CN106860446B - Compound amino acid injection 19AA-I composition for children and method for reducing oxygen content of compound amino acid injection - Google Patents

Compound amino acid injection 19AA-I composition for children and method for reducing oxygen content of compound amino acid injection Download PDF

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CN106860446B
CN106860446B CN201710257921.XA CN201710257921A CN106860446B CN 106860446 B CN106860446 B CN 106860446B CN 201710257921 A CN201710257921 A CN 201710257921A CN 106860446 B CN106860446 B CN 106860446B
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liquid medicine
injection
nitrogen
amino acid
compound amino
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CN106860446A (en
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杨西忠
蔡仕国
王平军
朱珺卿
吴建明
肖卫东
国秀艳
雷欢
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China Resources Double Crane Pharmaceutical Co Ltd
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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
    • A61K31/33—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
    • 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
    • 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, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [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
    • A61K31/41—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
    • 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
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • 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

Abstract

The invention relates to a compound amino acid injection 19AA-I composition for children and a method for reducing the oxygen content of the composition. The invention relates to a compound amino acid injection 19AA-I composition for children, which comprises the following components in part by weight: nineteen amino acids of isoleucine, leucine, lysine acetate, methionine, phenylalanine, threonine, tryptophan, valine, cysteine, histidine, tyrosine, alanine, arginine, proline, serine, aspartic acid, glutamic acid, glycine and taurine. The invention also relates to a preparation method of the pediatric compound amino acid injection 19AA-I composition. As described in the specification of the invention, the pediatric compound amino acid injection 19AA-I composition has excellent properties.

Description

Compound amino acid injection 19AA-I composition for children and method for reducing oxygen content of compound amino acid injection
Technical Field
The invention belongs to the technical field of medicines, particularly relates to the technical field of compound amino acid injection preparation, particularly relates to the technical field of preparation of pediatric compound amino acid injection 19AA-I, particularly relates to a method for improving the stability of a pediatric compound amino acid injection 19AA-I pharmaceutical composition, and particularly relates to a method for improving the pharmaceutical stability by effectively reducing the oxygen content in the pediatric compound amino acid injection 19AA-I pharmaceutical composition. The method of the invention provides possibility for preparing the pediatric compound amino acid injection 19AA-I with excellent quality.
Background
The Pediatric Compound Amino acid injection (19AA-I), the English name of which is Pediatric Compound Amino acid injection (19AA-I), is a vitamin, mineral and intestinal parenteral nutrition medicament, parenteral nutrition medicament and Amino acid preparation.
The pediatric compound amino acid injection (19AA-I) is a compound preparation, is a colorless or almost colorless clear liquid, and comprises the following components in every 1000 ml:
Figure BDA0001273917080000011
Figure BDA0001273917080000021
in the injection, the auxiliary materials are sodium bisulfite, total amino acid content is 60 g/L, total nitrogen content is 9.3 g/L, and electrolyte (mmol/L) is Na+About 5, CH3COO-About 56, Cl-<3, pH 5.5-7.0, and osmotic pressure (mOsm/L) about 525.
The compound amino acid injection (19AA-I) for children is intravenous parenteral nutrition infusion. It can be used in several areas: 1. premature infants, low-weight infants and newborns with inadequate oral intake of protein or intake due to various causes. 2. Various wounds: such as children with high catabolic state after burn, trauma and operation. 3. Various children with acute and chronic malnutrition, such as necrotizing enterocolitis, acute necrotizing pancreatitis, and chemotherapy drug reaction, which can not be taken orally or are insufficient in food intake. In addition, it can be used for treating female pregnancy reaction and fetal malnutrition, and is helpful for fetal development. Generally, the pediatric compound amino acid injection (19AA-I) can be suitable for children who can not take food through the stomach and intestine due to digestive system diseases; is suitable for children with hypoproteinemia caused by various diseases; is suitable for children suffering from severe wound, burn, septicemia, etc. with imbalance of nitrogen balance in vivo; is suitable for intractable diarrhea and malabsorption syndrome; it is suitable for the parenteral nutrition of premature infant and low-weight infant.
One specification of the pediatric compound amino acid injection (19AA-I) is 20 ml: 1.2g (total amino acids). The usage and dosage of the pediatric compound amino acid injection (19AA-I) are generally as follows: the medicine is administrated by adopting a central venous cannula or a peripheral vein, but the medicine needs to be slowly instilled; the weight of the medicine is 20-35 ml per kilogram of body every day or following the advice of a doctor; during infusion, 150-200 kcal of non-protein heat (glucose and fat milk) should be supplied to each gram of nitrogen, and vitamins, trace elements and the like are added.
The pharmacological toxicology of the compound amino acid injection (19AA-I) for children is as follows: 1. contains high-concentration essential amino acids for children, such as histidine, tyrosine, and cysteine. 2. Phenylalanine can be metabolized to tyrosine, but because the pediatric liver enzyme system is not sound, metabolism cannot proceed efficiently. Thus, the equilibrium of concentrations in plasma is maintained by increasing the amount of tyrosine and decreasing phenylalanine. 3. Methionine is a precursor of cysteine and taurine, and is also added with taurine due to the incompetence of liver enzyme system of children, and proper amount of cysteine is added according to body condition of children during application, so that the product has low methionine content. 4. The glycine content is low, and the increase of blood ammonia is prevented. 5. Contains appropriate amount of glutamic acid and aspartic acid due to high content in human milk. 6. Taurine is a metabolite of methionine and cysteine, is rich in human milk, and has effects of protecting cell membrane, promoting brain development, maintaining normal function of retina, preventing cholestasis, and enhancing function of cardiac muscle cell.
The pharmacokinetics of the compound amino acid injection (19AA-I) for children are as follows: amino acids provide a nitrogen source for the human body to synthesize proteins and other tissues, and are essential substances for maintaining human life. Besides providing nitrogen source for synthesizing protein, part of amino acid can be used as energy supply substance through oxidative decomposition, and the other small amount of amino acid can be converted into some physiologically active substances so as to maintain the functions of some tissues and organs, and various amino acids can be transferred between various tissues through blood to ensure the metabolism of amino acids in the tissues. The concentration of the plasma amino acid of normal human is not high, the total concentration is about 2 milligram molecules/liter, the vast majority is in cells, the concentration is lower for children, and the method is probably related to the rapid growth of children and more amino acid intake tissues. Therefore, children should have higher intake of amino acids than adults.
The compound amino acid injection (19AA-I) for children is sealed and stored in a cool and dark place (protected from light and not more than 20 ℃); the useful life under these conditions is usually 24 months. Existing execution standards of the pediatric compound amino acid injection (19AA-I) comprise national drug standard WS1- (X-507) -2003Z. At present, only a few companies including Huarun Shuanghe pharmaceutical industry Co., Ltd can produce the compound, and the national standard of medicine is H10920114.
The prior art has disclosed some methods and apparatus for preparing compound amino acid injection. For example, CN 102302489B (chinese patent application No. 201110196860.3) discloses a preparation method of a compound amino acid injection, which comprises the steps of removing oxygen in preparation equipment and dissolved oxygen in water by adopting the processes of vacuumizing and filling nitrogen in the preparation process of the injection, and solving the problems of yellowing of the liquid medicine and reduction of the content of amino acid due to unstable amino acid in the solution and easy oxidation; according to the preparation method, the amino acid component which is most difficult to dissolve, namely cystine, is dissolved by using low-concentration alkali liquor independently and then fed, and the rest amino acid components are fed at one time, so that the components do not need to be fed in multiple groups or at high temperature, and the preparation method has the advantages of simple feeding mode, low preparation temperature, short preparation time and the like, has lower requirements on production equipment conditions, and is easy to operate by production personnel.
CN 103301120B (Chinese patent application No. 201310254662.7) discloses a preparation method of a compound amino acid injection, which is characterized by comprising the following steps of weighing 18 amino acids, sodium bisulfite and sorbitol according to the formula amount of each 1000ml of the compound amino acid injection, adding water for injection into a tank, keeping the temperature at 65-75 ℃, adding NaOH so that the amino acids are dissolved into 0.1MNaOH, adding L-cystine, blowing nitrogen into the tank, stirring until the nitrogen is dissolved, adding water to 50% of the volume amount, then adding the sodium bisulfite and the rest of the 18 amino acids and sorbitol, stirring until the amino acids are completely dissolved, adsorbing by activated carbon, filtering, finely filtering, cooling and fixing the volume, introducing nitrogen all the time in the dissolving process, and introducing the nitrogen until the residual oxygen amount is less than 3% before filling.
CN104743148A (chinese patent application No. 201310733727.6) discloses a glass bottle filling machine, which comprises a support and a conveyor belt mounted on the support, a medicine filling device, a nitrogen filling device, a transition bottle-shifting tray and a plug-loading device are sequentially arranged beside the conveyor belt, the orifices of a plurality of nitrogen filling pipes in the nitrogen filling device are located above the bottle mouth of the glass bottle, and the nitrogen filling pipes are flexible pipes; in the medicine filling device, a flow limiting device is arranged on a medicine filling pipe of a rotary disc. The glass bottle filling machine provided by the invention is believed to solve the problem of high concentration of residual oxygen in the space in the bottle, ensure and improve the quality of the amino acid injection, and the residual oxygen in the glass bottle is less than or equal to 2.2 percent through inspection, reaches the control standard of foreign infusion manufacturers and is superior to the control standard of domestic infusion manufacturers.
Zhufuhua et al (Zhufuhua et al, research on preparation process of compound amino acid injection, China journal of medical industry, 2000, 31 (4): 154) disclose that two process recipes are designed according to test results such as orthogonal design for improving light transmittance and clarity and reducing local irritation of compound amino acid injection, and finished products (in which 14 domestic amino acids are used) are prepared according to the two process recipes. The quality of the product is believed to be better than that of the product sold on the market through inspection.
However, there is still a need in the art for improved methods for preparing pediatric compound amino acid injection (19 AA-I).
In order to ensure the excellent quality of the pediatric compound amino acid injection (19AA-I), for example, the pediatric compound amino acid injection meets the requirements of quality standards and has excellent physical and/or chemical stability, it is necessary to reduce the residual oxygen content in the injection, however, the existing method for reducing the residual oxygen content in the compound amino acid injection cannot meet the specific requirements of reducing the residual oxygen content in the pediatric compound amino acid injection 19 AA-I. Therefore, the technical personnel in the field still expect a method capable of effectively reducing the residual oxygen of the pediatric compound amino acid injection 19 AA-I.
Disclosure of Invention
The invention aims to provide a method for effectively reducing the oxygen content in a compound amino acid injection, and particularly provides a method for effectively reducing the dissolved oxygen and residual oxygen content of 19AA-I in a compound amino acid injection for children. The inventors have surprisingly found that the above object can be effectively achieved by the process of the invention. The present invention has been completed based on this finding.
In the present invention, when referring to the pediatric compound amino acid injection, if not stated otherwise, it refers to pediatric compound amino acid injection 19AA-I, i.e. an injection comprising 19 amino acids as described above. In the present invention, taurine is not an amino acid having a typical structure, but can be classified as one of amino acids in the art.
To this end, the invention provides, in a first aspect, a pharmaceutical composition of pediatric compound amino acid injection, comprising per 1000 ml:
Figure BDA0001273917080000041
Figure BDA0001273917080000051
the pediatric compound amino acid injection pharmaceutical composition according to any embodiment of the first aspect of the invention comprises per 1000 ml:
isoleucine 4.4～5.4g，
Leucine 7.5～9.5g，
Lysine acetate 4.4～5.4g，
Methionine 1.8～2.2g，
Phenylalanine 2.6～3.2g，
Threonine 2.2～2.8g，
Tryptophan 1.1～1.3g，
Valine 4.2～5.2g，
Cysteine 0.18～0.22g，
Histidine 2.6～3.2g，
Tyrosine 1.2～1.6g，
Alanine 2.9～3.5g，
Arginine 6.6～8.0g，
Proline 3.7～4.5g，
Serine 2.1～2.5g，
Aspartic acid 1.7～2.1g，
Glutamic acid 2.7～3.3g，
Glycine 2.0～2.4g，
Taurine 0.13～0.17g，
Water for injection The proper amount is 1000 ml.
The pediatric compound amino acid injection pharmaceutical composition according to any embodiment of the first aspect of the invention comprises per 1000 ml:
Figure BDA0001273917080000052
Figure BDA0001273917080000061
the pharmaceutical composition of pediatric compound amino acid injection according to any embodiment of the first aspect of the invention, further comprises an antioxidant.
The pharmaceutical composition of pediatric compound amino acid injection according to any embodiment of the first aspect of the invention, further comprises an antioxidant selected from sodium metabisulfite, sodium sulfite and sodium bisulfite. In one embodiment, the antioxidant is sodium bisulfite. In one embodiment, the amount of sodium bisulfite in the pharmaceutical composition of compound amino acid injection for children per 1000ml is 0.4-0.6 g, such as 0.45-0.55 g, such as 0.5 g.
The pediatric compound amino acid injection pharmaceutical composition according to any one of the embodiments of the first aspect of the present invention further comprises an acid-base regulator selected from the group consisting of: hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, sodium hydroxide, potassium hydroxide and sodium carbonate. In one embodiment, the amount of the pH regulator is such that the pH value of the pharmaceutical composition for injection is in the range of 5.5 to 7.0, such as in the range of 5.7 to 6.7, such as in the range of 5.8 to 6.3. In one embodiment, the pH adjusting agent is acetic acid, for example, glacial acetic acid.
The pediatric compound amino acid injection pharmaceutical composition according to any embodiment of the first aspect of the invention is prepared by a method comprising the following steps:
(1) charging nitrogen into water for injection at 85-85 ℃ in advance to ensure that the dissolved oxygen value is lower than 6 mg/L, and preserving heat for use in the subsequent steps;
(2) adding 5-10% of injection water according to the prescription amount into a liquid preparation tank which is used for fully replacing space air with nitrogen in advance, adding phenylalanine, tyrosine and taurine according to the prescription amount into the liquid preparation tank, stirring under the protection of nitrogen atmosphere to dissolve the medicines, adding 0.1-0.2 w/v% of needle activated carbon according to the volume of the liquid medicine, stirring and adsorbing for 15-60 minutes, filtering the liquid medicine (for example, rough filtering through a 30 mu m titanium filter stick) to remove carbon, adding nitrogen into the obtained liquid medicine until the dissolved oxygen value of the liquid medicine is within the range of 1.0-2.0 mg/L, preserving the temperature of the liquid medicine at 50-55 ℃ and keeping the liquid medicine for later use under the protection of nitrogen atmosphere;
(3) adding 50-60% of injection water according to the prescription amount into another liquid preparation tank which is used for fully replacing space air with nitrogen in advance, adding the rest solid materials (including various amino acids and optional antioxidants) according to the prescription amount, stirring under the protection of nitrogen atmosphere to dissolve the drugs, adding 0.1-0.2 w/v% of needle activated carbon according to the volume of the liquid medicine, stirring and adsorbing for 15-60 minutes, filtering the liquid medicine (for example, roughly filtering the liquid medicine by a 30 mu m titanium filter stick) to remove carbon, adding nitrogen into the obtained liquid medicine until the dissolved oxygen value of the liquid medicine is within the range of 1.5-3.0 mg/L, preserving the temperature of the liquid medicine at 50-55 ℃ and preserving the heat under the protection of nitrogen atmosphere for later use;
(4) adding the liquid medicine obtained in the step (2) into the liquid medicine tank obtained in the step (3) under the protection of nitrogen atmosphere, stirring uniformly, adding water for injection to the full amount of the prescription, adjusting the pH value of the liquid medicine to be within the range of 5.8-6.3 by using an acid-base regulator, then filling nitrogen into the obtained liquid medicine until the dissolved oxygen value of the liquid medicine is within the range of 1.0-2.5 mg/L, filtering the liquid medicine (for example, fine filtering through a 0.22 mu m microporous filter membrane, and repeating fine filtering for 2-4 times if necessary) to another liquid medicine tank in which space air is sufficiently replaced by nitrogen in advance, cooling the liquid medicine to 40-45 ℃ and keeping the liquid medicine for later use under the protection of nitrogen atmosphere;
(5) and (3) fully replacing the space air with nitrogen through a liquid medicine filling pipeline, filling the liquid medicine obtained in the step (4) into a glass bottle which is fully replaced with nitrogen in advance under the protection of nitrogen atmosphere, fully replacing the space in the medicine bottle with nitrogen so that the residual oxygen concentration is lower than 3%, sealing, and carrying out hot-pressing sterilization at 121 ℃ for 10-15 minutes to obtain the traditional Chinese medicine.
As is well known, the similar expressions such as the step (1) of filling nitrogen gas into the water for injection and the step (2) of filling nitrogen gas into the obtained liquid medicine until the dissolved oxygen value of the liquid medicine is within the range of 1.0 to 2.0 mg/L mean that nitrogen gas is filled into the liquid in a form of bubbling, for example, whereas the similar expressions such as the step (2) of sufficiently replacing the air in the space with nitrogen gas in advance in a liquid preparation tank, the step (5) of sufficiently replacing the air in the space with nitrogen gas in a nitrogen atmosphere, and the like mean that the air or gas in the corresponding space is replaced with nitrogen gas in an appropriate manner (for example, the manner of first vacuumizing and then filling nitrogen gas, for example, purging the space with nitrogen gas, and the like) are also known.
The pediatric compound amino acid injection pharmaceutical composition according to any one of the embodiments of the first aspect of the invention, wherein the fine filtration with a 0.22 μm microfiltration membrane is a fine filtration with a 0.22 μm fiber-mixed folding cartridge type microfiltration core.
It has been unexpectedly found that the single liquid preparation, carbon adsorption and nitrogen charging of phenylalanine, tyrosine and taurine reduces the dissolved oxygen value in the liquid medicine to a low range, the other liquid preparation, carbon adsorption and nitrogen charging of the rest materials reduce the dissolved oxygen value in the liquid medicine to a low range, and the mixing and nitrogen charging of the two liquid medicines reduce the dissolved oxygen value in the liquid medicine to a low range and fine filtration, so that the dissolved oxygen value of the final liquid medicine can be effectively reduced to below 3 mg/L, especially to below 2.5 mg/L, while the dissolved oxygen value of the liquid medicine can not be reduced to below 5 mg/L when all the materials are prepared together or prepared in other order and the final liquid medicine is charged with nitrogen, and it has been found that the injection with the dissolved oxygen value reduced to below 2.5 mg/L has obvious physical stability and chemical stability, and the specific dissolved oxygen value is higher than 5 mg/L.
The pediatric compound amino acid injection pharmaceutical composition according to any embodiment of the first aspect of the invention has an oxygen solubility value below 3 mg/L.
The pediatric compound amino acid injection pharmaceutical composition according to any embodiment of the first aspect of the invention has an oxygen solubility value below 2.5 mg/L.
According to the pharmaceutical composition of the pediatric compound amino acid injection, the dissolved oxygen value is in the range of 1.0-2.5 mg/L.
Further, the second aspect of the present invention provides a method for preparing a pharmaceutical composition of pediatric compound amino acid injection, wherein each 1000ml of the pharmaceutical composition of pediatric compound amino acid injection comprises:
isoleucine 3.9～5.9g，
Leucine 6.7～10.1g，
Lysine acetate 3.9～5.9g，
Methionine 1.6～2.4g，
Phenylalanine 2.3～3.5g，
Threonine 2.0～3.0g，
Tryptophan 0.95～1.45g，
Valine 3.8～5.6g，
Cysteine 0.16～0.24g，
Histidine 2.3～3.5g，
Tyrosine 1.1～1.7g，
Alanine 2.6～3.8g，
Arginine 5.8～8.8g，
Proline 3.3～4.9g，
Serine 1.8～2.8g，
Aspartic acid 1.5～2.3g，
Glutamic acid 2.4～3.6g，
Glycine 1.8～2.6g，
Taurine 0.12～0.18g，
Water for injection Proper amount to 1000 ml;
the method comprises the following steps:
(1) charging nitrogen into water for injection at 85-85 ℃ in advance to ensure that the dissolved oxygen value is lower than 6 mg/L, and preserving heat for use in the subsequent steps;
(2) adding 5-10% of injection water according to the prescription amount into a liquid preparation tank which is used for fully replacing space air with nitrogen in advance, adding phenylalanine, tyrosine and taurine according to the prescription amount into the liquid preparation tank, stirring under the protection of nitrogen atmosphere to dissolve the medicines, adding 0.1-0.2 w/v% of needle activated carbon according to the volume of the liquid medicine, stirring and adsorbing for 15-60 minutes, filtering the liquid medicine (for example, rough filtering through a 30 mu m titanium filter stick) to remove carbon, adding nitrogen into the obtained liquid medicine until the dissolved oxygen value of the liquid medicine is within the range of 1.0-2.0 mg/L, preserving the temperature of the liquid medicine at 50-55 ℃ and keeping the liquid medicine for later use under the protection of nitrogen atmosphere;
(3) adding 50-60% of injection water according to the prescription amount into another liquid preparation tank which is used for fully replacing space air with nitrogen in advance, adding the rest solid materials (including various amino acids and optional antioxidants) according to the prescription amount, stirring under the protection of nitrogen atmosphere to dissolve the drugs, adding 0.1-0.2 w/v% of needle activated carbon according to the volume of the liquid medicine, stirring and adsorbing for 15-60 minutes, filtering the liquid medicine (for example, roughly filtering the liquid medicine by a 30 mu m titanium filter stick) to remove carbon, adding nitrogen into the obtained liquid medicine until the dissolved oxygen value of the liquid medicine is within the range of 1.5-3.0 mg/L, preserving the temperature of the liquid medicine at 50-55 ℃ and preserving the heat under the protection of nitrogen atmosphere for later use;
(4) adding the liquid medicine obtained in the step (2) into the liquid medicine tank obtained in the step (3) under the protection of nitrogen atmosphere, stirring uniformly, adding water for injection to the full amount of the prescription, adjusting the pH value of the liquid medicine to be within the range of 5.8-6.3 by using an acid-base regulator, then filling nitrogen into the obtained liquid medicine until the dissolved oxygen value of the liquid medicine is within the range of 1.0-2.5 mg/L, filtering the liquid medicine (for example, fine filtering through a 0.22 mu m microporous filter membrane, and repeating fine filtering for 2-4 times if necessary) to another liquid medicine tank in which space air is sufficiently replaced by nitrogen in advance, cooling the liquid medicine to 40-45 ℃ and keeping the liquid medicine for later use under the protection of nitrogen atmosphere;
(5) and (3) fully replacing the space air with nitrogen through a liquid medicine filling pipeline, filling the liquid medicine obtained in the step (4) into a glass bottle which is fully replaced with nitrogen in advance under the protection of nitrogen atmosphere, fully replacing the space in the medicine bottle with nitrogen so that the residual oxygen concentration is lower than 3%, sealing, and carrying out hot-pressing sterilization at 121 ℃ for 10-15 minutes to obtain the traditional Chinese medicine.
The method according to any embodiment of the second aspect of the present invention, wherein the pharmaceutical composition of pediatric compound amino acid injection comprises per 1000 ml:
Figure BDA0001273917080000091
Figure BDA0001273917080000101
the method according to any embodiment of the second aspect of the present invention, wherein the pharmaceutical composition of pediatric compound amino acid injection comprises per 1000 ml:
Figure BDA0001273917080000102
Figure BDA0001273917080000111
the method according to any embodiment of the second aspect of the present invention, wherein the pharmaceutical composition of pediatric compound amino acid injection further comprises an antioxidant.
The method according to any embodiment of the second aspect of the present invention, wherein the pharmaceutical composition of pediatric compound amino acid injection further comprises an antioxidant selected from the group consisting of sodium metabisulfite, sodium sulfite, and sodium bisulfite. In one embodiment, the antioxidant is sodium bisulfite. In one embodiment, the amount of sodium bisulfite in the pharmaceutical composition of compound amino acid injection for children per 1000ml is 0.4-0.6 g, such as 0.45-0.55 g, such as 0.5 g.
The method according to any embodiment of the second aspect of the present invention, wherein the pharmaceutical composition of pediatric compound amino acid injection further comprises an acid-base modifier selected from the group consisting of: hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, sodium hydroxide, potassium hydroxide and sodium carbonate. In one embodiment, the amount of the pH regulator is such that the pH value of the pharmaceutical composition for injection is in the range of 5.5 to 7.0, such as in the range of 5.7 to 6.7, such as in the range of 5.8 to 6.3. In one embodiment, the pH adjusting agent is acetic acid, for example, glacial acetic acid.
The method according to any embodiment of the second aspect of the present invention, wherein the fine filtration with 0.22 μm microfiltration membrane is a fine filtration using a 0.22 μm mixed fiber pleated cartridge type microfiltration core.
According to the method of any embodiment of the second aspect of the invention, the prepared pediatric compound amino acid injection pharmaceutical composition has an oxygen solubility value below 3 mg/L.
According to the method of any embodiment of the second aspect of the invention, the prepared pediatric compound amino acid injection pharmaceutical composition has an oxygen solubility value below 2.5 mg/L.
According to the method of any embodiment of the second aspect of the invention, the oxygen solubility value of the prepared pediatric compound amino acid injection pharmaceutical composition is in the range of 1.0-2.5 mg/L.
According to any one embodiment of the invention, in the pharmaceutical composition of the pediatric compound amino acid injection, the total amino acid amount is 50-70 mg/m L, such as 55-65 mg/m L, the total nitrogen amount is 8-11 g/L, such as 8.5-10 g/L, such as 9.3 g/L, and the electrolyte (mmol/L) is Na+About 4.5 to 5.5 such as about 5, CH3COO-50 to 60, for example, about 56, Cl-<3, pH 5.5 to 7.0, in particular 5.7 to 6.5, and an osmotic pressure (mOsm/L) of about 450 to 600, for example about 525.
In the above-described steps of the preparation method of the present invention, although the specific steps described therein are distinguished in some detail or in language description from the steps described in the preparation examples of the detailed embodiments below, those skilled in the art can fully summarize the above-described method steps in light of the detailed disclosure throughout the present disclosure.
Any embodiment of any aspect of the invention may be combined with any other embodiment of the invention, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in any other embodiment of the invention, provided that they do not contradict.
The invention is further described below.
All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.
The compositions of the present invention include, in terms of the spirit and scope of the present invention, liquid medicine compositions that are formulated for a short period of time, and may also include compositions of the present invention formulated and sealed in glass for long term storage (e.g., for 1 to 3 years, such as for about 1.5 to 2.5 years, such as for about 2 years), so long as the dissolved oxygen values of these compositions are within the desired range of the present invention.
In the present invention, the composition of the present invention is a liquid composition such as an injection, which is sealed in a glass bottle, and the term "seal" or similar expressions can be understood as any type of seal, such as but not limited to, a fusion seal of an ampoule bottle, a sealing of a vial or a vial with a rubber plug, etc., as long as the seal can isolate the gas/liquid inside and outside the glass bottle.
In the present invention,% is a weight/weight percentage, unless otherwise specified.
In the present invention, the term "dissolved oxygen value" or "dissolved oxygen" or similar expressions refer to the amount of dissolved oxygen in a solution, and may generally be expressed in terms of the weight of oxygen contained per liter of solution (mg/L).
In the present invention, there are many methods for measuring dissolved oxygen in a solution, and measuring instruments are well developed, for example, a typical apparatus for monitoring dissolved oxygen in a solution is: the JPBJ-608 type portable dissolved oxygen analyzer is manufactured by Shanghai precision scientific instruments Co., Ltd; yet another typical instrument is the HACH
Figure BDA0001273917080000121
II fluorescence method dissolved oxygen analyzer. In the present invention, unless otherwise specified, the apparatus for measuring dissolved oxygen in each solution was the above-mentioned JPBJ-608 type portable dissolved oxygen analyzer.
The composition of the present invention may contain substantially no other pharmaceutical excipients, except for the active ingredient, the necessary pH adjusting agent, the optional antioxidant, and the solvent water for injection.
The amount of the solvent water in the composition of the present invention may not be particularly limited as long as it is added to 100% (volume or weight percentage).
Generally speaking, the amount of dissolved oxygen in medicinal water, particularly injection water, is in the range of 8-15 mg/L, and the inventor finds that the composition has good physical and/or chemical stability after the dissolved oxygen is reduced to a certain range, however, the content of the dissolved oxygen in the final injection can be effectively reduced only under the condition that three amino acids and other materials are respectively prepared into liquid independently and respectively filled with nitrogen in advance to reduce the dissolved oxygen, and the reduction of the content of the dissolved oxygen is crucial to obtaining the composition with excellent physicochemical properties, possibly due to the pharmaceutical properties.
In the present invention, it has been found that an injection which has not been sufficiently reduced in dissolved oxygen content is poor in stability, and exhibits not only chemical stability but also physical stability even at a lower temperature of storage.
In the present invention, it has been found that samples of the composition of the present invention are kept at a temperature of from 2 to 30 ℃, preferably from 5 to 25 ℃, preferably below 20 ℃, preferably from 8 to 20 ℃.
The preparation prepared by some examples of the invention has good product stability, and the quality of the preparation meets the requirement after long-term test for 2 years.
As is well known to those skilled in the art, fresh water for injection which has been stored for up to 48 hours usually has an oxygen solubility of 8 mg/L or more, and such water for injection actually used in the present invention has an oxygen solubility of 9.25. + -. 0.02 mg/L without being aerated with nitrogen.
The product is prepared by dissolving isoleucine in white crystal or crystalline powder, dissolving leucine in water, dissolving arginine in ethyl alcohol or ethyl ether, dissolving phenylalanine in white crystal or crystalline powder, dissolving leucine in hot water, dissolving methionine in dilute acid or sodium hydroxide solution, dissolving methionine in water, dissolving methionine in dilute acid or dissolving arginine in water, dissolving methionine in dilute acid or dissolving arginine in water, dissolving methionine in sodium, dissolving methionine in acetic acid, dissolving methionine in dilute acid, dissolving arginine in water, dissolving arginine in sodium chloride, dissolving arginine in water, dissolving methionine in sodium chloride, dissolving arginine in water, dissolving sodium chloride or sodium chloride in water, dissolving sodium chloride, dissolving in sodium chloride, dissolving sodium chloride in water, dissolving sodium chloride in ethyl alcohol, dissolving sodium chloride or sodium chloride in water, storing in sodium chloride, dissolving in sodium chloride, or sodium chloride in water, storing in sodium chloride, or sodium chloride in water, or sodium chloride, sodium.
The product prepared by the invention is generally named as the Compound Amino Acid Injection (19AA-I) for children in the common name, is named as Pediatric Compound Amino Acid Injection (19AA-I) in the English name, and has the following specifications in the concentration of the medicine): 20 ml: 1.2g (total amino acids), and the package can be 20ml ampoule bottle, or 100ml or 250ml glass bottle.
The product prepared by the invention is generally clear liquid with colorless or almost colorless property, and is indicated for intravenous parenteral nutrition transfusion, and is used for: 1. premature infants, low-weight infants and neonates with inadequate oral intake of protein or intake due to various causes; 2. various wounds: children with high metabolic state such as burn, trauma and postoperative; 3. various infants with acute and chronic malnutrition who cannot take food orally or are under-fed: such as necrotizing small intestine conjunctivitis, acute necrotizing pancreatitis, chemotherapy drug reaction, etc. The usage and dosage of the pediatric compound amino acid injection (19AA-I) can be as follows: 1. the medicine is administrated by adopting a central venous cannula or a peripheral vein, but the medicine needs to be slowly instilled; 2. the weight of the medicine is 20-35 ml per kilogram of body every day or following the advice of a doctor; 3. when in instillation, 150-200 kcal of non-protein heat (glucose, fat milk) should be supplied to each gram of nitrogen, and vitamins, trace elements and the like should be added.
Detailed Description
The invention is further described by the following examples, however, the scope of the invention is not limited to the following examples, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention.
Example 1:
the formula is as follows:
Figure BDA0001273917080000141
Figure BDA0001273917080000151
the preparation method comprises the following steps:
(1) charging nitrogen into water for injection at 85-85 ℃ in advance to ensure that the dissolved oxygen value is lower than 6 mg/L, and preserving heat for use in the subsequent steps;
(2) adding 10% of injection water according to the prescription amount into a liquid preparation tank which is used for fully replacing space air with nitrogen in advance, adding phenylalanine, tyrosine and taurine according to the prescription amount into the liquid preparation tank, stirring under the protection of nitrogen atmosphere to dissolve the medicines, adding 0.15 w/v% of needle activated carbon according to the volume of the liquid medicine, stirring and adsorbing for 30 minutes, filtering the liquid medicine (roughly filtering through a 30-micron titanium filter stick) to remove carbon to another liquid preparation tank which is used for fully replacing the space air with nitrogen in advance, then filling nitrogen into the obtained liquid medicine until the dissolved oxygen value of the liquid medicine is within the range of 1.0-2.0 mg/L, preserving the temperature of the liquid medicine at 50-55 ℃ and keeping for later use under the protection of nitrogen atmosphere;
(3) adding 60% of injection water according to the prescription amount into another liquid preparation tank which is used for fully replacing the air in the space by nitrogen in advance, adding the rest solid materials (including various amino acids and optional antioxidants) according to the prescription amount, stirring under the protection of nitrogen atmosphere to dissolve the drugs, adding 0.15 w/v% of needle activated carbon according to the volume of the liquid medicine, stirring and adsorbing for 30 minutes, filtering the liquid medicine (rough filtering by a 30-micron titanium filter stick) to remove the carbon, and adding nitrogen into the obtained liquid medicine until the dissolved oxygen value of the liquid medicine is within the range of 1.5-3.0 mg/L, preserving the temperature of the liquid medicine at 50-55 ℃ and keeping the liquid medicine for later use under the protection of nitrogen atmosphere;
(4) adding the liquid medicine obtained in the step (2) into the liquid medicine tank obtained in the step (3) under the protection of nitrogen atmosphere, stirring uniformly, adding injection water to the full amount of the prescription, adjusting the pH value of the liquid medicine to be within the range of 5.8-6.3 by using an acid-base regulator, then filling nitrogen into the obtained liquid medicine until the dissolved oxygen value of the liquid medicine is within the range of 1.0-2.5 mg/L, filtering the liquid medicine (finely filtering through a 0.22 mu m microporous filter membrane, and finely filtering repeatedly for 3 times) to another liquid preparation tank in which space air is sufficiently replaced by nitrogen in advance, cooling the liquid medicine to 40-45 ℃ and keeping for later use under the protection of nitrogen atmosphere;
(5) and (3) fully replacing the space air with nitrogen through a liquid medicine filling pipeline, filling the liquid medicine obtained in the step (4) into a glass bottle which is fully replaced with nitrogen in advance under the protection of nitrogen atmosphere, fully replacing the space in the medicine bottle with nitrogen so that the residual oxygen concentration is lower than 3%, sealing, and carrying out hot-pressing sterilization at 121 ℃ for 10 minutes to obtain the traditional Chinese medicine.
Example 2:
the formula is as follows:
Figure BDA0001273917080000161
Figure BDA0001273917080000171
the preparation method comprises the following steps:
(1) charging nitrogen into water for injection at 85-85 ℃ in advance to ensure that the dissolved oxygen value is lower than 6 mg/L, and preserving heat for use in the subsequent steps;
(2) adding 10% of injection water according to the prescription amount into a liquid preparation tank which is used for fully replacing space air with nitrogen in advance, adding phenylalanine, tyrosine and taurine according to the prescription amount into the liquid preparation tank, stirring under the protection of nitrogen atmosphere to dissolve the medicines, adding 0.15 w/v% of needle activated carbon according to the volume of the liquid medicine, stirring and adsorbing for 20 minutes, filtering the liquid medicine (roughly filtering through a 30 mu m titanium filter stick) to remove carbon to another liquid preparation tank which is used for fully replacing the space air with nitrogen in advance, then filling nitrogen into the obtained liquid medicine until the dissolved oxygen value of the liquid medicine is within the range of 1.0-2.0 mg/L, preserving the temperature of the liquid medicine at 50-55 ℃ and keeping for later use under the protection of nitrogen atmosphere;
(3) adding 50% of injection water according to the prescription amount into another liquid preparation tank which is used for fully replacing the air in the space by nitrogen in advance, adding the rest solid materials (including various amino acids and optional antioxidants) according to the prescription amount, stirring under the protection of nitrogen atmosphere to dissolve the drugs, adding 0.15 w/v% of needle activated carbon according to the volume of the liquid medicine, stirring and adsorbing for 40 minutes, filtering the liquid medicine (rough filtering by a 30 mu m titanium filter stick) to remove the carbon, and adding nitrogen into the obtained liquid medicine until the dissolved oxygen value of the liquid medicine is within the range of 1.5-3.0 mg/L, preserving the temperature of the liquid medicine at 50-55 ℃ and keeping the liquid medicine for later use under the protection of nitrogen atmosphere;
(4) adding the liquid medicine obtained in the step (2) into the liquid medicine tank obtained in the step (3) under the protection of nitrogen atmosphere, stirring uniformly, adding injection water to the full amount of the prescription, adjusting the pH value of the liquid medicine to be within the range of 5.8-6.3 by using an acid-base regulator, then filling nitrogen into the obtained liquid medicine until the dissolved oxygen value of the liquid medicine is within the range of 1.0-2.5 mg/L, filtering the liquid medicine (finely filtering through a 0.22 mu m microporous filter membrane, and finely filtering for 2 times repeatedly) to another liquid preparation tank in which space air is sufficiently replaced by nitrogen in advance, cooling the liquid medicine to 40-45 ℃ and keeping for later use under the protection of nitrogen atmosphere;
(5) and (3) fully replacing the space air with nitrogen through a liquid medicine filling pipeline, filling the liquid medicine obtained in the step (4) into a glass bottle which is fully replaced with nitrogen in advance under the protection of nitrogen atmosphere, fully replacing the space in the medicine bottle with nitrogen so that the residual oxygen concentration is lower than 3%, sealing, and carrying out hot-pressing sterilization at 121 ℃ for 15 minutes to obtain the traditional Chinese medicine.
Example 3:
the formula is as follows:
Figure BDA0001273917080000172
Figure BDA0001273917080000181
the preparation method comprises the following steps:
(1) charging nitrogen into water for injection at 85-85 ℃ in advance to ensure that the dissolved oxygen value is lower than 6 mg/L, and preserving heat for use in the subsequent steps;
(2) adding 10% of injection water according to the prescription amount into a liquid preparation tank which is used for fully replacing space air with nitrogen in advance, adding phenylalanine, tyrosine and taurine according to the prescription amount into the liquid preparation tank, stirring under the protection of nitrogen atmosphere to dissolve the medicines, adding 0.2 w/v% of needle activated carbon according to the volume of the liquid medicine, stirring and adsorbing for 40 minutes, filtering the liquid medicine (roughly filtering through a 30 mu m titanium filter stick) to remove carbon to another liquid preparation tank which is used for fully replacing the space air with nitrogen in advance, then filling nitrogen into the obtained liquid medicine until the dissolved oxygen value of the liquid medicine is within the range of 1.0-2.0 mg/L, preserving the temperature of the liquid medicine at 50-55 ℃ and keeping for later use under the protection of nitrogen atmosphere;
(3) adding 55% of injection water according to the prescription amount into another liquid preparation tank which is used for fully replacing the air in the space by nitrogen in advance, adding the rest solid materials (including various amino acids and optional antioxidants) according to the prescription amount, stirring under the protection of nitrogen atmosphere to dissolve the drugs, adding 0.2 w/v% of needle activated carbon according to the volume of the liquid medicine, stirring and adsorbing for 20 minutes, filtering the liquid medicine (rough filtering by a 30-micron titanium filter stick) to remove the carbon, and adding nitrogen into the obtained liquid medicine until the dissolved oxygen value of the liquid medicine is within the range of 1.5-3.0 mg/L, preserving the temperature of the liquid medicine at 50-55 ℃ and keeping for later use under the protection of nitrogen atmosphere;
(4) adding the liquid medicine obtained in the step (2) into the liquid medicine tank obtained in the step (3) under the protection of nitrogen atmosphere, stirring uniformly, adding injection water to the full amount of the prescription, adjusting the pH value of the liquid medicine to be within the range of 5.8-6.3 by using an acid-base regulator, then filling nitrogen into the obtained liquid medicine until the dissolved oxygen value of the liquid medicine is within the range of 1.0-2.5 mg/L, filtering the liquid medicine (finely filtering through a 0.22 mu m microporous filter membrane, and repeatedly finely filtering for 4 times) to another liquid preparation tank in which space air is sufficiently replaced by nitrogen in advance, cooling the liquid medicine to 40-45 ℃ and keeping for later use under the protection of nitrogen atmosphere;
(5) and (3) fully replacing the space air with nitrogen through a liquid medicine filling pipeline, filling the liquid medicine obtained in the step (4) into a glass bottle which is fully replaced with nitrogen in advance under the protection of nitrogen atmosphere, fully replacing the space in the medicine bottle with nitrogen so that the residual oxygen concentration is lower than 3%, sealing, and carrying out hot-pressing sterilization at 121 ℃ for 15 minutes to obtain the traditional Chinese medicine.
Example 4:
the formula is as follows:
the pediatric compound amino acid injection pharmaceutical composition according to any embodiment of the first aspect of the invention comprises per 1000 ml:
Figure BDA0001273917080000191
Figure BDA0001273917080000201
the preparation method comprises the following steps:
(1) charging nitrogen into water for injection at 85-85 ℃ in advance to ensure that the dissolved oxygen value is lower than 6 mg/L, and preserving heat for use in the subsequent steps;
(2) adding 5% of injection water according to the prescription amount into a liquid preparation tank which is used for fully replacing space air with nitrogen in advance, adding phenylalanine, tyrosine and taurine according to the prescription amount into the liquid preparation tank, stirring under the protection of nitrogen atmosphere to dissolve the medicines, adding 0.1 w/v% of needle activated carbon according to the volume of the liquid medicine, stirring and adsorbing for 15 minutes, filtering the liquid medicine (roughly filtering through a 30 mu m titanium filter stick) to remove carbon to another liquid preparation tank which is used for fully replacing the space air with nitrogen in advance, then filling nitrogen into the obtained liquid medicine until the dissolved oxygen value of the liquid medicine is within the range of 1.0-2.0 mg/L, preserving the temperature of the liquid medicine at 50-55 ℃ and keeping for later use under the protection of nitrogen atmosphere;
(3) adding 50% of injection water according to the prescription amount into another liquid preparation tank which is used for fully replacing the air in the space by nitrogen in advance, adding the rest solid materials (including various amino acids and optional antioxidants) according to the prescription amount, stirring under the protection of nitrogen atmosphere to dissolve the drugs, adding 0.1 w/v% of needle activated carbon according to the volume of the liquid medicine, stirring and adsorbing for 15 minutes, filtering the liquid medicine (rough filtering by a 30 mu m titanium filter stick) to remove the carbon, and adding nitrogen into the obtained liquid medicine until the dissolved oxygen value of the liquid medicine is within the range of 1.5-3.0 mg/L, preserving the temperature of the liquid medicine at 50-55 ℃ and keeping the liquid medicine for later use under the protection of nitrogen atmosphere;
(4) adding the liquid medicine obtained in the step (2) into the liquid medicine tank obtained in the step (3) under the protection of nitrogen atmosphere, stirring uniformly, adding injection water to the full amount of the prescription, adjusting the pH value of the liquid medicine to be within the range of 5.8-6.3 by using an acid-base regulator, then filling nitrogen into the obtained liquid medicine until the dissolved oxygen value of the liquid medicine is within the range of 1.0-2.5 mg/L, filtering the liquid medicine (finely filtering through a 0.22 mu m microporous filter membrane, and finely filtering repeatedly for 3 times) to another liquid preparation tank in which space air is sufficiently replaced by nitrogen in advance, cooling the liquid medicine to 40-45 ℃ and keeping for later use under the protection of nitrogen atmosphere;
(5) and (3) fully replacing the space air with nitrogen through a liquid medicine filling pipeline, filling the liquid medicine obtained in the step (4) into a glass bottle which is fully replaced with nitrogen in advance under the protection of nitrogen atmosphere, fully replacing the space in the medicine bottle with nitrogen so that the residual oxygen concentration is lower than 3%, sealing, and carrying out hot-pressing sterilization at 121 ℃ for 12 minutes to obtain the traditional Chinese medicine.
Example 5:
the formula is as follows:
Figure BDA0001273917080000202
Figure BDA0001273917080000211
the preparation method comprises the following steps:
(1) charging nitrogen into water for injection at 85-85 ℃ in advance to ensure that the dissolved oxygen value is lower than 6 mg/L, and preserving heat for use in the subsequent steps;
(2) adding 5% of injection water according to the prescription amount into a liquid preparation tank which is used for fully replacing space air with nitrogen in advance, adding phenylalanine, tyrosine and taurine according to the prescription amount into the liquid preparation tank, stirring under the protection of nitrogen atmosphere to dissolve the medicines, adding 0.15 w/v% of needle activated carbon according to the volume of the liquid medicine, stirring and adsorbing for 60 minutes, filtering the liquid medicine (roughly filtering through a 30 mu m titanium filter stick) to remove carbon to another liquid preparation tank which is used for fully replacing the space air with nitrogen in advance, then filling nitrogen into the obtained liquid medicine until the dissolved oxygen value of the liquid medicine is within the range of 1.0-2.0 mg/L, preserving the temperature of the liquid medicine at 50-55 ℃ and keeping for later use under the protection of nitrogen atmosphere;
(3) adding 60% of injection water according to the prescription amount into another liquid preparation tank which is used for fully replacing the air in the space by nitrogen in advance, adding the rest solid materials (including various amino acids and optional antioxidants) according to the prescription amount, stirring under the protection of nitrogen atmosphere to dissolve the drugs, adding 0.2 w/v% of needle activated carbon according to the volume of the liquid medicine, stirring and adsorbing for 60 minutes, filtering the liquid medicine (rough filtering by a 30-micron titanium filter stick) to remove the carbon, and adding nitrogen into the obtained liquid medicine until the dissolved oxygen value of the liquid medicine is within the range of 1.5-3.0 mg/L, preserving the temperature of the liquid medicine at 50-55 ℃ and keeping for later use under the protection of nitrogen atmosphere;
(4) adding the liquid medicine obtained in the step (2) into the liquid medicine tank obtained in the step (3) under the protection of nitrogen atmosphere, stirring uniformly, adding injection water to the full amount of the prescription, adjusting the pH value of the liquid medicine to be within the range of 5.8-6.3 by using an acid-base regulator, then filling nitrogen into the obtained liquid medicine until the dissolved oxygen value of the liquid medicine is within the range of 1.0-2.5 mg/L, filtering the liquid medicine (finely filtering through a 0.22 mu m microporous filter membrane, and finely filtering repeatedly for 3 times) to another liquid preparation tank in which space air is sufficiently replaced by nitrogen in advance, cooling the liquid medicine to 40-45 ℃ and keeping for later use under the protection of nitrogen atmosphere;
(5) and (3) fully replacing the space air with nitrogen through a liquid medicine filling pipeline, filling the liquid medicine obtained in the step (4) into a glass bottle which is fully replaced with nitrogen in advance under the protection of nitrogen atmosphere, fully replacing the space in the medicine bottle with nitrogen so that the residual oxygen concentration is lower than 3%, sealing, and carrying out hot-pressing sterilization at 121 ℃ for 10 minutes to obtain the traditional Chinese medicine.
As a result of the examination of all the finished injection solutions obtained in examples 1-5, the dissolved oxygen values of the solutions were all in the range of 1.3-2.2 mg/L, for example, the dissolved oxygen value of the injection solution of the finished injection solution obtained in example 1 was 1.6 mg/L.
Supplementary test 1 referring to examples 1 to 5 above, respectively, except that the step (2) is omitted during preparation, and the three raw materials involved in the step (2) are added together with the rest solid materials in the step (3), as a result, when nitrogen is filled into the obtained liquid medicine in the step (3) to reduce the dissolved oxygen value of the liquid medicine, the dissolved oxygen value is reduced to 5.2 mg/L and not to less than 5.0 mg/L to the maximum extent, and when nitrogen is filled into the obtained liquid medicine in the step (4) to reduce the dissolved oxygen value of the liquid medicine, the dissolved oxygen value is reduced to 5.3 mg/L and not to less than 5.0 mg/L to the maximum extent, and the dissolved oxygen value of the liquid medicine is detected to be within the range of 5.3 to 5.7 mg/L by referring to the 5 finished injection products prepared in examples 1 to 5 in the supplementary test 1.
Supplementary test 2 referring to example 1 above, except that three amino acids were not treated simultaneously in step (2), but were treated separately in 6 ways of (a) phenylalanine, (b) tyrosine, (c) phenylalanine + tyrosine, (d) taurine, (e) tyrosine + taurine, or (f) phenylalanine + taurine in step (2), in which 6 other two or one amino acid was added together with the remaining solid material in step (3), to thereby prepare 6 injections, as a result, the three (a) to (c) were filled with nitrogen in step (2) to thereby obtain a drug solution with a dissolved oxygen value of 2.5 mg/L or less, but were filled with nitrogen in step (3) to thereby obtain a drug solution with a dissolved oxygen value of 4.7 mg/L or less, and were filled with nitrogen in step (4) to thereby obtain a drug solution with a dissolved oxygen value of 4.6 mg/L or less, while the drug solution with nitrogen in step (2) to thereby obtain a drug solution with a dissolved oxygen value of 4.7 mg/L or less, and were filled with nitrogen in step (d) to thereby obtain a drug solution with a dissolved oxygen value of 395 mg/367 or less, but were not obtained from the drug solution with a dissolved oxygen in step (2) to thereby obtain a drug solution with a dissolved oxygen value of 3.5 mg/367 mg/34 or less, but were not obtained from the drug solution when the drug solution of 3.5 to thereby obtain a drug solution, but the drug solution of 3.5 mg, but the drug solution of 3, and the drug solution of 3.5 to 5 to 6 to 5 to thereby obtain a drug solution, but the drug solution of 3, but the drug solution of 3.5 to 6 to 5 to thereby obtain a drug solution.
Supplementary test 3, the injection solutions were prepared by filling nitrogen gas into the drug solutions according to CN 102302489B example 1, i.e., [0026] - [0034], and the dissolved oxygen value of the drug solutions was reduced to 2.5 mg/L or less in step (5) as [0033], and the dissolved oxygen value of the finally prepared injection solutions was measured to be 2.3 mg/L (this injection solution is labeled 489# a). the injection solutions were prepared according to CN 102302489B example 1, i.e., [0026] - [0034], and 0.1g of taurine (the amount relative to isoleucine) was simultaneously added when 17 amino acids were added in step (3) as [0031], and the dissolved oxygen value of the drug solutions was reduced to 5.4 mg/L at the maximum by filling nitrogen gas into the drug solutions when [0033] is filled with nitrogen gas as [ 5 ], and it was found that the dissolved oxygen value of the finally prepared injection solutions was measured to be 396 mg/56 (this injection solution is labeled 489B), and the residual oxygen content of the injection solutions was not reduced to 0.5 mg/593 ", which is found to be an ideal value when the oxygen content of the injection solutions is reduced by the conventional method, but the above-mentioned in the above-cited patent literature, and the residual oxygen content of the injection solutions was not reduced by filling the above-cited art.
The following tests were carried out under conditions where the injection was protected from light, unless otherwise specified.
Test example 1: examination of injectability
The injection liquid needs to be stored in a cool and dark place, so that the environment with the temperature close to 10 ℃ or even lower than 10 ℃ can be met during the storage and transportation process within the whole period of time. In particular, the injection of the present invention has an important index, namely, light transmittance, which is related to the clarity of the drug solution, and it is necessary to examine the performance of the injection under low temperature conditions.
All of the injections prepared in examples 1 to 5 and supplementary experiments 1 to 3 have light transmittance in the range of 99.6 to 99.8% before the high and low temperature cycles, indicating that the injections prepared in the above all have excellent light transmittance.
Placing the injection prepared by the method at the temperature of 4-6 ℃ for 7 days, and then placing the injection at the temperature of 25-28 ℃ for 7 days to complete a cycle; after subjecting the injection to three such high and low temperature cycles, i.e., a total of 42 days of treatment, the light transmittance of the injection was examined. After undergoing the above-mentioned high and low temperature cycles, different injections exhibited significantly different changes in light transmittance, with the following results: the light transmittance of five injections in examples 1 to 5 is maintained in the range of 99.3 to 99.5%, the light transmittance of 5 injections prepared in supplementary test 1 is reduced to the range of 93.1 to 94.6% and is already lower than the standard specification by more than 97%, the light transmittance of 6 injections prepared in supplementary test 2 is reduced to the range of 92.4 to 94.1% and is already lower than the standard specification by more than 97%, and the light transmittance of 489# a injection prepared in supplementary test 3 is maintained at 98.2% but the light transmittance of 489# b injection is reduced to the range of 92.6% and is already lower than the standard specification by more than 97%.
All the injections prepared in examples 1 to 5 and supplementary tests 1 to 3 were placed at a temperature of 15 to 18 ℃ for 12 months, and the light transmittance of the injections was measured, and the results showed that the light transmittance of the injections was in the range of 98.8 to 99.5%, and the injections were in accordance with the standard.
All the injections prepared in examples 1 to 5 and supplementary tests 1 to 3 were left at a temperature of 40 ℃ for 6 months to perform an accelerated test, and the light transmittance of the injections was measured at 6 months, and the results showed that the light transmittance of the injections was in the range of 97.2 to 98.7%, and all of the injections met the standard specification.
The results show that the light transmittance of the injections can meet the standard requirements under room temperature and high temperature accelerated test conditions no matter whether the dissolved oxygen value of the injections is reduced to below 3 mg/L, but the light transmittance of the injections with the dissolved oxygen value of below 3 mg/L is not changed basically when the injections are stored at low temperature, but the light transmittance of the injections with the dissolved oxygen value of more than 3 mg/L, particularly more than 4 mg/L, particularly more than 4.5 mg/L is unqualified when the injections are stored at low temperature, so that the light transmittance of the injections which are unqualified after the injections are subjected to high and low temperature cycles is still unqualified and not changed basically after the injections are placed at the temperature of 25-30 ℃ for 7 days, namely the light transmittance of the injections is not restored to the qualified state after the injections are subjected to high and low temperature cycles and irreversible, and the phenomenon is unacceptable for the liquid medicine which needs intravenous injection.
Test example 2: examination of injectability
All of the injections obtained in examples 1 to 5 and supplementary tests 1 to 3 were left at a temperature of 40C for 6 months to conduct an accelerated test, and the taurine content of the injection at 0 month and 6 months was measured, and the percentage obtained by dividing the taurine content at 6 months by the taurine content at 0 months and multiplying the result by 100% was taken as the remaining percentage of taurine in the injection. As a result: the residual percentage of taurine in all 5 injection batches of the injection solutions of the embodiments 1 to 5 is within the range of 98.2 to 99.6 percent; the residual percentage of taurine in the 5 injections prepared in the supplementary test 1 is 91.5-93.1%; the residual percentage of taurine in the 6 injections prepared in the supplementary test 2 and the injection in the supplementary test 3489# b are both within the range of 92.2-93.4%. These results indicate that taurocarbide in the injection prepared by the method of the present invention exhibits significantly better chemical stability, while the residual percentage of taurine in other injections is reduced to near the unacceptable lower 90% limit.
Test example 3: quality standard and detection of compound amino acid injection 19AA-I for children
The quality of the pediatric compound amino acid injection 19AA-I can be controlled by referring to the method carried by the national drug standard WS1- (X-507) -2003Z. Some of the main detection indicators of the standard are detected as follows:
the characteristics are as follows: the pediatric compound amino acid injection 19AA-I is colorless or almost colorless clear liquid.
pH value: the infant compound amino acid injection 19AA-I is taken, and the content is 5.5-7.0 determined according to the law (0631 of the general rule of the four parts of the Chinese pharmacopoeia 2015 edition).
Light transmittance: the light transmittance of the compound amino acid injection 19AA-I for children is measured at the wavelength of 430nm by an ultraviolet-visible spectrophotometry (0401 in the four parts of the pharmacopoeia 2015), and is not less than 97.0 percent.
Content determination:
the content of taurine is determined by a method for determining the content of taurine eye drops by high performance liquid chromatography carried on page 79 of the second part of Chinese pharmacopoeia of 2015 edition.
Amino acids: taking a proper amount of the pediatric compound amino acid injection 19AA-I, and performing separation and determination by using a proper amino acid analyzer or a high performance liquid chromatograph; preparing corresponding amino acid reference substance into reference substance solution with corresponding concentration, and measuring by the same method; calculating the content of various amino acids by peak area according to an external standard method; if the tryptophan content and the tyrosine content cannot be simultaneously measured, the measurement is carried out according to the following method;
tryptophan and tyrosine:
preparing reference solution by precisely weighing appropriate amount of tryptophan and tyrosine which are dried at 105 deg.C for 3 hr, respectively adding 0.1 mol/L sodium hydroxide solution to dissolve and dilute into solution containing tryptophan 12 μ g and tyrosine 14 μ g per 1ml, shaking up to obtain reference solution (1) and reference solution (2);
preparing a test solution, namely precisely measuring 2ml of the test solution, putting the test solution into a 200ml measuring flask, adding 0.1 mol/L sodium hydroxide solution to dilute the test solution to a scale, and shaking up;
tryptophan: the control solution (2) was subjected to ultraviolet-visible spectrophotometry (0401 in the fourth part of the pharmacopoeia 2015, China pharmacopoeia) at 280nm as the measurement wavelength (. lamda.2), and the wavelength of the isoabsorption point and the reference wavelength (. lamda.1) were selected at a wavelength of about 303nm (0.2 nm per interval). When Δ a ═ a λ 2 — a λ 1 ═ 0 is required, the absorbances of the control solution (1) and the test solution were measured at λ 2 and λ 1 wavelengths, respectively, and the difference in the absorbances (Δ a) was determined, and the tryptophan content was calculated by the following formula:
Figure BDA0001273917080000251
tyrosine: the control solution (1) was subjected to ultraviolet-visible spectrophotometry (0401, the fourth general rule of the pharmacopoeia 2015 edition of China), 244nm was used as the measurement wavelength (. lamda.2), and the wavelength of the isoabsorption point and the reference wavelength (. lamda.1) were selected at a wavelength of about 296nm (0.2 nm for each interval). When Δ a ═ a λ 2 — a λ 1 ═ 0 is required, the absorbances of the control solution (2) and the test solution were measured at λ 2 and λ 1 wavelengths, respectively, and the difference in the absorbances (Δ a) was determined, and the tyrosine content was calculated by the following formula:
Figure BDA0001273917080000252
all the injections obtained in examples 1 to 5 were determined to meet the WS1- (X-507) -2003Z standard.
In addition, all the injection solutions obtained in examples 1-5 were left at room temperature for 24 months and then measured according to WS1- (X-507) -2003Z standard, and the results showed that the respective contents of them remained within the ranges specified by the standard, indicating that the injection solutions prepared by the present invention have excellent stability.
The above-mentioned embodiments are merely preferred embodiments for fully illustrating the present invention, and the scope of the present invention is not limited thereto. The equivalent substitution or change made by the technical personnel in the technical field on the basis of the invention is all within the protection scope of the invention. The protection scope of the invention is subject to the claims.

Claims (12)

1. The method for preparing the pediatric compound amino acid injection pharmaceutical composition comprises, per 1000ml, 3.9-5.9 g of isoleucine, 6.7-10.1 g of leucine, 3.9-5.9 g of lysine acetate, 1.6-2.4 g of methionine, 2.3-3.5 g of phenylalanine, 2.0-3.0 g of threonine, 0.95-1.45 g of tryptophan, 3.8-5.6 g of valine, 0.16-0.24 g of cysteine, 2.3-3.5 g of histidine, 1.1-1.7 g of tyrosine, 2.6-3.8 g of alanine, 5.8-8.8 g of arginine, 3.3-4.9 g of proline, 1.8-2.8 g of serine, 1.5-2.3 g of aspartic acid, 2.4-3.6 g of glutamic acid, 1.8-2.6 g of glycine, 0.12.12 g of taurine, 0.8-2.8 g of taurine, L mg of water per 1000ml of the pharmaceutical composition, and the method comprises the following steps:
(1) charging nitrogen into water for injection at 85-85 ℃ in advance to ensure that the dissolved oxygen value is lower than 6 mg/L, and preserving heat for use in the subsequent steps;
(2) adding 5-10% of injection water according to the prescription amount into a liquid preparation tank which is used for fully replacing space air with nitrogen in advance, adding phenylalanine, tyrosine and taurine according to the prescription amount into the liquid preparation tank, stirring under the protection of nitrogen atmosphere to dissolve the medicines, adding 0.1-0.2 w/v% of needle activated carbon according to the volume of the liquid medicine, stirring and adsorbing for 15-60 minutes, filtering the liquid medicine to remove carbon until the space air is fully replaced with nitrogen in advance into another liquid preparation tank, then filling nitrogen into the obtained liquid medicine until the dissolved oxygen value of the liquid medicine is within the range of 1.0-2.0 mg/L, preserving the temperature of the liquid medicine at 50-55 ℃ and keeping the liquid medicine for later use under the protection of nitrogen atmosphere;
(3) adding 50-60% of injection water according to the prescription amount into another liquid preparation tank which is used for fully replacing the air in the space in advance by using nitrogen, adding the rest solid materials according to the prescription amount, stirring under the protection of nitrogen atmosphere to dissolve the medicine, adding 0.1-0.2 w/v% of active carbon for injection according to the volume of the liquid medicine, stirring and adsorbing for 15-60 minutes, filtering the liquid medicine to remove the carbon, filling nitrogen into the obtained liquid medicine until the dissolved oxygen value of the liquid medicine is within the range of 1.5-3.0 mg/L, preserving the temperature of the liquid medicine at 50-55 ℃ and keeping the liquid medicine for later use under the protection of nitrogen atmosphere;
(4) adding the liquid medicine obtained in the step (2) into the liquid medicine tank obtained in the step (3) under the protection of nitrogen atmosphere, stirring uniformly, adding water for injection to the full amount of the prescription, adjusting the pH value of the liquid medicine to be within the range of 5.8-6.3 by using an acid-base regulator, then filling nitrogen into the obtained liquid medicine until the dissolved oxygen value of the liquid medicine is within the range of 1.0-2.5 mg/L, filtering the liquid medicine to another liquid medicine tank in which space air is fully replaced by nitrogen in advance, cooling the liquid medicine to 40-45 ℃ and keeping for later use under the protection of nitrogen atmosphere;
(5) the liquid medicine filling pipeline is used for fully replacing space air with nitrogen, the liquid medicine obtained in the step (4) is filled into a glass bottle which is fully replaced with nitrogen in advance under the protection of nitrogen atmosphere, the space in the liquid medicine bottle is fully replaced with nitrogen so that the residual oxygen concentration is lower than 3%, the opening is sealed, and the liquid medicine is obtained after 10-15 minutes of hot-pressing sterilization at the temperature of 121 ℃;
wherein, the filtration in the step (2) and the step (3) is rough filtration by a titanium filter stick with the diameter of 30 μm.
2. The method according to claim 1, wherein the pharmaceutical composition of pediatric compound amino acid injection comprises per 1000 ml: 4.4-5.4 g of isoleucine, 7.5-9.5 g of leucine, 4.4-5.4 g of lysine acetate, 1.8-2.2 g of methionine, 2.6-3.2 g of phenylalanine, 2.2-2.8 g of threonine, 1.1-1.3 g of tryptophan, 4.2-5.2 g of valine, 0.18-0.22 g of cysteine, 2.6-3.2 g of histidine, 1.2-1.6 g of tyrosine, 2.9-3.5 g of alanine, 6.6-8.0 g of arginine, 3.7-4.5 g of proline, 2.1-2.5 g of serine, 1.7-2.1 g of aspartic acid, 2.7-3.3 g of glutamic acid, 2.0-2.4 g of glycine, 0.13-0.17 g of taurine and a proper amount of water for injection to 1000 ml.
3. The method according to claim 1, wherein the pharmaceutical composition of pediatric compound amino acid injection comprises per 1000 ml: 4.9g of isoleucine, 8.4g of leucine, 4.9g of lysine acetate, 2.0g of methionine, 2.9g of phenylalanine, 2.5g of threonine, 1.2g of tryptophan, 4.7g of valine, 0.2g of cysteine, 2.9g of histidine, 1.4g of tyrosine, 3.2g of alanine, 7.3g of arginine, 4.1g of proline, 2.3g of serine, 1.9g of aspartic acid, 3.0g of glutamic acid, 2.2g of glycine, 0.15g of taurine and a proper amount of water for injection of 1000 ml.
4. The method according to claim 1, wherein the pharmaceutical composition of pediatric compound amino acid injection further comprises an antioxidant selected from the group consisting of sodium metabisulfite, sodium sulfite, and sodium bisulfite.
5. The method of claim 4, wherein the antioxidant is sodium bisulfite; the amount of sodium bisulfite in each 1000ml of the pediatric compound amino acid injection pharmaceutical composition is 0.4-0.6 g.
6. The method according to claim 1, wherein the pharmaceutical composition of pediatric compound amino acid injection further comprises an acid-base modifier selected from the group consisting of: hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, sodium hydroxide, potassium hydroxide, sodium carbonate; the dosage of the acid-base regulator is such that the pH value of the injection pharmaceutical composition is within the range of 5.5-7.0.
7. The method according to claim 6, wherein the pH adjusting agent is acetic acid.
8. The method according to claim 1, wherein the filtration in the step (4) is fine filtration through a 0.22 μm microporous membrane, and the fine filtration is repeated 2 to 4 times if necessary.
9. The method according to any one of claims 1 to 8, wherein the total amount of amino acids in the pharmaceutical composition of pediatric compound amino acid injection is 50 to 70mg/m L.
10. The method according to any one of claims 1 to 8, wherein the total nitrogen content in the pharmaceutical composition of pediatric compound amino acid injection is 8 to 11 g/L.
11. The method according to any one of claims 1 to 8, wherein the electrolyte concentration of the pharmaceutical composition of pediatric Compound amino acid injection is Na/L calculated by mmol/L+Is 4.5 to 5.5, CH3COO-Is 50 to 60 in terms of Cl-<3。
12. The method according to any one of claims 1 to 8, wherein the pH value of the pharmaceutical composition of pediatric compound amino acid injection is 5.5 to 7.0, and the osmotic pressure is 450 to 600 mOsm/L.
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