CN109381460B - Pharmaceutical composition containing 18 amino acids and preparation method thereof - Google Patents

Pharmaceutical composition containing 18 amino acids and preparation method thereof Download PDF

Info

Publication number
CN109381460B
CN109381460B CN201710677077.6A CN201710677077A CN109381460B CN 109381460 B CN109381460 B CN 109381460B CN 201710677077 A CN201710677077 A CN 201710677077A CN 109381460 B CN109381460 B CN 109381460B
Authority
CN
China
Prior art keywords
water
volume ratio
pharmaceutical composition
mass
dissolved oxygen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201710677077.6A
Other languages
Chinese (zh)
Other versions
CN109381460A (en
Inventor
甘丰瑞
饶萌
喻颖利
甘周阳
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wuhan Yibantian Technology Development Co ltd
Hubei Halfsky Pharmaceuticals Co ltd
Original Assignee
Wuhan Yibantian Technology Development Co ltd
Hubei Halfsky Pharmaceuticals Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wuhan Yibantian Technology Development Co ltd, Hubei Halfsky Pharmaceuticals Co ltd filed Critical Wuhan Yibantian Technology Development Co ltd
Priority to CN201710677077.6A priority Critical patent/CN109381460B/en
Publication of CN109381460A publication Critical patent/CN109381460A/en
Application granted granted Critical
Publication of CN109381460B publication Critical patent/CN109381460B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • A61K31/33—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
    • 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]
    • 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
    • A61K31/33—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
    • 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
    • A61K31/33—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention discloses a pharmaceutical composition containing 18 amino acids and a preparation method thereof. The invention provides a pharmaceutical composition containing 18 amino acids, which comprises tyrosine, leucine, isoleucine, phenylalanine, aspartic acid, valine, threonine, proline, methionine, glutamic acid, lysine acetate, arginine, alanine, glycine, histidine, serine, tryptophan, cysteine, 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

Pharmaceutical composition containing 18 amino acids and preparation method thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a pharmaceutical composition containing 18 amino acids and a preparation method thereof.
Background
The compound amino acid injection (18 AA-IX) is a sterilized water solution prepared by adding auxiliary materials into 18 amino acids, and is clinically used for patients with acute and chronic renal insufficiency to develop hypoalbuminemia, hypotrophic state and amino acid supplementation before and after operation.
The compound amino acid injection (18 AA-IX) of the national food and drug administration standard WS1-XG-022-2011-2012 contains 0.50g of sodium bisulfite per liter (18 AA-IX) of the injection.
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 part of amino acid in the amino acid solution is easy to oxidize, an antioxidant is needed 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.
So far, no Chinese patent application related to compound amino acid injection (18 AA-IX) has been searched.
It is therefore worth studying to explore the production of 18 amino acid pharmaceutical compositions free of sulfites.
Disclosure of Invention
The invention aims to solve the technical problems that the existing 18 amino acid pharmaceutical composition contains antioxidants so as to cause various adverse reactions and the like, so that the invention provides the 18 amino acid pharmaceutical composition and the preparation method thereof, and the pharmaceutical composition can not contain sulfite antioxidants, so that the potential safety hazard of sulfite to human bodies can be thoroughly eliminated, the clinical use is safer, and the effective period is longer.
The invention provides a pharmaceutical composition containing 18 amino acids, which comprises tyrosine, leucine, isoleucine, phenylalanine, aspartic acid, valine, threonine, proline, methionine, glutamic acid, lysine acetate, arginine, alanine, glycine, histidine, serine, tryptophan, cysteine, a pH value regulator, and water;
The mass volume ratio of the tyrosine to the water is 0.475-0.525 g/L;
the mass volume ratio of the leucine to the water is 9.200-10.800 g/L;
the mass volume ratio of the isoleucine to the water is 6.900-8.100 g/L;
the mass volume ratio of the phenylalanine to the water is 4.750-5.250 g/L;
the mass volume ratio of the aspartic acid to the water is 0.230-0.270 g/L;
the mass volume ratio of valine to water is 6.900-8.100 g/L;
the mass volume ratio of threonine to water is 2.300-2.700 g/L;
the mass volume ratio of the proline to the water is 1.840-2.160 g/L;
the mass volume ratio of the methionine to the water is 4.600-5.400 g/L;
the mass volume ratio of the glutamic acid to the water is 0.230-0.270 g/L;
the mass volume ratio of the lysine acetate to the water is 6.440-7.560 g/L;
the mass volume ratio of the arginine to the water is 2.760-3.240 g/L;
the mass volume ratio of the alanine to the water is 2.760-3.240 g/L;
The mass volume ratio of the glycine to the water is 1.380-1.620 g/L;
the mass volume ratio of the histidine to the water is 2.300-2.700 g/L;
the mass volume ratio of serine to water is 0.920-1.080 g/L;
the mass volume ratio of the tryptophan to the water is 2.300-2.700 g/L;
the mass volume ratio of the cysteine to the water is 0.230-0.270 g/L;
the content of dissolved oxygen in the pharmaceutical composition is below 1.5 mg/L; the pH of the pharmaceutical composition is 5.5-6.5 (e.g., 6.0).
The mass-volume ratio of the tyrosine to the water can be 0.50g/L.
The mass-volume ratio of the leucine to the water can be 10.00g/L.
The mass-to-volume ratio of the isoleucine to the water can be 7.50g/L.
The mass-volume ratio of the phenylalanine to the water can be 5.00g/L.
The mass-to-volume ratio of the aspartic acid to the water can be 0.25g/L.
The mass volume ratio of valine to water can be 7.50g/L.
The mass-volume ratio of threonine to water can be 2.50g/L.
The mass volume ratio of the proline to the water can be 2.0g/L.
The mass-to-volume ratio of methionine to water can be 5.0g/L.
The mass-volume ratio of the glutamic acid to the water can be 0.25g/L.
The mass-volume ratio of the lysine acetate to the water can be 7.00g/L.
The mass-volume ratio of the arginine to the water can be 3.00g/L.
The mass-volume ratio of the alanine to the water can be 3.00g/L.
The mass volume ratio of the glycine to the water can be 1.50g/L.
The mass-volume ratio of the histidine to the water can be 2.50g/L.
The mass-volume ratio of serine to water can be 1.00g/L.
The mass-volume ratio of tryptophan to water can be 2.50g/L.
The mass-volume ratio of the cysteine to the water can be 0.25g/L.
The pH adjustor is used for adjusting the pH of the pharmaceutical composition, and may be one or two of pH adjustor conventionally used in the art, such as aqueous citric acid solution, aqueous acetic acid solution, aqueous sodium citrate solution, and aqueous sodium acetate solution. 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 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. Other amino acids are as such.
The lysine acetate may be present in the pharmaceutical composition in the form of lysine. Other amino acids are as such.
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 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 tyrosine, the leucine, the isoleucine, the phenylalanine, the aspartic acid, the valine, the threonine, the proline, the methionine, the glutamic acid, the lysine acetate, the arginine, the alanine, the glycine, the histidine, the serine, the tryptophan, the cysteine, the pH adjustor, and the water.
The content of dissolved oxygen in the pharmaceutical composition can be less than 1.3mg/L, less than 1.2mg/L, less than 1.1mg/L, less than 1.0mg/L, 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 amino acid supplementation before and after hypoalbuminemia, hypotrophic state or operation of patients with acute and chronic renal insufficiency.
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 carried out at 121 ℃ for 8 minutes.
The invention also provides a preparation method of the 18 amino acid-containing pharmaceutical composition, which comprises the following steps:
mixing the components under nitrogen atmosphere to obtain a pharmaceutical composition containing 18 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., 1.5mg/L, 1.3mg/L, 1.2mg/L, 1.1mg/L, 1.0mg/L, 0.8mg/L, or 0.5 mg/L), nitrogen substitution is performed (i.e., evacuation < means to withdraw a part of gas, the degree of withdrawal may be determined by a person skilled in the art, nitrogen filling is performed, the time for which the nitrogen substitution is performed may be determined by a person skilled in the art, depending on the situation), or may be performed at the end, and the number of times of the nitrogen substitution may be determined by a person in the art depending on the situation, so 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.g., 1.5mg/L, 1.3mg/L, 1.8 mg/L, 1.0.5 mg/L, 0.1.5 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 tyrosine, the leucine, the isoleucine, the valine, the aspartic acid, the phenylalanine and the methionine in a nitrogen atmosphere to obtain a liquid medicine 1;
(2) Mixing the liquid medicine 1 with threonine, proline, glutamic acid, lysine acetate, arginine, alanine, glycine, histidine and serine in nitrogen atmosphere 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 under the nitrogen atmosphere to obtain liquid medicine 4;
(5) Mixing the liquid medicine 4 with the cysteine under the nitrogen atmosphere, adding the pH value regulator to enable the pH value to be 5.5-6.5, and then adding the rest water to obtain liquid medicine 5;
(6) Fine filtering the liquid medicine 5 in nitrogen atmosphere to obtain a pharmaceutical composition containing 18 amino acids;
when the above steps (e.g., one or more of steps 1, 2, 3, 4, 5 and 6, e.g., all of steps 6, e.g., at least step 6) are monitored for dissolved oxygen content, then a nitrogen substitution (i.e., evacuating < means evacuating a portion of the gas, the extent of evacuation may be determined by a person skilled in the art, filling with nitrogen gas, the time for which the nitrogen substitution may be determined by a person skilled in the art, if the dissolved oxygen content is found to be greater than the upper limit of dissolved oxygen content in the pharmaceutical composition (e.g., 1.5mg/L, 1.3mg/L, 1.2mg/L, 1.1mg/L, 1.0mg/L, 0.8mg/L, or 0.5 mg/L) is performed, and the time for which the nitrogen substitution may be determined by a person skilled in the art, if the dissolved oxygen content is found to be greater than the upper limit of dissolved oxygen content in the pharmaceutical composition, and the combination may be determined to be less than the upper limit of dissolved oxygen content of 1.5mg/L, e.g., 1.1mg/L, 1.0mg/L, 0.0 mg/L, 0.8mg/L, 0.5mg/L or 0.5mg/L is performed by a person skilled in the art).
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 70% of the total amount.
In step (1) above, a "portion of the water" may be treated by methods conventional in the art, such as: and water subjected to heat preservation under nitrogen atmosphere. The nitrogen atmosphere is as described above. The temperature of the heat preservation can be 70-80 ℃, and the time of the heat preservation can be 15min.
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 above step (1), the temperature at the time of the mixing may be a temperature conventional in the art, for example, 70 to 80 ℃.
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 45 ℃.
In the above step (2), the temperature at the time of the mixing may be a temperature conventional in the art, for example, 40 to 45 ℃.
In the step (3), the activated carbon may be activated carbon conventional in the art, for example, activated carbon (for injection) specified in the chinese pharmacopoeia 2015. The mass to volume ratio of the activated carbon to the pharmaceutical composition may be conventional in the art, for example 0.5g/L. The activated carbon may be first wetted with the water when in use.
In the step (3), the liquid medicine 2 and the activated carbon may be mixed for a time period which is conventional in the art, for example, for 15 minutes until the adsorption is completed.
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 filter 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, 30 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 to 45 ℃.
In the above step (4), the temperature at the time of the mixing may be a temperature conventional in the art, for example, 40 to 45 ℃.
In the above step (5), the "remaining water" means water obtained by subtracting the "part of the water" in the step (1), for example, 30% of the total amount.
In the step (5), 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 step (5), the temperature at the time of the mixing may be a temperature conventional in the art, for example, 40 to 45 ℃.
In the step (6), 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 above step (6), the temperature at the time of the mixing may be a temperature conventional in the art, for example, 40 to 45 ℃.
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., 1.5mg/L, 1.3mg/L, 1.2mg/L, 1.1mg/L, 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 18 amino acid-containing pharmaceutical composition, the 18 amino acid-containing pharmaceutical composition is prepared;
(2) The pharmaceutical composition containing 18 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 carried out at 121 ℃ for 8 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 1.5%.
The volume ratio of the gas to the container may be conventional in the art (i.e., the volume ratio remaining in the container after conventional filling), for example, 0.06 to 0.20, still for example, 0.08 to 0.12, still for example, 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 1.0 percent, and can also be below 0.5 percent.
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 carried out at 121 ℃ for 8 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: the compound amino acid injection can be stably stored under the condition of not containing the pyrosulfite or sulfite antioxidant by controlling the content of dissolved oxygen in the injection and the content of oxygen in the headspace of the injection storage container, so that the harm of the pyrosulfite or sulfite antioxidant to human bodies is thoroughly solved. 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 18AA
The components and the amounts of the components in the compound amino acid injection 18AA are shown in the following table:
tyrosine 0.50g Glutamic acid 0.25g
Leucine (leucine) 10.00g Lysine acetate 7.00g
Isoleucine (Ile) 7.50g Arginine (Arg) 3.00g
Phenylalanine (Phe) 5.00g Alanine (Ala) 3.00g
Aspartic acid 0.25g Glycine (Gly) 1.50g
Valine (valine) 7.50g Histidine 2.50g
Threonine (Thr) 2.50g Serine (serine) 1.00g
Proline (proline) 2.00g Tryptophan 2.50g
Methionine 5.00g Cysteine (S) 0.25g
Acetic acid solution of 0.1mol/L Proper amount of Water for injection Proper amount of
The total amount was 1000ml.
The preparation method comprises the following steps:
(1) Weighing each raw material and auxiliary materials according to the prescription;
(2) Taking 70% of the total amount of water for injection, keeping the water temperature at 70 ℃, performing nitrogen replacement operation on the reaction kettle for 3 times, and introducing nitrogen at a constant temperature.
(3) Under the protection of nitrogen flow, the dissolved oxygen is monitored to be less than 1.5mg/L, and the tyrosine, leucine, isoleucine, valine, aspartic acid, phenylalanine and methionine with the prescribed amounts are added. Stirring until dissolved.
(4) Cooling to 40deg.C under nitrogen flow protection, adding threonine, proline, glutamic acid, lysine acetate, arginine, alanine, glycine, histidine and serine, and stirring to dissolve. 0.05% activated carbon (w/v, wetted with appropriate amount of water for injection) was added and adsorbed at 40℃for 15min. The solution was filtered back through a titanium core filter (pore size 3 μm) for 30min.
(5) Under the protection of nitrogen flow, monitoring that the dissolved oxygen is below 1.5mg/L, adding the tryptophan with the prescription amount, adding the cysteine with the prescription amount after complete dissolution, and adding the acetic acid solution with the concentration of 0.1mol/L after complete dissolution, so that the pH value is 6.0, and fixing the volume.
(6) Filtering the liquid medicine through a 0.45 mu m and 0.22 mu m polyether sulfone microporous filter element under the protection of nitrogen flow to obtain the liquid medicine with dissolved oxygen below 1.5 mg/L.
(7) The liquid medicine was filled into 200ml infusion bottles under nitrogen flow protection, wherein the air volume was 20ml. Vacuum pumping, nitrogen filling, plugging, controlling the headspace oxygen below 1.5%, capping, sterilizing at 121deg.C for 8 min under wet heat, and inspecting.
EXAMPLE 2 preparation of Compound amino acid injection 18AA
The components and the amounts of the components in the compound amino acid injection 18AA are shown in the following table:
tyrosine 0.475g Glutamic acid 0.230g
Leucine (leucine) 9.200g Lysine acetate 6.440g
Isoleucine (Ile) 6.900g Arginine (Arg) 2.760g
Phenylalanine (Phe) 4.750g Alanine (Ala) 2.760g
Aspartic acid 0.230g Glycine (Gly) 1.380g
Valine (valine) 6.900g Histidine 2.300g
Threonine (Thr) 2.300g Serine (serine) 0.920g
Proline (proline) 1.840g Tryptophan 2.300g
Methionine 4.600g Cysteine (S) 0.230g
0.1mol/L sodium acetate solution Proper amount of Water for injection Proper amount of
The total amount was 1000ml.
The preparation method comprises the following steps:
(1) Weighing each raw material and auxiliary materials according to the prescription;
(2) Taking 70% of the total amount of water for injection, keeping the water temperature at 80 ℃, performing nitrogen replacement operation on the reaction kettle for 3 times, and introducing nitrogen at a constant temperature.
(3) Under the protection of nitrogen flow, the dissolved oxygen is monitored to be less than 1.3mg/L, and the tyrosine, leucine, isoleucine, valine, aspartic acid, phenylalanine and methionine with the prescribed amounts are added. Stirring until dissolved.
(4) Cooling to 45deg.C under nitrogen flow protection, adding threonine, proline, glutamic acid, lysine acetate, arginine, alanine, glycine, histidine and serine, and stirring to dissolve. 0.05% activated carbon (w/v, wetted with appropriate amount of water for injection) was added and adsorbed at 45℃for 15min. The solution was filtered back through a titanium core filter (pore size 3 μm) for 30min.
(5) Under the protection of nitrogen flow, monitoring that the dissolved oxygen is below 1.3mg/L, adding the tryptophan with the prescription amount, adding the cysteine with the prescription amount after complete dissolution, and adding the sodium acetate solution with the concentration of 0.1mol/L after complete dissolution, so that the pH value is 6.5, and fixing the volume.
(6) Filtering the liquid medicine through a 0.45 mu m and 0.22 mu m polyether sulfone microporous filter element under the protection of nitrogen flow to obtain the liquid medicine with the dissolved oxygen below 1.3 mg/L.
(7) The liquid medicine was filled into 100ml infusion bottles under the protection of nitrogen flow, wherein the air volume was 6ml. Vacuum pumping, nitrogen filling, plugging, controlling the headspace oxygen below 1.5%, capping, sterilizing at 121deg.C for 8 min under wet heat, and inspecting.
Example 3 preparation of Compound amino acid injection 18AA
The components and the amounts of the components in the compound amino acid injection 18AA are shown in the following table:
the total amount was 1000ml.
The preparation method comprises the following steps:
(1) Weighing each raw material and auxiliary materials according to the prescription;
(2) Taking 70% of the total amount of water for injection, keeping the water temperature at 70 ℃, performing nitrogen replacement operation on the reaction kettle for 3 times, and introducing nitrogen at a constant temperature.
(3) Under the protection of nitrogen flow, the dissolved oxygen is monitored to be below 0.5mg/L, and the tyrosine, leucine, isoleucine, valine, aspartic acid, phenylalanine and methionine with the prescribed amounts are added. Stirring until dissolved.
(4) Cooling to 40deg.C under nitrogen flow protection, adding threonine, proline, glutamic acid, lysine acetate, arginine, alanine, glycine, histidine and serine, and stirring to dissolve. 0.05% activated carbon (w/v, wetted with appropriate amount of water for injection) was added and adsorbed at 40℃for 15min. The solution was filtered back through a titanium core filter (pore size 3 μm) for 30min.
(5) Under the protection of nitrogen flow, monitoring that the dissolved oxygen is below 0.5mg/L, adding the tryptophan with the prescription amount, adding the cysteine with the prescription amount after complete dissolution, and adding the citric acid solution with the concentration of 0.1mol/L after complete dissolution, so that the pH value is 5.5, and fixing the volume.
(6) Filtering the liquid medicine through a 0.45 mu m and 0.22 mu m polyether sulfone microporous filter element under the protection of nitrogen flow to obtain the liquid medicine with dissolved oxygen below 0.5 mg/L.
(7) The liquid medicine was filled into 100ml infusion bottles under the protection of nitrogen flow, wherein the air volume was 12ml. Vacuum pumping, nitrogen filling, plugging, controlling the headspace oxygen below 0.5%, capping, sterilizing at 121deg.C for 8 min under wet heat, and inspecting.
EXAMPLE 4 preparation of Compound amino acid injection 18AA
The components and the amounts of the components in the compound amino acid injection 18AA are shown in the following table:
tyrosine 0.50g Glutamic acid 0.25g
Leucine (leucine) 10.00g Lysine acetate 7.00g
Isoleucine (Ile) 7.50g Arginine (Arg) 3.00g
Phenylalanine (Phe) 5.00g Alanine (Ala) 3.00g
Aspartic acid 0.25g Glycine (Gly) 1.50g
Valine (valine) 7.50g Histidine 2.50g
Threonine (Thr) 2.50g Serine (serine) 1.00g
Proline (proline) 2.00g Tryptophan 2.50g
Methionine 5.00g Cysteine (S) 0.25g
Sodium citrate solution of 0.1mol/L Proper amount of Water for injection Proper amount of
The total amount was 1000ml.
The preparation method comprises the following steps:
(1) Weighing each raw material and auxiliary materials according to the prescription;
(2) Taking 70% of the total amount of water for injection, keeping the water temperature at 70 ℃, performing nitrogen replacement operation on the reaction kettle for 3 times, and introducing nitrogen at a constant temperature.
(3) Under the protection of nitrogen flow, the dissolved oxygen is monitored to be less than 1.0mg/L, and the tyrosine, leucine, isoleucine, valine, aspartic acid, phenylalanine and methionine with the prescribed amounts are added. Stirring until dissolved.
(4) Cooling to 40deg.C under nitrogen flow protection, adding threonine, proline, glutamic acid, lysine acetate, arginine, alanine, glycine, histidine and serine, and stirring to dissolve. 0.05% activated carbon (w/v, wetted with appropriate amount of water for injection) was added and adsorbed at 40℃for 15min. The solution was filtered back through a titanium core filter (pore size 3 μm) for 30min.
(5) Under the protection of nitrogen flow, monitoring that the dissolved oxygen is below 1.0mg/L, adding the tryptophan with the prescription amount, adding the cysteine with the prescription amount after complete dissolution, and adding the sodium citrate solution with the concentration of 0.1mol/L after complete dissolution, so that the pH value is 5.5, and fixing the volume.
(6) Filtering the liquid medicine through a 0.45 mu m and 0.22 mu m polyether sulfone microporous filter element under the protection of nitrogen flow to obtain the liquid medicine with dissolved oxygen below 1.0 mg/L.
(7) The liquid medicine was filled into 250ml infusion bottles under nitrogen flow protection, wherein the air volume was 30ml. Vacuum pumping, nitrogen filling, plugging, controlling the headspace oxygen below 1.0%, capping, sterilizing at 121deg.C for 8 min under wet heat, and inspecting.
EXAMPLE 5 preparation of Compound amino acid injection 18AA
The components and the amounts of the components in the compound amino acid injection 18AA are shown in the following table:
tyrosine 0.50g Glutamic acid 0.25g
Leucine (leucine) 10.00g Lysine acetate 7.00g
Isoleucine (Ile) 7.50g Arginine (Arg) 3.00g
Phenylalanine (Phe) 5.00g Alanine (Ala) 3.00g
Aspartic acid 0.25g Glycine (Gly) 1.50g
Valine (valine) 7.50g Histidine 2.50g
Threonine (Thr) 2.50g Serine (serine) 1.00g
Proline (proline) 2.00g Tryptophan 2.50g
Methionine 5.00g Cysteine (S) 0.25g
Sodium citrate solution of 0.1mol/L Proper amount of Water for injection Proper amount of
The total amount was 1000ml.
The preparation method comprises the following steps:
(1) Weighing each raw material and auxiliary materials according to the prescription;
(2) Taking 70% of the total amount of water for injection, keeping the water temperature at 70 ℃, performing nitrogen replacement operation on the reaction kettle for 3 times, and introducing nitrogen at a constant temperature.
(3) Under the protection of nitrogen flow, the dissolved oxygen is monitored to be below 0.8mg/L, and the tyrosine, leucine, isoleucine, valine, aspartic acid, phenylalanine and methionine with the prescribed amounts are added. Stirring until dissolved.
(4) Cooling to 40deg.C under nitrogen flow protection, adding threonine, proline, glutamic acid, lysine acetate, arginine, alanine, glycine, histidine and serine, and stirring to dissolve. 0.05% activated carbon (w/v, wetted with appropriate amount of water for injection) was added and adsorbed at 40℃for 15min. The solution was filtered back through a titanium core filter (pore size 3 μm) for 30min.
(5) Under the protection of nitrogen flow, monitoring that the dissolved oxygen is below 0.8mg/L, adding the tryptophan with the prescription amount, adding the cysteine with the prescription amount after complete dissolution, adding the sodium citrate solution with the concentration of 0.1mol/L after complete dissolution, and keeping the pH value at 5.5 and constant volume.
(6) Filtering the liquid medicine through a 0.45 mu m and 0.22 mu m polyether sulfone microporous filter element under the protection of nitrogen flow to obtain the liquid medicine with dissolved oxygen below 0.8 mg/L.
(7) The liquid medicine was filled into 500ml infusion bottles under the protection of nitrogen flow, wherein the air volume was 50ml. Vacuum pumping, nitrogen filling, plugging, controlling the headspace oxygen below 1.0%, capping, sterilizing at 121deg.C for 8 min under wet heat, and inspecting.
EXAMPLE 6 preparation of Compound amino acid injection 18AA
The components and the amounts of the components in the compound amino acid injection 18AA are shown in the following table:
tyrosine 0.50g Glutamic acid 0.25g
Leucine (leucine) 10.00g Lysine acetate 7.00g
Isoleucine (Ile) 7.50g Arginine (Arg) 3.00g
Phenylalanine (Phe) 5.00g Alanine (Ala) 3.00g
Aspartic acid 0.25g Glycine (Gly) 1.50g
Valine (valine) 7.50g Histidine 2.50g
Threonine (Thr) 2.50g Serine (serine) 1.00g
Proline (proline) 2.00g Tryptophan 2.50g
Methionine 5.00g Cysteine (S) 0.25g
Sodium citrate solution of 0.1mol/L Proper amount of Water for injection Proper amount of
The total amount was 1000ml.
The preparation method comprises the following steps:
(1) Weighing each raw material and auxiliary materials according to the prescription;
(2) Taking 70% of the total amount of water for injection, keeping the water temperature at 70 ℃, performing nitrogen replacement operation on the reaction kettle for 3 times, and introducing nitrogen at a constant temperature.
(3) Under the protection of nitrogen flow, the dissolved oxygen is monitored to be less than 1.2mg/L, and the tyrosine, leucine, isoleucine, valine, aspartic acid, phenylalanine and methionine with the prescribed amounts are added. Stirring until dissolved.
(4) Cooling to 40deg.C under nitrogen flow protection, adding threonine, proline, glutamic acid, lysine acetate, arginine, alanine, glycine, histidine and serine, and stirring to dissolve. 0.05% activated carbon (w/v, wetted with appropriate amount of water for injection) was added and adsorbed at 40℃for 15min. The solution was filtered back through a titanium core filter (pore size 3 μm) for 30min.
(5) Under the protection of nitrogen flow, monitoring that the dissolved oxygen is below 1.2mg/L, adding the tryptophan with the prescription amount, adding the cysteine with the prescription amount after complete dissolution, and adding the sodium citrate solution with the concentration of 0.1mol/L after complete dissolution, so that the pH value is 5.5, and fixing the volume.
(6) Filtering the liquid medicine through a 0.45 mu m and 0.22 mu m polyether sulfone microporous filter element under the protection of nitrogen flow to obtain the liquid medicine with dissolved oxygen below 1.2 mg/L.
(7) The liquid medicine was filled into 500ml infusion bottles under the protection of nitrogen flow, wherein the air volume was 100ml. Vacuum pumping, nitrogen filling, plugging, controlling the headspace oxygen below 1.0%, capping, sterilizing at 121deg.C for 8 min under wet heat, and inspecting.
Effect example 1 residual oxygen amount: 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 of preparation, not performing nitrogen replacement, not vacuumizing and filling nitrogen to press plugs, and using water for injection without deoxidizing filtration membrane treatment), compound amino acid injection (18 AA-IX) samples were prepared, and the limits of dissolved oxygen and headspace oxygen in the samples are shown in Table 1:
Table 1 limits of dissolved oxygen and headspace oxygen in samples
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
In the preparation process, nitrogen is simply introduced, the dissolved oxygen of the sample can only be controlled between 3.0 and 4.0mg/L, and the headspace oxygen can only be controlled between 2.8 and 4.8 percent.
Blank (ck): and the nitrogen is not filled (the dissolved oxygen in the solution is 7.2mg/L and the headspace oxygen is 20.6 percent when the nitrogen is not filled).
Each group of 30 bottles was tested, the test samples were placed in a 60℃incubator and kept in air circulation, and the samples were sampled and examined for their properties, transmittance, cysteine content, etc. on days 0,5 and 10, and the test results were determined on the basis of the examination 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; if the dissolved oxygen and the headspace oxygen in the liquid medicine are controlled by introducing nitrogen only in the configuration process, the dissolved oxygen can be controlled at 3.0mg/L, the headspace oxygen is controlled at 2.8%, and the sample combined with the dissolved oxygen and the headspace oxygen is still unqualified, so that improvement is needed.
Effect example 2 residual oxygen amount: test of dissolved oxygen and headspace oxygen limitation
Referring to the recipe and preparation process of example 1 (but with only full nitrogen introduction and no nitrogen substitution during the formulation, the water for injection used was not treated with the deoxygenated filtration membrane), compound amino acid injection (18 AA-IX) samples were prepared, and the limits of dissolved oxygen and headspace oxygen in the samples 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) 7.2 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
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 7.2mg/L and the headspace oxygen is 20.6 percent when the nitrogen is not filled).
Each group of 30 bottles was tested, the test samples were placed in a 60℃incubator and kept in air circulation, and the samples were sampled and examined for their properties, transmittance, cysteine content, etc. on days 0,5 and 10, and the test results were determined on the basis of the examination results on day 10, and the results are 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; if nitrogen is only introduced in the whole process of preparation, the novel filling machine capable of vacuumizing is synchronously vacuumized during filling, the dissolved oxygen can only be controlled at 2.9mg/L, the headspace oxygen is controlled at 0.7%, and the sample combined with the dissolved oxygen is still unqualified, so that the novel filling machine is obviously improved compared with the sample filled with nitrogen only, and the novel filling machine is in need of improvement.
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 used is not treated by an oxygen removal filtering membrane), compound amino acid injection (18 AA-IX) samples are 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 samples 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) 7.2 1.1 1.3 1.5 1.7
Headspace oxygen (%) 20.6 0.5 1.0 1.5 1.7
In the preparation process, the vacuum pumping and nitrogen filling are carried out simultaneously (namely, the dissolved oxygen monitoring is carried out, and the nitrogen replacement is carried out after the upper limit of the monitoring is exceeded), the vacuum pumping is carried out continuously during the filling, the dissolved oxygen of the sample can only 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 7.2mg/L and the headspace oxygen is 20.6 percent when the nitrogen is not filled).
Each group of 30 bottles was tested, the test samples were placed in a 60℃incubator and kept in air circulation, and the samples were sampled and examined for their properties, transmittance, cysteine content, etc. on days 0,5 and 10, and the test results were determined on the basis of the examination results on day 10, and the results are 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; the preparation process is carried out simultaneously with the nitrogen filling, the vacuum pumping is carried out continuously during the filling, the dissolved oxygen is controlled below 1.5mg/L, the headspace oxygen is controlled below 1.5%, and the sample is qualified. However, unacceptable samples may be produced, so that further improvements in production conditions are made.
Effect example 4 residual oxygen amount: test of dissolved oxygen and headspace oxygen limitation
Preparing a compound amino acid injection (18 AA-IX) sample according to the prescription and the preparation process of the embodiment 1, adding an deoxidizing filtering membrane on an injection water preparation device, adding deoxidized injection water into a preparation tank, adding a vacuum pump on the preparation tank, carrying out vacuumizing and nitrogen filling simultaneously in the preparation process, and continuously carrying out vacuumizing during filling, wherein 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) 7.2 0.8 1.0 1.2 1.5
Headspace oxygen (%) 20.6 0.5 1.0 1.5 1.5
The preparation process is carried out simultaneously with the nitrogen filling, the vacuum pumping is carried out continuously during the filling, the dissolved oxygen energy of the sample is controlled between 0.8 and 1.5mg/L, and the headspace oxygen energy is controlled between 0.5 and 1.5 percent.
Blank (ck): and the nitrogen is not filled (the dissolved oxygen in the solution is 7.2mg/L and the headspace oxygen is 20.6 percent when the nitrogen is not filled).
Each group of 30 bottles was tested, the test samples were placed in a 60℃incubator and kept in air circulation, and the samples were sampled and examined for their properties, transmittance, cysteine content, etc. on days 0,5 and 10, and the test results were determined on the basis of the examination results on day 10, and the results are 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 1.5mg/L, the headspace oxygen is controlled below 1.5%, and the sample is qualified. When the dissolved oxygen is controlled below 1.5mg/L, the degradation amount of cysteine is obviously reduced along with the reduction of headspace oxygen; when the headspace oxygen is controlled below 1.5%, the degradation amount of cysteine 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 commercial sodium bisulfite-containing like product
Different samples of injection solutions (18 AA-IX) of a pharmaceutical composition containing 18 amino acids were prepared according to the sample recipe and preparation process of example 1:
Test group 1: the dissolved oxygen in the container is 1.0mg/L, the headspace oxygen is 1.0%, and sodium bisulphite is not added
Test group 2: reference to national medicinesStandard WS 1 XG-022-2011-2012 specifies that the sodium bisulphite content is 0.50g/L, which is the same as the like products currently on the market.
To examine the stability of the prepared samples, we used an accelerated test method to place the tested samples in a 60 ℃ incubator to increase their oxidation rate. If the light shielding agent can be kept stable under the acceleration condition, the light shielding agent has better stability under the light shielding condition at the temperature of 5-25 ℃. And (3) producing 40 bottles in each group, taking 10 bottles in each batch, and placing the 10 bottles in a 60 ℃ incubator respectively to keep air circulation. 10 bottles are taken on the 5 th day, the 10 th day and the 30 th day respectively according to the national pharmaceutical standard WS of the national food and drug administration 1 XG-022-2011-2012, the appearance, transmittance and pH of the samples were examined, and the results are shown in Table 9, table 10, table 11 and Table 12.
Table 9 results of the test on day 0 samples
Table 10 sample results of the test at 5 days
Compared with the 0 day result, the content of the cysteine can reflect the oxidation degree of the sample, and the higher the content of the cysteine, the smaller the oxidation degree of the sample, the better the stability of the sample. The results show that: the property, light transmittance and cysteine indicated content of the two groups of test samples on day 5 were not significantly different.
Table 11 sample detection results at 10 days
And compared with the results of 0 day and 5 days, the property, the light transmittance and the cysteine representation content of the two groups of test samples at the 10 th day show slight difference, and the quality of the products obtained by the test groups 1 and 2 is all qualified through the accelerated test.
Table 12 sample results of detection at 30 days
Compared with the results of 0 day, 5 days and 10 days, the characteristics, the light transmittance and the cysteine expression contents of the two groups of test samples on the 30 th day show slight differences, and the quality of the products obtained by the test groups 1 and 2 is all qualified through the acceleration test.
The experimental result shows that the property, the light transmittance, the cysteine expression content and the like of the sodium bisulfite-containing product of the sample without sodium bisulfite under the condition of effectively controlling the dissolved oxygen and the headspace oxygen can be the same as those of the sodium bisulfite-containing product, and completely accords with the requirements of national standards of similar medicines.
Effect example 6 sample quality detection
To examine the quality of the product of the invention, we respectively read 0 month, 1 month, 2 months, 3 months and 6 months after the product is manufactured according to the national pharmaceutical standard WS of the national food and pharmaceutical administration 1 The standard of-XG-022-2011-2012' Compound amino acid injection (18 AA-IX) ".
The detection result shows that: the dissolved oxygen is controlled at 1.0mg/L, the headspace oxygen is controlled at 1.0%, all indexes of the sample without sodium bisulphite are qualified, and the product is qualified. The specific detection results are shown in tables 13 and 14.
TABLE 13 quality detection results of injection of 18 amino acid-containing pharmaceutical compositions
/>
Table 14 shows the results of quality detection of injection of 18 amino acids in pharmaceutical composition
From the above detection results, the preparation of the invention is according to the national food and drug administration standard WS 1 -XG-022-2011-2012 test, the results are in compliance. The indexes of the sample have no obvious change in the acceleration test for 6 months, which indicates that the quality of the sample is stable. The product of the invention has good stability, and the technical scheme of the invention is also reflected, which is feasible and effective.

Claims (7)

1. A method of preparing a pharmaceutical composition stored in a container, comprising the steps of:
(1) Mixing the components of the pharmaceutical composition under nitrogen atmosphere to obtain a pharmaceutical composition containing 18 amino acids; the mixing is under the monitoring of the dissolved oxygen content, and when the dissolved oxygen content of the composition in the mixing process is found to be larger than the upper limit of the dissolved oxygen content in the pharmaceutical composition, nitrogen substitution is carried out;
the preparation method comprises the following steps:
(a) Mixing part of water with tyrosine, leucine, isoleucine, valine, aspartic acid, phenylalanine, and methionine under nitrogen atmosphere to obtain liquid medicine 1;
(b) Mixing the liquid medicine 1 with threonine, proline, glutamic acid, lysine acetate, arginine, alanine, glycine, histidine and serine in nitrogen atmosphere to obtain liquid medicine 2;
(c) Mixing the liquid medicine 2 with active carbon in nitrogen atmosphere, and then removing the active carbon to obtain liquid medicine 3;
(d) Mixing the liquid medicine 3 with tryptophan under the nitrogen atmosphere to obtain liquid medicine 4;
(e) Mixing the liquid medicine 4 with cysteine under the nitrogen atmosphere, adding a pH value regulator to enable the pH value to be 5.5-6.5, and then adding the rest water to obtain liquid medicine 5;
(f) Finely filtering the liquid medicine 5 in nitrogen atmosphere to obtain a pharmaceutical composition containing 18 amino acids;
(2) Storing a pharmaceutical composition containing 18 amino acids in a container, wherein a gas exists in the container, and the volume percentage of oxygen in the gas is below 1.5%, so as to obtain the pharmaceutical composition stored in the container;
the pharmaceutical composition comprises tyrosine, leucine, isoleucine, phenylalanine, aspartic acid, valine, threonine, proline, methionine, glutamic acid, lysine acetate, arginine, alanine, glycine, histidine, serine, tryptophan, cysteine, a pH value regulator, and water;
The mass volume ratio of the tyrosine to the water is 0.475-0.525 g/L;
the mass volume ratio of the leucine to the water is 9.200-10.800 g/L;
the mass volume ratio of the isoleucine to the water is 6.900-8.100 g/L;
the mass volume ratio of the phenylalanine to the water is 4.750-5.250 g/L;
the mass volume ratio of the aspartic acid to the water is 0.230-0.270 g/L;
the mass volume ratio of valine to water is 6.900-8.100 g/L;
the mass volume ratio of threonine to water is 2.300-2.700 g/L;
the mass volume ratio of the proline to the water is 1.840-2.160 g/L;
the mass volume ratio of the methionine to the water is 4.600-5.400 g/L;
the mass volume ratio of the glutamic acid to the water is 0.230-0.270 g/L;
the mass volume ratio of the lysine acetate to the water is 6.440-7.560 g/L;
the mass volume ratio of the arginine to the water is 2.760-3.240 g/L;
the mass volume ratio of the alanine to the water is 2.760-3.240 g/L;
The mass volume ratio of the glycine to the water is 1.380-1.620 g/L;
the mass volume ratio of the histidine to the water is 2.300-2.700 g/L;
the mass volume ratio of serine to water is 0.920-1.080 g/L;
the mass volume ratio of the tryptophan to the water is 2.300-2.700 g/L;
the mass volume ratio of the cysteine to the water is 0.230-0.270 g/L;
the content of dissolved oxygen in the pharmaceutical composition is below 1.5 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.
2. The method of preparing a pharmaceutical composition according to claim 1, wherein the mass to volume ratio of tyrosine to water is 0.50g/L;
and/or the mass-to-volume ratio of the leucine to the water is 10.00g/L;
and/or the mass-to-volume ratio of the isoleucine to the water is 7.50g/L;
and/or the mass-volume ratio of the phenylalanine to the water is 5.00g/L;
and/or the mass-to-volume ratio of the aspartic acid to the water is 0.25g/L;
And/or the mass-volume ratio of valine to water is 7.50g/L;
and/or the mass-volume ratio of threonine to water is 2.50g/L;
and/or the mass-volume ratio of the proline to the water is 2.0g/L;
and/or the mass-to-volume ratio of methionine to water is 5.0g/L;
and/or the mass-volume ratio of the glutamic acid to the water is 0.25g/L;
and/or the mass-volume ratio of the lysine acetate to the water is 7.00g/L;
and/or the mass-to-volume ratio of the arginine to the water is 3.00g/L;
and/or the mass-volume ratio of the alanine to the water is 3.00g/L;
and/or the mass-volume ratio of the glycine to the water is 1.50g/L;
and/or the mass-volume ratio of the histidine to the water is 2.50g/L;
and/or the mass-volume ratio of serine to water is 1.00g/L;
and/or the mass-volume ratio of the tryptophan to the water is 2.50g/L;
and/or the mass-volume ratio of the cysteine to the water is 0.25g/L;
And/or the pH of the pharmaceutical composition is 6.0;
and/or the pH value regulator is one or two of citric acid aqueous solution, acetic acid aqueous solution, sodium citrate aqueous solution and sodium acetate aqueous solution;
and/or, the water is water for injection;
and/or the content of dissolved oxygen in the pharmaceutical composition is below 1.3 mg/L;
and/or, the pharmaceutical composition is in the form of a homogeneous solution;
and/or the pharmaceutical composition is used for amino acid supplementation before and after acute and chronic renal insufficiency patients with hypoalbuminemia, hypotrophic state or operation.
3. The method of preparing a pharmaceutical composition 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 1.2 mg/L;
and/or the pharmaceutical composition is in the form of injection.
4. A method of preparing a pharmaceutical composition according to claim 3, wherein the content of dissolved oxygen in the pharmaceutical composition is less than 1.1 mg/L;
And/or the injection is a large infusion.
5. The method of claim 1, wherein the amount of dissolved oxygen in the pharmaceutical composition is less than 1.0 mg/L.
6. The method of claim 1, wherein the amount of dissolved oxygen in the pharmaceutical composition is less than 0.8 mg/L.
7. The method of preparing a pharmaceutical composition according to claim 1, wherein the content of dissolved oxygen in the pharmaceutical composition is less than 0.5 mg/L;
and/or, the pharmaceutical composition consists of the tyrosine, the leucine, the isoleucine, the phenylalanine, the aspartic acid, the valine, the threonine, the proline, the methionine, the glutamic acid, the lysine acetate, the arginine, the alanine, the glycine, the histidine, the serine, the tryptophan, the cysteine, the pH regulator, and the water.
CN201710677077.6A 2017-08-09 2017-08-09 Pharmaceutical composition containing 18 amino acids and preparation method thereof Active CN109381460B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201710677077.6A CN109381460B (en) 2017-08-09 2017-08-09 Pharmaceutical composition containing 18 amino acids and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710677077.6A CN109381460B (en) 2017-08-09 2017-08-09 Pharmaceutical composition containing 18 amino acids and preparation method thereof

Publications (2)

Publication Number Publication Date
CN109381460A CN109381460A (en) 2019-02-26
CN109381460B true CN109381460B (en) 2023-09-01

Family

ID=65414988

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710677077.6A Active CN109381460B (en) 2017-08-09 2017-08-09 Pharmaceutical composition containing 18 amino acids and preparation method thereof

Country Status (1)

Country Link
CN (1) CN109381460B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN102743379A (en) * 2012-07-30 2012-10-24 李慧 Composition containing eighteen amino acids

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4528925B2 (en) * 2003-05-30 2010-08-25 独立行政法人理化学研究所 Amino acid composition and fluid replacement

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN102743379A (en) * 2012-07-30 2012-10-24 李慧 Composition containing eighteen amino acids

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DTDPA-PITC联合柱前衍生化HPLC法同时测定复方氨基酸注射液中18种氨基酸的含量;阚微娜等;《中国药房》;20140326;第25卷(第12期);1122-1125 *

Also Published As

Publication number Publication date
CN109381460A (en) 2019-02-26

Similar Documents

Publication Publication Date Title
CN101439031B (en) Pharmaceutical composition containing 18 kinds of amino acid
CN101439036B (en) Pharmaceutical composition containing 18 kinds of amino acid
CN102008433A (en) Fasudil salt injection for improving stability and preparation method thereof
CN114642729B (en) Coagulation factor X activator composition
CN102626409B (en) A kind of pharmaceutical composition containing 18 seed amino acids
CN109381460B (en) Pharmaceutical composition containing 18 amino acids and preparation method thereof
CN101933922B (en) Amino acid composition containing new antioxidant
CN104840418A (en) Fasudil hydrochloride injection composition and preparation method thereof
CN105919931A (en) Stable fasudil hydrochloride injection and preparation method thereof
CN106727523B (en) A kind of preparation method and products thereof of 18 Amino Acid Compound Injections without antioxidant and pH adjusting agent
CN109381457B (en) Pharmaceutical composition containing 14 amino acids and preparation method thereof
CN101791315B (en) Compound monoammonium glycyrrhizinate S pharmaceutical composition and method for preparing high-capacity injection
CN109381459B (en) Pharmaceutical composition containing 10 amino acids and preparation method thereof
CN109381423B (en) Pharmaceutical composition containing 19 amino acids and preparation method thereof
CN115487140A (en) Coenzyme Q10 injection and preparation method thereof
WO2020029443A1 (en) Tirofiban hydrochloride injection and preparation method therefor
CN107496349A (en) Filling ambroxol hydrochloride injection composition of a kind of plastic ampoule and preparation method thereof
CN112999148A (en) Compound amino acid composition and preparation method thereof
CN103830166B (en) Preparation method of hypertonic resuscitation fluid and application thereof
CN101664385B (en) Ibutilide fumarate injection and preparation method thereof
CN106806884B (en) N (2) -L-alanyl-L-glutamine injection and preparation method thereof
CN102600139B (en) A kind of pharmaceutical composition containing 20 seed amino acids
CN110840911A (en) Compound amino acid injection
CN116440158B (en) Iron sucrose composition, and preparation method and application thereof
CN110314132B (en) Ornithine aspartate injection and preparation method thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant