoxidizing filtration membrane), a compound amino acid injection (14 AA) sample is prepared, a vacuum pump is added on a preparation tank, vacuum pumping and nitrogen filling are simultaneously carried out in the preparation process, vacuum pumping is continuously carried out during filling, and the limits of dissolved oxygen and headspace oxygen in the sample are shown in Table 5:
TABLE 5 limitation of dissolved oxygen and headspace oxygen in samples
| Test group | Ck | 1 | 2 | 3 | 4 |
| Dissolved oxygen (mg/L) | 7.5 | 1.1 | 1.3 | 1.5 | 1.7 |
| Headspace oxygen (%) | 20.2 | 0.5 | 1.0 | 1.5 | 1.7 |
The vacuum pumping and nitrogen filling are carried out simultaneously in the preparation process, the vacuum pumping is carried out continuously during the filling, the dissolved oxygen of the sample can be controlled between 1.1 and 1.7mg/L, and the headspace oxygen can be controlled between 0.5 and 1.7 percent.
Blank (ck): and the nitrogen is not filled (the dissolved oxygen in the solution is 7.5mg/L and the headspace oxygen is 20.2 percent when the nitrogen is not filled).
Each group of 30 bottles was tested, the test samples were placed in a 60℃incubator, kept air-circulated, and the samples were sampled and examined for their properties, tryptophan marker content, etc. on days 0,5, 10, and the test results were determined on day 10, with the results shown in Table 6.
TABLE 6 test conditions Table of limits of dissolved oxygen and headspace oxygen in samples
The test results show that: samples that were not nitrogen-filled were unstable during storage; in the preparation process, vacuumizing and nitrogen filling are carried out simultaneously, vacuumizing is carried out continuously during filling, the dissolved oxygen is controlled below 1.5mg/L, the headspace oxygen is controlled below 1.5%, and the sample is still unqualified.
Effect example 4 residual oxygen amount: test of dissolved oxygen and headspace oxygen limitation
According to the prescription and the preparation process of the invention, a compound amino acid injection (14 AA) sample is prepared, a dissolved oxygen absorber (namely an deoxidizing filtering membrane) is additionally arranged on an injection water preparation device, the absorbed injection water is added into a preparation tank, a vacuum pump is additionally arranged on the preparation tank, the vacuum pumping and the nitrogen filling are simultaneously carried out in the preparation process, the vacuum pumping is continuously carried out during the filling, and the limit of dissolved oxygen and headspace oxygen in the sample is shown in Table 7:
TABLE 7 limitation of dissolved oxygen and headspace oxygen in samples
| Test group | Ck | 1 | 2 | 3 | 4 |
| Dissolved oxygen (mg/L) | 7.5 | 0.8 | 1.0 | 1.2 | 1.5 |
| Headspace oxygen (%) | 20.2 | 0.5 | 1.0 | 1.5 | 1.5 |
The vacuum pumping and nitrogen filling are carried out simultaneously in the preparation process, the vacuum pumping is carried out continuously during the filling, the dissolved oxygen of the sample can only be controlled between 0.8 and 1.5mg/L, and the headspace oxygen can be controlled between 0.5 and 1.5 percent.
Blank (ck): and the nitrogen is not filled (the dissolved oxygen in the solution is 7.5mg/L and the headspace oxygen is 20.2 percent when the nitrogen is not filled).
Each group of 30 bottles was tested, the test samples were placed in a 60℃incubator, kept air-circulated, and the samples were sampled and examined for their properties, tryptophan marker content, etc. on days 0,5, 10, and the test results were determined on day 10, with the results shown in Table 8.
Table 8 table of test conditions for limits of dissolved oxygen and headspace oxygen in samples
The test results show that: the dissolved oxygen of the final sample can be controlled below 1.0mg/L, the headspace oxygen can be controlled below 1.0%, and the samples are all qualified. When the dissolved oxygen is controlled below 1.0mg/L, the degradation amount of tryptophan is obviously reduced along with the reduction of headspace oxygen; when the headspace oxygen is controlled below 1.0%, the degradation amount of tryptophan is obviously reduced along with the reduction of dissolved oxygen; we consider that: simultaneously, the dissolved oxygen and the headspace oxygen in the container are controlled to have stronger protection effect on amino acid.
Effect example 5 stability comparison test of sample and sodium bisulfite-containing like product
Test group 1: according to the invention, the compound amino acid injection 14AA is prepared according to the embodiment 1, and the dissolved oxygen content in the prepared compound amino acid injection 14AA is controlled to be 1.0mg/L, and the headspace oxygen content is controlled to be 1.0%.
Test group 2: volume 06E 6-81, which refers to the standards issued by the ministry of health (two parts), specifies that sodium bisulphite is contained in an amount of 0.50g/L, which is the same as the like products currently on the market.
The samples of test group 1 and test group 2 were placed in a 60 ℃ incubator using an accelerated test method to increase their oxidation rate. If the stability is maintained under accelerated conditions, the stability under light shielding conditions is better at 5-25 ℃. 40 bottles of samples are prepared in each of the test group 1 and the test group 2, 10 bottles of samples are taken and respectively placed in a constant temperature box at 60 ℃ to be placed, and air circulation is kept. Samples were tested for appearance and tryptophan content on days 5, 10, and 30 according to the Ministry of health (Ministry of health) release (Ministry of health) Standard, volume 06, E6-81, and the results are shown in tables 9, 10, 11, and 12.
TABLE 9 Properties of samples at day 0, tryptophan content
TABLE 10 Properties and tryptophan content of samples at day 5
The higher the tryptophan content, which can reflect the extent to which the sample is oxidized, the less the sample is oxidized, indicating that the better the stability of the sample, compared to the 0 day results. The results show that: the test samples of the two groups have no significant difference in the properties and tryptophan content on day 5.
TABLE 11 Properties and tryptophan content of samples at day 10
And compared with the results of 0 day and 5 days, the characteristics and tryptophan content of the two groups of test samples at the 10 th day show slight differences, and the quality of the products obtained by the test groups 1 and 2 is totally qualified through an acceleration test.
Table 12 Properties and tryptophan content of the samples at day 30
Compared with the results of 0 day, 5 days and 10 days, the 30 th-day characters and tryptophan contents of the two groups of test samples show slight differences, and the quality of the products obtained by the test groups 1 and 2 is totally qualified through the accelerated test.
From the experimental results, the content of the dissolved oxygen and the headspace oxygen in the compound amino acid injection 14AA is controlled, so that the properties, tryptophan content and the like of the sample are not obviously different from those of the sodium bisulfite-containing sample on days 0, 5, 10 and 30 under the condition of not adding sodium bisulfite, and the requirements of the national standard of medicines are completely met.
Effect example 6 sample quality detection
The product after 180 days of acceleration test is checked according to the standard of drug standard issued by Ministry of health (two parts) volume 06E 6-81, "Compound amino acid injection (14 AA)".
The detection result shows that: the compound amino acid injection 14AA prepared according to the example 1, wherein the dissolved oxygen content is controlled to be 1.0mg/L, and the headspace oxygen content is controlled to be 1.0%. Each index of the sample is qualified, and the product is qualified. The specific test results are shown in tables 13 and 14.
TABLE 13 quality detection results of injection of pharmaceutical composition containing 14 amino acids
TABLE 14 quality detection results of injection of pharmaceutical composition containing 14 amino acids
From the above detection results, the compound amino acid injection 14AA prepared according to example 1, wherein the dissolved oxygen content was controlled to be 1.0mg/L, the headspace oxygen content was controlled to be 1.0%, and the results were confirmed to be in compliance with the regulations by test in accordance with the Ministry of health (division II) release drug standard, volume 06, E6-81. In the acceleration test of 6 months, each index of the sample has no obvious change, which indicates that the quality of the prepared sample is stable.
Claims (5)
1. A method for preparing a pharmaceutical composition stored in a container, the pharmaceutical composition comprising isoleucine, leucine, lysine acetate, methionine, phenylalanine, threonine, tryptophan, valine, alanine, arginine, histidine, proline, serine, glycine, a pH adjustor, and water;
The mass volume ratio of the isoleucine to the water is 5.31-6.49g/L;
the mass volume ratio of the leucine to the water is 6.93-8.47g/L;
the mass volume ratio of the lysine acetate to the water is 7.83-9.57g/L;
the mass volume ratio of the methionine to the water is 4.05-4.95g/L;
the mass volume ratio of the phenylalanine to the water is 4.32-5.28g/L;
the mass volume ratio of threonine to water is 3.06-3.74g/L;
the mass volume ratio of the tryptophan to the water is 1.17-1.43g/L;
the mass volume ratio of the valine to the water is 5.04-6.16g/L;
the mass volume ratio of the alanine to the water is 5.40-6.60g/L;
the mass volume ratio of the arginine to the water is 7.28-8.91g/L;
the mass volume ratio of the histidine to the water is 2.16-2.64g/L;
the mass volume ratio of the proline to the water is 8.55-10.45g/L;
the mass volume ratio of serine to water is 4.50-5.50g/L;
the mass volume ratio of the glycine to the water is 10.71-13.09g/L;
the content of dissolved oxygen in the pharmaceutical composition is below 1.0 mg/L; the pH value of the pharmaceutical composition is 5.5-6.5;
The pharmaceutical composition does not contain an antioxidant;
the pharmaceutical composition does not contain a metal ion chelating agent;
the preparation method of the pharmaceutical composition stored in the container comprises the following steps:
(1) Mixing part of the water with the isoleucine, the leucine, the methionine, the valine and the phenylalanine in a nitrogen atmosphere to obtain a liquid medicine 1;
(2) Mixing the liquid medicine 1 with the lysine acetate, the threonine, the arginine, the histidine, the alanine, the glycine, the proline and the serine in a nitrogen atmosphere, adding the pH value regulator to enable the pH value to be 5.5-6.5, and then adding the rest of water to obtain liquid medicine 2;
(3) Mixing the liquid medicine 2 with active carbon in nitrogen atmosphere, and then removing the active carbon to obtain liquid medicine 3;
(4) Mixing the liquid medicine 3 with the tryptophan, the activated carbon and the rest of the water under the nitrogen atmosphere, and finely filtering to obtain a pharmaceutical composition containing 14 amino acids;
(5) Storing the pharmaceutical composition containing 14 amino acids in a container, wherein gas exists in the container, and the volume percentage of oxygen in the gas is below 1.0%, so as to obtain the pharmaceutical composition stored in the container;
The mixing is under the monitoring of the content of dissolved oxygen, and when the content of the dissolved oxygen of the composition in the mixing process is found to be larger than the upper limit of the content of the dissolved oxygen in the pharmaceutical composition, nitrogen substitution is carried out;
in the step (3), the mass-to-volume ratio of the active carbon to the pharmaceutical composition is 0.0003g/ml;
in the step (4), the mass-volume ratio of the active carbon to the pharmaceutical composition is 0.0001g/ml.
2. The method of claim 1, wherein the mass to volume ratio of isoleucine to water is 5.9g/L;
and/or the mass-to-volume ratio of the leucine to the water is 7.7g/L;
and/or the mass-volume ratio of the lysine acetate to the water is 8.7g/L;
and/or the mass-to-volume ratio of methionine to water is 4.5g/L;
and/or the mass-to-volume ratio of the phenylalanine to the water is 4.8g/L;
and/or the mass-to-volume ratio of threonine to water is 3.4g/L;
and/or the mass-to-volume ratio of the tryptophan to the water is 1.3g/L;
and/or the mass-to-volume ratio of valine to water is 5.6g/L;
And/or the mass-to-volume ratio of the alanine to the water is 6.0g/L;
and/or the mass-to-volume ratio of the arginine to the water is 8.1g/L;
and/or the mass-to-volume ratio of the histidine to the water is 2.4g/L;
and/or the mass-to-volume ratio of the proline to the water is 9.5g/L;
and/or the mass-to-volume ratio of serine to water is 5.0g/L;
and/or the mass-volume ratio of the glycine to the water is 11.9g/L;
and/or the pH of the pharmaceutical composition is 6.0;
and/or the pH value regulator is one or two of glacial acetic acid, citric acid aqueous solution, acetic acid aqueous solution, sodium citrate aqueous solution and sodium acetate aqueous solution;
and/or, the lysine acetate is present in the pharmaceutical composition in the form of lysine;
and/or, the water is water for injection;
and/or the content of dissolved oxygen in the pharmaceutical composition is below 0.8 mg/L;
and/or, the pharmaceutical composition is in the form of a homogeneous solution;
and/or, the pharmaceutical composition is used for parenteral support of patients with acute and chronic renal insufficiency; severe renal failure due to major surgery, trauma or sepsis, and acute and chronic renal failure.
3. The method of preparing a pharmaceutical composition stored in a container according to claim 2, wherein the aqueous solution of citric acid has a concentration of 0.1mol/L;
and/or the concentration of the acetic acid aqueous solution 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 content of dissolved oxygen in the pharmaceutical composition is below 0.5 mg/L;
and/or the pharmaceutical composition is in the form of injection.
4. A method of preparing a pharmaceutical composition stored in a container according to claim 3, wherein the injectable solution is a bolus infusion solution.
5. The method of claim 4, wherein said pharmaceutical composition comprises said isoleucine, said leucine, said lysine acetate, said methionine, said phenylalanine, said threonine, said tryptophan, said valine, said alanine, said arginine, said histidine, said proline, said serine, said glycine, said pH adjustor, and said water.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101357118A (en) * | 2008-09-26 | 2009-02-04 | 郑飞雄 | Medicine composition containing 15 kinds of amino acid and preparation method thereof |
| CN102743379A (en) * | 2012-07-30 | 2012-10-24 | 李慧 | Composition containing eighteen amino acids |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101357118A (en) * | 2008-09-26 | 2009-02-04 | 郑飞雄 | Medicine composition containing 15 kinds of amino acid and preparation method thereof |
| CN102743379A (en) * | 2012-07-30 | 2012-10-24 | 李慧 | Composition containing eighteen amino acids |
Non-Patent Citations (1)
| Title |
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| 黄明秋等."14-氨基酸注射液800.《药理学》.1986,第148页. * |
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