WO2021203607A1 - 一种畜用复方氨基酸注射液的制备方法 - Google Patents

一种畜用复方氨基酸注射液的制备方法 Download PDF

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WO2021203607A1
WO2021203607A1 PCT/CN2020/109810 CN2020109810W WO2021203607A1 WO 2021203607 A1 WO2021203607 A1 WO 2021203607A1 CN 2020109810 W CN2020109810 W CN 2020109810W WO 2021203607 A1 WO2021203607 A1 WO 2021203607A1
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amino acid
compound amino
acid injection
nitrogen
protection
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French (fr)
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牛志勇
陈淑芳
李凤英
郭艳玉
赵素娟
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河北科星药业有限公司
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    • 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
    • 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
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals

Definitions

  • the invention belongs to the technical field of animal husbandry and veterinary medicine, and relates to a preparation method of animal injection, in particular to a preparation method of animal compound amino acid injection.
  • the supplementary liquid used to enhance the physical fitness of animals mainly uses glucose injection, sodium chloride injection and glucose sodium chloride injection. These three injections mainly play the role of supplementing water and energy, and regulating the balance of body electrolytes, but they cannot improve the nutritional status of the animal body and supplement the amino acids required by the animal body, and thus cannot effectively regulate the animal's feed intake, especially for the weak During the onset of the disease, the animals need to supplement amino acids to improve their nutrition to promote the recovery of the animals.
  • the Chinese invention patent with the patent number 201210000911.5 discloses a technical solution of compound amino acid injection.
  • the technical solution is mainly used for the treatment of animal diseases and the restoration of the body during the recovery period after the disease, supplementing the essential and non-essential amino acids required by the animal body.
  • this method uses carbon dioxide gas for protection in the preparation of animal compound amino acid injections, and the cost of carbon dioxide is relatively high;
  • carbon dioxide can be slightly soluble in water, which virtually increases the amount of carbon dioxide used in the preparation of compound amino acid injections for livestock, and further increases production costs;
  • the purpose of the present invention is to provide a method for preparing a compound amino acid injection for livestock, so as to solve the problem of high preparation cost of the injection for livestock.
  • a preparation method of compound amino acid injection for animal use includes the following steps in sequence:
  • group B amino acids in parts by weight, include: 1.00 to 4.00 parts of arginine hydrochloride, 0.80 to 2.54 parts of histidine hydrochloride, 2.89 to 4.00 parts of leucine, 0.50 to 2.00 parts of isoleucine, 1.00 ⁇ 4.50 parts of lysine hydrochloride, 1.00 ⁇ 2.96 parts of phenylalanine, 0.80 ⁇ 2.11 parts of threonine, 0.50 ⁇ 2.50 parts of valine, 0.50 ⁇ 2.10 parts of methionine, 1.00 ⁇ 3.45 parts of glycine, 0.80 ⁇ 3.00 parts of alanine, 0.50 to 2.40 parts of proline, 0.25 to 1.50 parts of serine, 0.50 to 1.25 parts of aspartic acid, 0.80 to 2.25 parts of glutamic acid, 0.20 to 0.70 parts of tryptophan, 0.05 to 0.15 parts of tyrosine Acid and 0.20 ⁇ 1.00 parts of cysteine hydrochloride;
  • the ratio of parts by weight to parts by volume is kg:L;
  • activated carbon is added to the intermediate solution D, decolorized, and filtered to prepare the animal compound amino acid injection.
  • the prepared animal compound amino acid injection is sterilized.
  • the animal compound amino acid injection is filled.
  • step 1) the water for injection is prepared through sterilization.
  • the weight-volume ratio of the activated carbon to the intermediate solution D is 0.5-1 kg:1000L.
  • the decolorization temperature is 20-35°C, and the time is 30-40 min;
  • Filtration includes coarse filtration and fine filtration in turn.
  • the fine filtration is a microporous filter element filtration.
  • the pore size of the microporous filter element is 0.45 ⁇ m, 0.22 ⁇ m, or 0.20 ⁇ m.
  • the residual oxygen content in the container during the filling process is less than or equal to 3%.
  • the sterilization temperature is 110-121°C, and the time is 15-40 min.
  • the present invention reduces the cost of preparing compound amino acid injection by changing to nitrogen protection and feeding conditions, and the details are as follows:
  • the present invention uses nitrogen protection instead, which reduces the production cost
  • the animal compound amino acid injection prepared by the invention is suitable for body repair during the treatment of animal diseases and during the recovery period after the disease.
  • This embodiment is a preparation method of a compound amino acid injection for animals. Taking 1000L compound injection for animals as an example, the specific preparation method includes the following steps in sequence:
  • sodium bisulfite has the effect of preventing the oxidation of tryptophan and tyrosine. Adding sodium bisulfite before each amino acid has a better antioxidant effect.
  • Disodium ethylenediaminetetraacetic acid can be combined with the raw materials.
  • Metal ions carry out chelation to avoid the catalytic oxidation of amino acids by metal ions, and dissolve sodium bisulfite and disodium edetate before adding each amino acid.
  • Tryptophan in compound amino acid injection is a component that is easy to oxidize and decompose.
  • Other amino acids may also be oxidized and decomposed.
  • the stability of amino acids is greatly affected by the oxygen content in the liquid. The higher the oxygen content, the more the amino acid is oxidized and decomposed, the worse the stability, and the darker the color of the drug solution. Therefore, nitrogen protection is used at the beginning of the preparation, which can effectively reduce the oxygen content in the drug solution, so that the amino acid can be sterilized and stored later. The process is more stable.
  • the use of nitrogen instead of carbon dioxide for protection during the preparation process can effectively reduce production costs and can further reduce the oxygen content in the injection.
  • arginine hydrochloride, histidine hydrochloride, lysine hydrochloride, and cysteine hydrochloride are used to increase the solubility of arginine, histidine, lysine and cysteine.
  • the compound hydrochloric acid makes the solution acidic in the preparation process of the animal amino acid injection, and also increases the solubility of other amino acids, so that the content of each amino acid in the animal amino acid injection is increased.
  • tyrosine and tryptophan are unstable, the content of tyrosine and tryptophan decreases drastically as the temperature rises. Therefore, the dissolved content of tyrosine and tryptophan is relatively high in the solution at 60 ⁇ 70°C (the content of tryptophan is relatively high). At 100°C, it increased by 7.4 to 9.0%, and the tyrosine content also increased).
  • arginine hydrochloride, histidine hydrochloride, leucine, isoleucine, lysine hydrochloride, phenylalanine, and threonine at a time at 60 ⁇ 70°C.
  • Acid, valine, methionine, glycine, alanine, proline, serine, aspartic acid, glutamic acid, tryptophan, tyrosine and cysteine hydrochloride to the base solution A Dissolution, can effectively reduce the oxidation of tryptophan and tyrosine in the process of dissolving, and improve the solubility of tryptophan and tyrosine.
  • ⁇ -aminobutyric acid Because the content of ⁇ -aminobutyric acid is relatively high at 60-100°C, but it is unstable, and it is easily soluble in water, so the best effect is to dissolve ⁇ -aminobutyric acid at 20-35°C.
  • the pH value is controlled at 5.5-6.8, the content of each amino acid is controlled at 80.0-120.0%, the osmolality is not much different, and the amino acid can be stored stably in the solution.
  • solution E which is a compound amino acid injection for livestock.
  • Adding 0.05-0.1% activated carbon for decolorization will reduce the content of each amino acid to varying degrees. This is because as the amount of activated carbon increases, the amount of amino acids adsorbed increases, especially tryptophan and tyrosine. When the added amount is 0.05%, the activated carbon has an adsorption effect on amino acids, but after the activated carbon is adsorbed and then sterilized, the solution has good clarity and the sample is stable. In order to improve product quality, 0.05-0.1% activated carbon is added to the preparation process, and the amount of tryptophan and tyrosine raw materials that have a greater impact on the adsorption is appropriately increased during feeding.
  • Step 4) Prepare bottled animal compound amino acid injection:
  • the residual oxygen content in the infusion bottle has been controlled below 3.0%.
  • the residual oxygen content in the infusion bottle is controlled below 3.0%, which can effectively improve the stability of the amino acids in the injection.
  • Example 2-6 Preparation method of compound amino acid injection for animal use
  • Examples 2 to 6 are respectively a preparation method of a compound amino acid injection for animal use, which is basically the same as the preparation method in Example 1, except that the amount of each amino acid raw material and the parameters in each step are different. Taking 1000L animal compound injection as an example, the amount of specific active ingredient raw materials is weighed according to the amount of each active ingredient raw material given in Table 1. The specific active ingredient raw materials are shown in Table 1; each of the examples Various process parameters in the steps, the specific parameters are shown in Table 2:
  • the accelerated test is placed for 6 months at a temperature of 40 ⁇ 2°C and a relative humidity of 75 ⁇ 5%, and samples are taken at the end of the 0th, 1st, 2nd, 3rd and 6th months of the test period.
  • the quality standard of "National Food and Drug Administration Drug Standards" WS1-(X-324)-2003Z has been tested, and the specific test results are shown in Table 4:
  • the preparation method of the present invention can prepare more Stable compound amino acid injection for livestock.
  • Example 7 According to the quality inspection method of Example 7, the compound amino acid injections for animals prepared in Examples 1 to 6 after being placed for 24 months were compared with the existing compound amino acid injections for animals.
  • the specific test results See Table 5:
  • Bovine viral diarrhea is more susceptible to young cows, and generally exhibits mild symptoms, but sometimes it breaks out suddenly, and the whole group shows severe symptoms.
  • Acute clinical symptoms include sudden fever, body temperature rising to 40-42°C, leukopenia, lack of food or refusal to eat, rumination ceases, rapid breathing and heartbeat, cough, runny nose, oral mucosa flushing, increased saliva, and subsequent erosions and diarrhea Like water, it lasts for several days, with bubbles and blood mixed in the stool. In severe cases, they die of dehydration and exhaustion.
  • the course of the disease is 1 to 3 weeks, and the morbidity and mortality of calves can be greater than 90%.
  • the clinical symptoms of chronic type are not obvious, and the sick cattle show slow growth and development, weight loss, and continuous or intermittent diarrhea. The course of the disease is 2 to 6 months.
  • the compound amino acid injection for livestock has a promoting effect on the recovery of frailty after cattle diarrhea, which can increase the appetite of cattle, shorten the recovery period, and accelerate the recovery of growth.
  • the compound amino acid injections for livestock prepared in Examples 1 to 6 are better than the existing compound amino acid injections for livestock in recovering frailty after diarrhea in cattle.
  • Dogs of different ages, genders, and breeds can develop canine parvovirus disease throughout the year (mainly puppies, especially puppies before and after weaning are most susceptible).
  • the clinical symptoms of this disease include depression, loss of appetite, severe vomiting, diarrhea, and blood in the stool.
  • the dog will die due to imbalance of water and electrolyte balance, loss of nutrients in the body and acidosis.
  • the morbidity rate is 20-100%, and the mortality rate is 50-100%.
  • fasting and drinking are required. Therefore, the key to rehydration, energy and nutrients is the key to the sick dog. Otherwise, the sick dog is prone to hypoproteinemia and edema. Due to frequent vomiting, oral drugs should not be used.
  • Infusion therapy is the key to treatment. , Timely replenishment of energy, protein and nutrients required by the animal body is the top priority.
  • the Beagle dog of Beijing Amerseys Biotechnology Co., Ltd. had diarrhea symptoms. After the clinical symptoms combined with parvovirus test paper, it was diagnosed as parvovirus disease.
  • the treatment plan is the plan shown in Table 7 and the antibiotic kanamycin sulfate , 10mg/kg and ATP-2Na, 1mL combined treatment.
  • the animal compound amino acid injection can provide timely nutrition for dogs after the disease. After the injection, the dog’s appetite will increase significantly, the weight will be restored, and it will help to resolve symptoms such as vomiting and dehydration, and can reduce the death of the sick dog. Rate.
  • the compound amino acid injections for animals prepared in Examples 1 to 6 have better recovery effects on sick dogs than the existing compound amino acid injections for animals.
  • Embodiments 1 to 6 are only preferred embodiments of the present invention, and are not intended to limit other forms of the present invention.
  • anyone familiar with the profession may use the above technical content as inspiration to make changes or modifications. They are equivalent embodiments with equivalent changes, but simple modifications, equivalent changes and modifications made to the above embodiments without departing from the technical essence of the claims of the present invention still fall within the protection scope of the claims of the present invention.

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Abstract

一种畜用复方氨基酸注射液的制备方法，包括在氮气保护下加入抗氧剂；在氮气保护下于60～70℃一次性加入18种氨基酸，再在氮气保护下于20～35℃加入γ-氨基丁酸、脱色等步骤，解决了畜用注射液制备成本高的问题。通过改用氮气保护，降低了生产成本；同时，通过在60～70℃条件下一次性加入18种氨基酸，减少了操作过程，降低了劳动强度；同时由于酪氨酸、色氨酸在60～70℃时溶液含量较高，于60～70℃时溶解各氨基酸，能够有效增加注射液中各氨基酸的含量；制备的畜用复方氨基酸注射液适用于畜牧动物疾病治疗期间及病后恢复期的机体修复。

Description

一种畜用复方氨基酸注射液的制备方法 技术领域
本发明属于畜牧兽医技术领域，涉及一种畜用注射液的制备方法，具体地说是一种畜用复方氨基酸注射液的制备方法。
背景技术
目前用于增强动物体能的补充液主要使用葡萄糖注射液、氯化钠注射液和葡萄糖氯化钠注射液。这三种注射液主要起补充水分和能量，以及调节机体电解质的平衡作用，但无法改善动物机体营养状况和补充动物机体所需氨基酸，进而无法有效调节动物采食量，尤其针对是体弱、发病期间的动物，更需要通过补充氨基酸提高营养，进而促进动物的痊愈。
一般体弱、发病的动物大多表现出食欲下降、采食量减少、身体虚弱等症状，其体内营养物质由于上述症状随着时间的延长，大量流失。如果上述症状不及时改善，将导致动物生长缓慢甚至死亡，进而为养殖业带来较大的经济损失。
专利号为201210000911.5的中国发明专利公开了一种复方氨基酸注射液的技术方案，该技术方案主要用于动物疾病治疗及病后恢复期的机体修复，补充动物机体所需的必须氨基酸和非必须氨基酸，辅助治疗疾病和病后恢复期增强体能，增加动物的采食量。
该技术方案对动物疾病治疗及病后恢复期的机体修复有一定的疗效，虽然该发明专利公开了复方氨基酸注射液的制备方法，但制备畜用复方氨基酸注射液过程中仍存在成本高的缺陷，存在上述缺陷的具体原因如下：
其一，该方法在制备畜用复方氨基酸注射液中使用二氧化碳气体进行保护，二氧化碳成本相对较高；
其二，二氧化碳能够微溶于水，无形中增加了二氧化碳在制备畜用复方氨 基酸注射液过程中的使用量，进一步，增加了生产成本；
其三，由于现有技术中公开的畜用复方氨基酸的制备方法采用分三次加料，增加了劳动强度，提高了劳动过程中人员的用量，进而增加了生产成本。
综上所述，现有的畜用复方氨基酸注射液中氨基酸制备成本高，不利于畜用复方氨基酸注射液的推广。
发明内容
本发明的目的，是要提供一种畜用复方氨基酸注射液的制备方法，以解决畜用注射液制备成本高的问题。
为了实现上述目的，本发明采用的技术方案是：
一种畜用复方氨基酸注射液的制备方法，包括依次进行的以下步骤：
步骤1)制备基础液：
在氮气保护下，取重量份数600～800份注射用水，加入重量份数0.50～2.00份亚硫酸氢钠和0.10～0.30份乙二胺四乙酸二钠，75～100℃溶解，制得基础液A；
步骤2)制备中间溶液：
在氮气保护下，基础液A中一次性加入B组氨基酸，60～70℃溶解，自然降温至20～35℃，制得溶液C；
其中，B组氨基酸，以重量份数计，包括：1.00～4.00份盐酸精氨酸、0.80～2.54份盐酸组氨酸、2.89～4.00份亮氨酸、0.50～2.00份异亮氨酸、1.00～4.50份盐酸赖氨酸、1.00～2.96份苯丙氨酸、0.80～2.11份苏氨酸、0.50～2.50份缬氨酸、0.50～2.10份甲硫氨酸、1.00～3.45份甘氨酸、0.80～3.00份丙氨酸、0.50～2.40份脯氨酸、0.25～1.50份丝氨酸、0.50～1.25份门冬氨酸、0.80～2.25份谷氨酸、0.20～0.70份色氨酸、0.05～0.15份酪氨酸和0.20～1.00份盐酸半胱氨酸；
在氮气保护下，溶液C中加入重量份数0.50～2.00份γ-氨基丁酸，20～35℃溶解后，调节pH值至5.5～6.8，定容至体积份数1000份，制得中间溶液D；
其中，重量份数与体积份数单位的比为kg：L；
步骤3)制备畜用复方氨基酸注射液：
在氮气保护下，中间溶液D中加入活性炭，脱色，过滤，制得所述畜用复方氨基酸注射液。
作为一种限定，对制得的所述畜用复方氨基酸注射液进行灭菌。
作为进一步限定，灭菌前，在氮气保护下，灌装所述畜用复方氨基酸注射液。
作为另一种限定，步骤1)中，注射用水经杀菌制得。
作为进一步限定，步骤3)中，活性炭与中间溶液D的重量体积的比为0.5～1kg：1000L。
作为再进一步限定，步骤3)中，脱色的温度为20～35℃、时间为30～40min；
过滤依次包括粗滤和精滤。
作为更进一步限定，精滤为微孔滤芯过滤。
作为更进一步限定，微孔滤芯的孔径为0.45μm、0.22μm或0.20μm。
作为再进一步限定，所述灌装过程中容器内残氧量≤3％。
作为进一步限定，所述灭菌的温度为110～121℃、时间为15～40min。
本发明与现有技术相比，通过改用氮气保护和加料条件，降低了制备复方氨基酸注射液的成本，具体如下：
其一，本发明改用氮气保护，降低了生产成本；
其二，本发明通过在60～70℃条件下一次性加入18种氨基酸，减少了操作过程，降低了劳动强度，进而降低了生产生本；
其三，由于色氨酸、酪氨酸在60～70℃时溶液含量较高，因此于60～70℃时溶解各氨基酸，能够有效增加注射液中各氨基酸的含量。
本发明制备的畜用复方氨基酸注射液适用于畜牧动物疾病治疗期间及病后 恢复期的机体修复。
具体实施方式
下面通过具体实施例对本发明做进一步详细说明，应当理解所描述的实施例仅用于解释本发明，并不限定本发明。
实施例1一种畜用复方氨基酸注射液的制备方法
本实施例为一种畜用复方氨基酸注射液的制备方法，以1000L畜用复方注射液为例，其具体制备方法包括依次进行的以下步骤：
步骤1)制备基础液：
将1000L注射用水经煮沸杀菌40min，备用；
称量0.89kg亚硫酸氢钠和0.10kg乙二胺四乙酸二钠，备用；
取800L杀菌后的注射用水，在氮气保护下，将0.89kg亚硫酸氢钠和0.10kg乙二胺四乙酸二钠加入到水温为95℃的注射用水中，搅拌待其完全溶解，制得基础液A。
其中，亚硫酸氢钠具有防止色氨酸和酪氨酸氧化的作用，在各氨基酸之前加入亚硫酸氢钠，抗氧化作用更佳，乙二胺四乙酸二钠可以和原料中所带入的金属离子进行螯合作用，避免金属离子催化氧化氨基酸，在加入各氨基酸之前先溶解亚硫酸氢钠和乙二胺四乙酸二钠。
复方氨基酸注射液中色氨酸是属于易于氧化分解的成分，其他氨基酸也存在氧化分解的可能，在生产及储存过程中，氨基酸的稳定性受药液中氧含量影响较大，药液中含氧量越高，氨基酸氧化分解越多，稳定性越差，药液颜色加深，因此在制备开始时就使用氮气保护，能够有效降低药液中氧的含量，使得氨基酸在之后的灭菌及储存过程中更加稳定。
同时，使用氮气代替二氧化碳在制备过程中进行保护，能够有效降低生产成本，并且能够进一步的降低注射液中的含氧量。
步骤2)制备中间溶液：
称取1.00kg盐酸精氨酸、2.54kg盐酸组氨酸、3.49kg亮氨酸、1.52kg异亮氨酸、3.33kg盐酸赖氨酸、2.96kg苯丙氨酸、0.80kg苏氨酸、2.50kg缬氨酸、1.79kg甲硫氨酸、0.32kg色氨酸、3.24kg甘氨酸、0.80kg丙氨酸、2.40kg脯氨酸、0.15kg酪氨酸、0.25kg丝氨酸、0.76kg盐酸半胱氨酸、0.50kg门冬氨酸、1.34kg谷氨酸，统称为B组氨基酸；
在氮气保护下，将B组氨基酸一次性加至温度为100℃的基础液A中，搅拌溶解，制得溶液C，溶液C自然降温至30℃；
称取0.89kgγ-氨基丁酸，备用；
在氮气保护下，取0.89kgγ-氨基丁酸加入为温度为30℃的溶液C中，搅拌溶解，加入注射用水至近1000L，用质量浓度为20％氢氧化钠溶液调节pH值至6.0，定容至1000L，制得中间溶液D。
本发明中利用改用盐酸精氨酸、盐酸组氨酸、盐酸赖氨酸和盐酸半胱氨酸，增加了精氨酸、组氨酸、赖氨酸和半胱氨酸的溶解度，同时，复合的盐酸使得畜用氨基酸注射液制备过程中溶液呈酸性，也增加了其他各氨基酸的溶解度，使得畜用氨基酸注射液中各氨基酸的含量得到了提高。
由于酪氨酸、色氨酸不稳定，随着温度升高，含量反而大幅度下降，因此酪氨酸、色氨酸在60～70℃的溶液内溶解含量较高(其中色氨酸含量相对于100℃时提高了7.4～9.0％，酪氨酸含量也有所提高)。综合考虑含量与溶解时间等因素，于60～70℃条件下一次性加入盐酸精氨酸、盐酸组氨酸、亮氨酸、异亮氨酸、盐酸赖氨酸、苯丙氨酸、苏氨酸、缬氨酸、甲硫氨酸、甘氨酸、丙氨酸、脯氨酸、丝氨酸、门冬氨酸、谷氨酸、色氨酸、酪氨酸和盐酸半胱氨酸至基础液A中溶解，能够有效降低色氨酸和酪氨酸溶解过程中的氧化作用，并提高色氨酸和酪氨酸的溶解度。
由于γ-氨基丁酸在60～100℃时含量较高，但是不稳定，且其易溶于水，因此将γ-氨基丁酸在20～35℃时溶解，效果最佳。
在制备复方氨基酸注射液过程中，将pH值控制在5.5～6.8，各氨基酸含量控制在80.0～120.0％之间，渗透压摩尔浓度差别不大，氨基酸在溶液中能够稳定储存。
步骤3)制备畜用复方氨基酸注射液：
在氮气保护下，将1kg活性炭加入到温度为30℃的中间溶液D中，脱色30min，经粗滤、0.45μm的微孔滤芯精滤，制得溶液E，即为畜用复方氨基酸注射液。
加入0.05～0.1％的活性炭脱色，各氨基酸含量均有不同程度的降低，这是由于随着活性炭加入量的增加，氨基酸被吸附量增加，尤其是色氨酸和酪氨酸。加入量为0.05％时，活性炭对氨基酸有吸附作用，但经活性炭吸附后再经灭菌，溶液澄明度良好，样品稳定。为提高产品质量，在制备工艺中加入0.05～0.1％的活性炭，并在投料时对吸附适当增加对其影响较大的色氨酸和酪氨酸原料投料量。
步骤4)制备瓶装的畜用复方氨基酸注射液：
在氮气保护下，将溶液E灌装至1000mL输液瓶中，115℃灭菌30min，灯检合格，制得瓶装的畜用复方氨基酸注射液；
整个灌装过程中输液瓶中残氧量一直控制在3.0％以下。
在灌装过程中将输液瓶中残氧量控制在3.0％以下，能够有效提高注射液中各氨基酸的稳定性。
实施例2～6一种畜用复方氨基酸注射液的制备方法
实施例2～6分别为一种畜用复方氨基酸注射液的制备方法，与实施例1中的制备方法基本相同，不同之处在于各氨基酸原料的用量，以及各步骤中的参 数有区别。以1000L畜用复方注射液为例，制成其具体有效成分原料的用量分别按照表1中给出的各有效成分原料的用量称量，具体有效成分原料见表1；各实施例中的各步骤中各项工艺参数，具体参数见表2：
表1实施例2～6中有效成分的原料用量一览表
Figure PCTCN2020109810-appb-000001
表2实施例2～6中各项工艺参数一览表
Figure PCTCN2020109810-appb-000002
Figure PCTCN2020109810-appb-000003
实施例2～6其它部分的内容，与实施例1相同。
对实施例1～6制备的畜用复方氨基酸注射液中各氨基酸含量与现有畜用复方氨基酸注射液中各氨基酸含量进行对比，具体情况见表3：
表3实施例1～6中制得的畜用复方氨基酸注射液质量检测结果一览表
Figure PCTCN2020109810-appb-000004
Figure PCTCN2020109810-appb-000005
由表3可知，实施例1～6制备的畜用复方氨基酸注射液的颜色相对于现有畜用复方氨基酸注射液由微黄色变成无色透明，且相对于现有的畜用复方氨基酸注射液色氨酸、脯氨酸、γ-氨基丁酸的含量更高、更平稳。
实施例7畜用复方氨基酸注射液的质量检测
本实施例对实施例1中的制备方法所制得的畜用复方氨基酸注射液，进行了质量检测。具体检测方法如下：
加速试验在温度40±2℃、相对湿度75±5％的条件下放置6个月，在试验期间第0个月、1个月、2个月、3个月、6个月末分别取样，按《国家食品药品监督管理局药品标准》WS1-(X-324)-2003Z的质量标准进行了检测，具体检测结果见表4：
表4畜用复方氨基酸注射液质量检测结果
Figure PCTCN2020109810-appb-000006
由表4可知，实施例1制备的畜用复方氨基酸注射液经过加速试验，各指标无明显变化，样品质量稳定性良好，具有很好的稳定性，因此，本发明的制备方法能够制备出更加稳定的畜用复方氨基酸注射液。
实施例8畜用复方氨基酸注射液的稳定性对比
分别按照实施例7的质量检测方法，分别对放置24个月后的实施例1～6中制得的畜用复方氨基酸注射液和现有畜用复方氨基酸注射液进行质量检测对比，具体检测结果见表5：
表5畜用复方氨基酸注射液质量检测对比结果
Figure PCTCN2020109810-appb-000007
Figure PCTCN2020109810-appb-000008
由表5可知，现有的畜用复方氨基酸注射液放置24个月后，色氨酸、脯氨酸、γ-氨基丁酸、酪氨酸的含量均有所下降，而本发明制备的畜用复方氨基酸注射液则更加稳定，含量变化不大。
实施例9畜用复方氨基酸注射液的应用
本实施例分别利用实施例1～6中制得的畜用复方氨基酸注射液和现有的畜用复方氨基酸注射液，将其应用于试验动物，具体方式如下：
a1)治疗牛病毒性腹泻上的应用
牛病毒性腹泻病，幼龄牛较易感，一般表现轻度症状，但有时突然暴发，全群表现严重症状。急性型临床症状表现为突然发热，体温升高至40～42℃，白细胞减少，少食或拒食，反刍停止，呼吸、心跳加快，咳嗽、流鼻涕，口腔黏膜潮红，唾液增多，继而出现糜烂，腹泻如水，持续数天，粪便中混有气泡和血液。严重者因脱水和衰竭而死。病程1～3周，犊牛发病死亡率可大于90％。慢性型临床症状不明显，病牛呈现生长发育缓慢，消瘦，持续或间歇性腹泻病程2～6个月。
分别采用实施例1～6中制得的畜用复方氨基酸注射液，进行临床试验：
莱西市众合兴牧的荷斯坦牛，存在腹泻症状，经当地兽医确诊，是由于感染牛病毒引起的，遂采用表6所示的方案配合盐酸林可霉素(使用量为3g/头)进行治疗。
表6畜用复方氨基酸注射液在牛病毒性腹泻上的应用
Figure PCTCN2020109810-appb-000009
Figure PCTCN2020109810-appb-000010
由表6可知，畜用复方氨基酸注射液对牛腹泻后体弱恢复具有促进作用，能够使牛食欲增加，恢复期缩短，生长恢复加快。而实施例1～6中制备的畜用复方氨基酸注射液对牛腹泻后体弱恢复的作用优于现有的畜用复方氨基酸注射液。
a2)治疗犬细小病毒上的应用
不同年龄、性别、品种的犬一年四季均可发生犬细小病毒病(主要是幼犬，特别是断奶前后的幼犬最易感)。本病的临床症状为患犬精神沉郁，食欲废绝，剧烈呕吐，腹泻，便血，严重者会因水、电解质平衡失调，体内营养物质大量流失并发酸中毒而死亡。发病率为20～100％，死亡率为50～100％。病犬发病期间需禁食禁饮，因此对病犬的补液、能量和营养物质是关键，否则病犬易产生低蛋白血症而出现水肿，由于频繁呕吐，不宜使用口服药物，采用输液疗法是治疗的关键，及时补充动物机体所需能量、蛋白和营养物质是重中之重。
分别采用实施例1～6中制得的畜用复方氨基酸注射液，进行了临床试验：
北京安默赛斯生物科技有限公司的比格犬，存在腹泻症状，经临床症状结合细小病毒试纸检测，诊断为细小病毒病，其治疗方案是表7所示的方案与抗菌素硫酸卡那霉素、10mg/kg和ATP-2Na、1mL配合治疗。
表7畜用复方氨基酸注射液在犬细小病毒上的应用
Figure PCTCN2020109810-appb-000011
由表7可知，畜用复方氨基酸注射液能够使犬病后及时补充营养，注射后，犬只食欲明显增加，体重恢复增长，有助于呕吐、脱水等症状的消退，且能够降低病犬的死亡率。而实施例1～6中制备的畜用复方氨基酸注射液对病犬恢复的作用优于现有的畜用复方氨基酸注射液。
需要注意，实施例1～6，仅是本发明的较佳实施例，并非是对本发明所作的其他形式的限定，任何熟悉本专业的技术人员都可能利用上述技术内容作为启示加以变更或改型为等同变化的等效实施例，但凡是未脱离本发明权利要求的技术实质，对以上实施例所作出的简单修改、等同变化与改型，仍属于本发 明权利要求保护的范围。

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  1. 一种畜用复方氨基酸注射液的制备方法，其特征在于，该制备方法包括依次进行的以下步骤：
    步骤1)制备基础液：
    在氮气保护下，取注射用水加入亚硫酸氢钠和乙二胺四乙酸二钠，75～100℃溶解，制得基础液A；
    步骤2)制备中间溶液：
    在氮气保护下，基础液A中加入B组氨基酸组，60～70℃溶解后，降温至20～35℃，制得溶液C；
    其中，B组氨基酸包括盐酸精氨酸、盐酸组氨酸、亮氨酸、异亮氨酸、盐酸赖氨酸、苯丙氨酸、苏氨酸、缬氨酸、甲硫氨酸、甘氨酸、丙氨酸、脯氨酸、丝氨酸、门冬氨酸、谷氨酸、色氨酸、酪氨酸和盐酸半胱氨酸；
    在氮气保护下，溶液C中加入γ-氨基丁酸，20～35℃溶解后，调节pH值至5.5～6.8，定容，制得中间溶液D；
    步骤3)制备畜用复方氨基酸注射液：
    在氮气保护下，中间溶液D中加入活性炭，脱色，过滤，制得所述畜用复方氨基酸注射液。
  2. 根据权利要求1所述的一种畜用复方氨基酸注射液的制备方法，其特征在于，对制得的所述畜用复方氨基酸注射液进行灭菌。
  3. 根据权利要求2所述的一种畜用复方氨基酸注射液的制备方法，其特征在于，灭菌前，在氮气保护下，灌装所述畜用复方氨基酸注射液。
  4. 根据权利要求1-3中任一项所述的一种畜用复方氨基酸注射液的制备方法，其特征在于，步骤1)中，注射用水经杀菌制得。
  5. 根据权利要求4所述的一种畜用复方氨基酸注射液的制备方法，其特征在于，步骤3)中，活性炭与中间溶液D的重量体积的比为0.5～1kg：1000L。
  6. 根据权利要求5所述的一种畜用复方氨基酸注射液的制备方法，其特征在于，步骤3)中，脱色的温度为20～35℃、时间为30～40min；
    过滤依次包括粗滤和精滤。
  7. 根据权利要求6所述的一种畜用复方氨基酸注射液的制备方法，其特征在于，精滤为微孔滤芯过滤。
  8. 根据权利要求7所述的一种畜用复方氨基酸注射液的制备方法，其特征在于，微孔滤芯的孔径为0.45μm、0.22μm或0.20μm。
  9. 根据权利要求3所述的一种畜用复方氨基酸注射液的制备方法，其特征在于，所述灌装过程中容器内残氧量≤3％。
  10. 根据权利要求2或3所述的一种畜用复方氨基酸注射液的制备方法，其特征在于，所述灭菌的温度为110～121℃、时间为15～40min。
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