WO2021203605A1 - 畜用复方氨基酸注射液及其制备方法 - Google Patents

畜用复方氨基酸注射液及其制备方法 Download PDF

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WO2021203605A1
WO2021203605A1 PCT/CN2020/109660 CN2020109660W WO2021203605A1 WO 2021203605 A1 WO2021203605 A1 WO 2021203605A1 CN 2020109660 W CN2020109660 W CN 2020109660W WO 2021203605 A1 WO2021203605 A1 WO 2021203605A1
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amino acid
parts
compound amino
acid injection
livestock
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French (fr)
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陈淑芳
李凤英
赵素娟
郭艳玉
李艳
王伟光
邢江盼
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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
    • 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
    • A61K31/185—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
    • 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
    • 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
    • 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 livestock injection and a preparation method thereof, in particular to a compound amino acid injection for livestock and a preparation method thereof.
  • 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.
  • Adjuvant treatment of diseases and post-ill recovery period to enhance physical fitness and increase animal feed intake.
  • this technical solution has a certain effect on the treatment of animal diseases and the restoration of the body during the recovery period after the disease, the compound amino acid injection for animals still has the defect of low content, which is not conducive to the recovery of the animal body.
  • the specific reasons for the above defects are as follows:
  • the pH value of animal compound amino acid injection limits its inability to increase the overall amino acid content by increasing amino acids, resulting in low amino acid content in animal amino acid injections;
  • the existing compound amino acid injections for livestock have low amino acid content, which is not conducive to the rapid recovery of the animal body.
  • the purpose of the present invention is to provide a compound amino acid injection for animals to solve the problem of low amino acid content in the injection for animals;
  • Another object of the present invention is to provide a method for preparing the above-mentioned compound amino acid injection for livestock.
  • a compound amino acid injection for animal use the raw materials for making its active ingredients include: group A amino acids, group B amino acids, group C amino acids and antioxidants;
  • group A amino acids in parts by weight, include: 1.00 to 11.20 parts of arginine hydrochloride, 0.80 to 6.80 parts of histidine hydrochloride, 2.89 to 16.60 parts of leucine, 0.50 to 13.50 parts of isoleucine, 1.00 ⁇ 12.70 parts of lysine hydrochloride, 1.00 ⁇ 16.30 parts of phenylalanine, 0.80 ⁇ 6.50 parts of threonine, 0.50 ⁇ 12.60 parts of valine, 0.50 ⁇ 8.80 parts of methionine, 1.00 ⁇ 18.24 parts of glycine, 0.80 ⁇ 16.30 parts alanine, 0.50-9.50 parts proline, 0.25-7.50 parts serine, 0.50-6.00 parts aspartic acid, 0.75-18.60 parts glutamic acid;
  • Group B amino acids in parts by weight, include: 0.20 ⁇ 4.50 parts tryptophan, 0.05 ⁇ 1.40 parts tyrosine, 0.10 ⁇ 1.00 parts cysteine hydrochloride;
  • Group C amino acids in parts by weight, include: 0.50 ⁇ 2.00 parts of ⁇ -aminobutyric acid;
  • Antioxidants in parts by weight, include: 0.50 ⁇ 2.00 parts of sodium bisulfite and 0.10 ⁇ 0.30 parts of disodium ethylenediaminetetraacetic acid;
  • the raw materials used to make it also include, make up to 1000 parts by volume with water;
  • the ratio of parts by weight to parts by volume is kg:L.
  • the present invention also provides a preparation method of the compound amino acid injection for livestock, which includes the following steps in sequence:
  • the ratio of parts by weight to parts by volume is kg:L;
  • activated carbon is added to the intermediate solution G, decolorized, and filtered to prepare the animal compound amino acid injection.
  • the inert gas is nitrogen.
  • the prepared animal compound amino acid injection is sterilized.
  • the animal compound amino acid injection is filled under the protection of inert gas before sterilization.
  • step 1) the water for injection is prepared through sterilization.
  • the weight-volume ratio of the activated carbon to the intermediate solution G is 0.5-1 kg:1000L.
  • the temperature of decolorization is 20 to 35° C., and the time is 30 to 40 min;
  • Filtration includes coarse filtration and fine filtration in turn;
  • 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 improves the content and stability of the amino acid in the compound amino acid injection for livestock by adjusting the formula and process parameters of the amino acid.
  • the details are as follows:
  • the present invention changes the pH value of the animal amino acid injection by adjusting the amount of leucine, using arginine hydrochloride, histidine hydrochloride, lysine hydrochloride, and cysteine hydrochloride to change the pH value of the animal amino acid injection and increase the amino acid.
  • the solubility of Amino Acid which in turn increases the content of each amino acid in the animal amino acid injection, makes the product more stable, saves production costs, and has better curative effects.
  • the total amount of amino acids is increased by about 10%, and the tryptophan content is increased. About 20%;
  • the present invention prepares animal amino acid injections by changing the feeding conditions, which shortens the dissolution time, thereby reducing the preparation time and improving the efficiency;
  • the preparation method of stepwise feeding increases the stability of tryptophan, tyrosine and ⁇ -aminobutyric acid, and improves the solubility of tryptophan, tyrosine and ⁇ -aminobutyric acid;
  • the preparation method of stepwise feeding can effectively prevent the oxidation of tryptophan, tyrosine and ⁇ -aminobutyric acid, thereby increasing the amount of tryptophan, tyrosine and ⁇ -aminobutyric acid in animal amino acid injections.
  • the content of GABA The content of GABA.
  • the invention is suitable for body repair during the treatment of livestock diseases and during the recovery period after the disease.
  • Examples 1 to 6 are respectively a compound amino acid injection for animal use.
  • the active ingredients are made of the same raw materials. The difference is that the amount of raw materials in different embodiments is different. The amount is calculated in parts by weight. The following table is injected per 1000L Liquid as an example, the amount of active ingredients used is shown in Table 1:
  • Example 1 The following is the preparation method of the compound amino acid injection for animals in Example 1. Taking 1000L compound injection for animals as an example, it includes the following steps in sequence:
  • nitrogen can also be replaced with carbon dioxide or argon.
  • Sodium bisulfite has the effect of preventing the oxidation of tryptophan and tyrosine. Therefore, adding sodium bisulfite before adding each amino acid has a better antioxidant effect; disodium ethylenediaminetetraacetate can be combined with the raw materials.
  • the metal ions perform chelation to prevent the metal ions from catalyzing the oxidation of amino acids. Therefore, in this embodiment, the sodium bisulfite and disodium edetate are dissolved before each amino acid is added.
  • 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, inactive gas protection is used at the beginning of the preparation, which can effectively reduce the oxygen content in the drug solution and make the amino acid sterilize afterwards. And more stable during storage.
  • nitrogen can also be replaced by carbon dioxide or argon;
  • nitrogen can also be replaced by carbon dioxide or argon;
  • nitrogen can also be replaced with carbon dioxide or argon.
  • the dissolution time of amino acids decreases with the increase of temperature.
  • the dissolution time is the shortest, and when the temperature is higher than 70°C, most of the amino acid content changes no longer change significantly.
  • each amino acid is added step by step to add arginine hydrochloride, histidine hydrochloride, leucine, isoleucine, lysine hydrochloride, phenylalanine, threonine, and va Acid, methionine, glycine, alanine, proline, serine, aspartic acid, glutamic acid are dissolved between 70 ⁇ 100°C, tryptophan and tyrosine are dissolved at 60 ⁇ 70°C Dissolve at the same time, and at the same time dissolve cysteine hydrochloride, in order to reduce the oxidation of tryptophan and tyrosine in the process of dissolving.
  • ⁇ -aminobutyric acid has a high solubility 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 H which is a compound amino acid injection for livestock;
  • nitrogen can also be replaced with carbon dioxide or argon.
  • the content of each amino acid will decrease to varying degrees. This is because as the amount of activated carbon increases, the adsorbed amount of amino acids will increase, especially tryptophan and tyrosine.
  • 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.
  • 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:
  • nitrogen can also be replaced by carbon dioxide or argon; the residual oxygen content in the infusion bottle has been controlled below 3.0% during the entire filling process.
  • 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.
  • the compound amino acid injections for animal use prepared in Examples 1 to 6 increased the amount of leucine to make the ratio of amino acid injections for animal use more suitable. Instead, arginine hydrochloride, histidine hydrochloride, and lysine hydrochloride were used instead. Acid and cysteine hydrochloride increase the solubility of arginine, histidine, lysine and cysteine.
  • the compound hydrochloric acid makes the solution acidic during the preparation of animal amino acid injection, which also increases The solubility of other amino acids increases the content of each amino acid in the animal amino acid injection.
  • the content of each amino acid in the animal compound amino acid injection in Examples 1 to 6 is the same as that of the existing animal compound amino acid injection.
  • Table 3 The specific conditions are shown in Table 3:
  • 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 standards of "National Food and Drug Administration Drug Standards" WS1 ⁇ (X ⁇ 324) ⁇ 2003Z have been tested, and the specific testing 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 animal use prepared in Examples 1 to 6 and the existing compound amino acid injections for animal use were tested and compared after being placed for 24 months.
  • the specific test results are as follows :
  • 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. has diarrhea symptoms. After the clinical symptoms and the parvovirus test paper, the diagnosis is parvovirus disease.
  • the treatment plan is the plan shown in Table 7 and the 10mg/kg antibiotic sulfate card. Namycin and 1mL/kg of ATP ⁇ 2Na are combined for 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.

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Abstract

一种畜用复方氨基酸注射液，该注射液的有效成分包括动物机体所需的18种氨基酸和γ-氨基丁酸，通过调整亮氨酸的用量、改用盐酸精氨酸、盐酸组氨酸、盐酸赖氨酸和盐酸半胱氨酸，提高了畜用氨基酸注射液中各氨基酸的含量，使得产品更加稳定，节约了生产成本，同时具有更好的疗效，解决了现有畜用复方氨基酸注射液含量较低的问题；上述畜用复方氨基酸注射液的制备方法，采用分步加料制备畜用氨基酸注射液，增加了色氨酸、酪氨酸和γ-氨基丁酸的稳定性和溶解度，防止其氧化，解决了现有畜用复方氨基酸注射液稳定性差的问题；所述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

畜用复方氨基酸注射液及其制备方法 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及其制备方法，具体地说是一种畜用复方氨基酸注射液及其制备方法。
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。虽然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，但畜用复方氨基酸注射液仍存在含量低的缺陷，不利于动物机体的恢复，存在上述缺陷的具体原因如下：
其一，由于畜用复方氨基酸注射液制备过程中溶解度的限制，造成畜用复方畜用氨基酸注射液中氨基酸含量低；
其二，畜用复方氨基酸注射液的pH值限制了其不能够通过增加氨基酸而提高整体氨基酸的含量，造成畜用氨基酸注射液中氨基酸含量低；
其三，由于现有技术中制备畜用复方氨基酸注射液过程中酪氨酸、色氨酸容易氧化，进一步导致畜用复方氨基酸注射液中的酪氨酸和色氨酸含量降低，。
尤其是，现有技术中，畜用复方氨基酸注射液制备过程中是在二氧化碳保护下，将酪氨酸和其他氨基酸一并加入到75～95℃的基础液中。由于酪氨酸在高温下不稳定，容易氧化变质，因此上述制备方法降低了畜用复方氨基酸注射液的稳定性的同时，也降低了注射液中氨基酸的含量，不利于畜用复方氨基酸注射液的制备和储存。
综上所述，现有的畜用复方氨基酸注射液中氨基酸含量低，不利于动物机体的快速恢复。
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，以解决畜用注射液中各氨基酸含量低的问题；
本发明的另一个目的，是要提供上述畜用复方氨基酸注射液的制备方法。
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，制成它的有效成分的原料包括：A组氨基酸、B组氨基酸、C组氨基酸和抗氧剂；
其中，A组氨基酸，以重量份数计，包括：1.00～11.20份盐酸精氨酸、0.80～6.80份盐酸组氨酸、2.89～16.60份亮氨酸、0.50～13.50份异亮氨酸、1.00～12.70份盐酸赖氨酸、1.00～16.30份苯丙氨酸、0.80～6.50份苏氨酸、0.50～12.60份缬氨酸、0.50～8.80份甲硫氨酸、1.00～18.24份甘氨酸、0.80～16.30份丙氨酸、0.50～9.50份脯氨酸、0.25～7.50份丝氨酸、0.50～6.00份门冬氨酸、0.75～18.60份谷氨酸；
B组氨基酸，以重量份数计，包括：0.20～4.50份色氨酸、0.05～1.40份酪氨酸、0.10～1.00份盐酸半胱氨酸；
C组氨基酸，以重量份数计，包括：0.50～2.00份γ-氨基丁酸；
抗氧剂，以重量份数计，包括：0.50～2.00份亚硫酸氢钠、0.10～0.30份乙二胺四乙酸二钠；
制成它的原料还包括，用水补至体积份数1000份；
其中，重量份数与体积份数的比例关系为kg：L。
本发明还提供了上述畜用复方氨基酸注射液的一种制备方法，包括依次进行的以下步骤：
步骤1)制备基础液：
在非活性气体保护下，取重量份数计600～800份注射用水加入抗氧剂，75～100℃溶解，制得基础液D；
步骤2)制备中间溶液：
在非活性气体保护下，基础液D中加入A组氨基酸，70～100℃溶解，自然降温至60～70℃，制得溶液E；
在非活性气体保护下，溶液E中加入B组氨基酸，60～70℃溶解，自然降温至20～35℃，制得溶液F；
在非活性气体保护下，溶液F中加入C组氨基酸，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G；
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：
在非活性气体保护下，中间溶液G中加入活性炭，脱色，过滤，制得所述畜用复方氨基酸注射液。
作为本发明的一种限定，所述非活性气体为氮气。
作为本发明的进一步限定，对制得的所述畜用复方氨基酸注射液进行灭菌。
作为本发明的再进一步限定，灭菌前，在非活性气体保护下，灌装所述畜 用复方氨基酸注射液。
作为本发明的一种限定，步骤1)中，注射用水经杀菌制得。
作为本发明的进一步限定，步骤3)中，活性炭与中间溶液G的重量体积比为0.5～1kg：1000L。
作为本发明的进一步限定，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、精滤；
精滤为微孔滤芯过滤；
微孔滤芯的孔径为0.45μm、0.22μm或0.20μm。
作为本发明的更进一步限定，所述灌装过程中容器内残氧量≤3％。
作为本发明的再进一步限定，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，通过调整氨基酸的配方和工艺参数，提高了畜用复方氨基酸注射液中氨基酸的含量和稳定性，具体如下：
其一，本发明通过调整亮氨酸的用量、改用盐酸精氨酸、盐酸组氨酸、盐酸赖氨酸和盐酸半胱氨酸，改变了畜用氨基酸注射液的pH值，增加了氨基酸的溶解度，进而提高了畜用氨基酸注射液中各氨基酸的含量，使得产品更加稳定，节约了生产成本，同时具有更好的疗效，其中氨基酸总量提高了约10％，色氨酸含量提高了约20％；
其二，本发明通过改变加料条件制备畜用氨基酸注射液，缩短了溶解时间，进而减少了制备时间，提高了效率；
其三，采用分步加料的制备方法，增加了色氨酸、酪氨酸和γ-氨基丁酸的稳定性，提高了色氨酸、酪氨酸和γ-氨基丁酸的溶解度；
其四，采用分步加料的制备方法，能够有效防止色氨酸、酪氨酸和γ-氨基 丁酸的氧化作用，进而提高了畜用氨基酸注射液中色氨酸、酪氨酸和γ-氨基丁酸的含量。
本发明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1～6 畜用复方氨基酸注射液及其制备方法
实施例1～6分别为一种畜用复方氨基酸注射液，制成它的有效成分的原料相同，不同之处在于不同实施例中原料的用量不同，按照重量份数计，下表以每1000L注射液为例，其中使用有效成分原料的用量见表1：
表1 各有效成分原料的用量比一览表
Figure PCTCN2020109660-appb-000001
Figure PCTCN2020109660-appb-000002
下述为实施例1中的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，包括依次进行的以下步骤：
步骤1)制备基础液：
取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注射用水，在氮气保护下，将称量好的亚硫酸氢钠和乙二胺四乙酸二钠加入到800L水温为95℃注射用水中，搅拌待其完全溶解，制得基础液D；
其中，氮气也可以使用二氧化碳或氩气替代。
亚硫酸氢钠具有防止色氨酸和酪氨酸氧化的作用，因此在加入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，因此本实施例中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非活性气体保护，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。
步骤2)制备中间溶液：
称取1kg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、0.8kg苏氨酸、12.6kg缬氨酸、1.79kg 甲硫氨酸、3.24kg甘氨酸、0.8kg丙氨酸、2.4kg脯氨酸、0.25kg丝氨酸、0.5kg门冬氨酸、1.34kg谷氨酸，称为A组氨基酸；
在氮气保护下，将称量好的A组氨基酸加至温度为100℃的基础液D中，搅拌溶解，制得溶液E，溶液E自然降温至70℃；
其中，氮气也可以使用二氧化碳或氩气替代；
称量1.32kg色氨酸、0.15kg酪氨酸、0.76kg盐酸半胱氨酸，统称为B组氨基酸；
在氮气保护下，将称量好的B组氨基酸加至温度为70℃的溶液E中，搅拌溶解，制得溶液F，溶液F自然降温至30℃；
其中，氮气也可以使用二氧化碳或氩气替代；
在氮气保护下，将0.89kgγ-氨基丁酸加入至温度为30℃的溶液F中，搅拌溶解，加入注射用水至近1000L，再用质量浓度为20％氢氧化钠溶液调节pH值至6.0，最终定容至1000L，制得中间溶液G；
其中，氮气也可以使用二氧化碳或氩气替代。
氨基酸的溶解时间随温度的升高而缩短，温度为100℃时，溶解时间最短，而高于70℃时的各温度条件下，大部分氨基酸含量变化不再发生明显变化。
但由于酪氨酸、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℃的溶液内的溶解含量较高(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，分步加入各氨基酸，将盐酸精氨酸、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、谷氨酸于70～100℃之间溶解，将色氨酸和酪氨酸于60～70℃时溶解，并同时溶解盐酸半胱氨酸，以降低色氨酸和酪氨酸溶解过程中的氧化作用。
由于γ-氨基丁酸在60～100℃时溶解度较高，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G中，脱色30min，经粗滤、0.45μm的微孔滤芯精滤，得溶液H，即为畜用复方氨基酸注射液；
其中，氮气也可以使用二氧化碳或氩气替代。
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，氨基酸的被吸附量也会增加，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H灌装至1000mL输液瓶中，115℃灭菌30min，灯检合格，得瓶装的畜用复方氨基酸注射液；
其中，氮气也可以使用二氧化碳或氩气替代；整个灌装过程中输液瓶内残氧量一直控制在3.0％以下。
在灌装过程中将输液瓶内残氧量控制在3.0％以下，能够有效提高注射液中各氨基酸的稳定性。
下述分别为实施例2～6中的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，制备步骤与实施例1的制备方法相同，不同之处在于步骤中各项工艺参数有差别，具体不同工艺参数见下表：
表2 实施例2～6的不同参数
Figure PCTCN2020109660-appb-000003
实施例2～6其它部分的内容，与实施例1相同。
实施例1～6制备的畜用复方氨基酸注射液，通过增加了亮氨酸的用量，使得畜用氨基酸注射液配比更加合适，而改用盐酸精氨酸、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，实施例1～6中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的具体情况见表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 PCTCN2020109660-appb-000004
Figure PCTCN2020109660-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均有所提高，且其他检查相关项均已全部合格。
实施例7 畜用复方氨基酸注射液的稳定性检测
本实施例对实施例1制备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 PCTCN2020109660-appb-000006
Figure PCTCN2020109660-appb-000007
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，对实施例1～6中制得的畜用复方氨基酸注射液、现有畜用复方氨基酸注射液放置24个月后分别进行质量检测对比，具体检测结果如下：
表5 畜用复方氨基酸注射液质量检测对比结果
Figure PCTCN2020109660-appb-000008
Figure PCTCN2020109660-appb-000009
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1～6制得的畜用复方氨基酸注射液中的各氨基酸含量均高于现有的畜用复方氨基酸注射液，其在24个月内稳定，质量可控，安全可靠。
实施例9 畜用复方氨基酸注射液的应用
本实施例将实施例1～6中的畜用复方氨基酸注射液应用于试验动物，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。
采用实施例1～6中任意一种畜用复方氨基酸注射液与现有畜用复方氨基酸注射液，分别进行临床试验：
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 PCTCN2020109660-appb-000010
Figure PCTCN2020109660-appb-000011
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。
采用实施例1～6中任意一种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10mg/kg抗菌素硫酸卡那霉素和1mL/kg的ATP～2Na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 PCTCN2020109660-appb-000012
Figure PCTCN2020109660-appb-000013
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。

Claims (10)

  1. 一种畜用复方氨基酸注射液，其特征在于，制成它的有效成分的原料包括：A组氨基酸、B组氨基酸、C组氨基酸和抗氧剂；
    其中，A组氨基酸，以重量份数计，包括：1.00～11.20份盐酸精氨酸、0.80～6.80份盐酸组氨酸、2.89～16.60份亮氨酸、0.50～13.50份异亮氨酸、1.00～12.70份盐酸赖氨酸、1.00～16.30份苯丙氨酸、0.80～6.50份苏氨酸、0.50～12.60份缬氨酸、0.50～8.80份甲硫氨酸、1.00～18.24份甘氨酸、0.80～16.30份丙氨酸、0.50～9.50份脯氨酸、0.25～7.50份丝氨酸、0.50～6.00份门冬氨酸、0.75～18.60份谷氨酸；
    B组氨基酸，以重量份数计，包括：0.20～4.50份色氨酸、0.05～1.40份酪氨酸、0.10～1.00份盐酸半胱氨酸；
    C组氨基酸，以重量份数计，包括：0.50～2.00份γ-氨基丁酸；
    抗氧剂，以重量份数计，包括：0.50～2.00份亚硫酸氢钠、0.10～0.30份乙二胺四乙酸二钠。
  2. 权利要求1所述的畜用复方氨基酸注射液的一种制备方法，其特征在于，包括依次进行的以下步骤：
    步骤1)制备基础液：
    在非活性气体保护下，取注射用水加入抗氧剂，75～100℃溶解，制得基础液D；
    步骤2)制备中间溶液：
    在非活性气体保护下，基础液D中加入A组氨基酸，70～100℃溶解，降温至60～70℃，制得溶液E；
    在非活性气体保护下，溶液E中加入B组氨基酸，60～70℃溶解，降温至20～35℃，制得溶液F；
    在非活性气体保护下，溶液F中加入C组氨基酸，20～35℃溶解后，调节pH值至5.5～6.8，定容，制得中间溶液G；
    步骤3)制备畜用复方氨基酸注射液：
    在非活性气体保护下，中间溶液G中加入活性炭，脱色，过滤，制得所述畜用复方氨基酸注射液。
  3. 根据权利要求2所述的畜用复方氨基酸注射液的制备方法，其特征在于，所述非活性气体为氮气。
  4. 根据权利要求3所述的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。
  5. 根据权利要求4所述的畜用复方氨基酸注射液的制备方法，其特征在于，灭菌前，在非活性气体保护下，灌装所述畜用复方氨基酸注射液。
  6. 根据权利要求2～5中任一项所述的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。
  7. 根据权利要求6所述的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G的重量体积比为0.5～1kg：1000L。
  8. 根据权利要求6所述的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、精滤。
  9. 根据权利要求5所述的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4或5所述的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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