WO2021012686A1 - 盐酸纳洛酮注射液及其制备方法 - Google Patents

盐酸纳洛酮注射液及其制备方法 Download PDF

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WO2021012686A1
WO2021012686A1 PCT/CN2020/078915 CN2020078915W WO2021012686A1 WO 2021012686 A1 WO2021012686 A1 WO 2021012686A1 CN 2020078915 W CN2020078915 W CN 2020078915W WO 2021012686 A1 WO2021012686 A1 WO 2021012686A1
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naloxone hydrochloride
hydrochloride injection
injection
content
ethylenediaminetetraacetate
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PCT/CN2020/078915
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English (en)
French (fr)
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刘军
黄梅
李南汐
高先庆
袁仕云
杨春玮
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广东奇方药业有限公司
舒美奇成都生物科技有限公司
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Publication of WO2021012686A1 publication Critical patent/WO2021012686A1/zh

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes

Definitions

  • the present invention belongs to the technical field of medicine. Specifically, the present invention relates to naloxone hydrochloride injection, which is formulated to have strong heat resistance and maintain the amount of related substances at an extremely low level under the conditions of high temperature sterilization and long-term storage. Thus, the high quality of the liquid preparation can be maintained. In addition, the present invention also relates to a preparation method of the naloxone hydrochloride injection.
  • Naloxone the chemical name is 17-allyl-4,5a-epoxy-3,14-dihydroxymorphinan-6-one, usually in the form of hydrochloride, is an opioid receptor antagonist It is mainly used to reverse the narcotic analgesia and respiratory depression caused by morphine substances (drugs), and can be used to rescue poisoning caused by alcohol and other substances.
  • Chinese patent (application) CN101590014A adopts strict pH control between 3.0 and 4.0 and filled with inert gas to prevent oxidative deterioration and reduce related substances, but it does not involve attention to heat resistance
  • Chinese patent (application) CN101732313A A pharmaceutical composition of naloxone hydrochloride and polyethylene glycol is disclosed, which is used to solve the problem of light instability of naloxone hydrochloride injection, but does not involve attention to heat resistance
  • Chinese patent (application ) CN104127380A relates to a naloxone hydrochloride injection, which includes naloxone hydrochloride, sugars, organic acids and water for injection, but does not involve attention to heat resistance
  • Chinese patent (application) CN103877016A uses a certain amount of Malic acid increases the stability of the naloxone hydrochloride aqueous solution, but does not involve the concern about heat resistance.
  • naloxone hydrochloride has poor heat resistance in aqueous solutions, the clarity, color, related substances, and content of the injection are easily disqualified after high temperature sterilization or long-term storage, which is not conducive to high temperature sterilization or long-term storage. And as mentioned above, in the face of this defect, no existing technology can effectively deal with it.
  • naloxone hydrochloride injection liquid preparations Chinese patents (applications) CN102274196A, CN1562023A, CN1615867A and CN103877578A all relate to freeze-dried powder injections of naloxone hydrochloride.
  • naloxone hydrochloride injection After arduous research, a new prescription for naloxone hydrochloride injection was unexpectedly developed to enhance its heat resistance. It is suitable for high temperature sterilization and long-term storage. It can be sterilized by overkilling with F0 value of 15. What is more unexpected is that the prescription of the naloxone hydrochloride injection has expanded its pH range suitable for high-temperature sterilization and long-term storage, and is closer to neutral pH, which is beneficial to improve compliance during injection. In addition, the naloxone hydrochloride injection has few prescription ingredients, low cost, and easy control of the preparation process, which is very conducive to popularization and application.
  • the technical problem to be solved by the present invention is to provide a new preparation of naloxone hydrochloride injection and its preparation method, which greatly improves the thermal stability of naloxone hydrochloride injection. Under the conditions of high temperature sterilization and long-term storage, the relative substance The amount remains at an extremely low level.
  • the present invention provides a sterilized naloxone hydrochloride injection, which is composed of naloxone hydrochloride, sodium chloride, ethylenediaminetetraacetate, hydrochloric acid, related substances and water for injection
  • the composition has a pH of 3.0 to 6.5.
  • sterilization refers to sterilization at 121°C for 15 minutes.
  • This preferred sterilization method is the first choice in the EU sterilization method selection decision tree, and its F0 value reaches 15.
  • the prescription of the naloxone hydrochloride injection in the first aspect of the present invention can withstand this preferred sterilization method, and only after sterilization in this way, the amount of related substances remains at an extremely low level.
  • the ethylenediaminetetraacetate can be disodium ethylenediaminetetraacetate or calcium sodium ethylenediaminetetraacetate.
  • Disodium ethylenediaminetetraacetic acid is the disodium salt of EDTA, which can be referred to as EDTA-2Na for short.
  • the content of disodium edetate is 0.001 mg/ml to 0.1 mg/ml, such as 0.001, 0.01 or 0.1 mg/ml.
  • Calcium sodium ethylenediaminetetraacetate is the calcium and disodium salt of EDTA, which can be referred to as EDTA-CaNa2 for short.
  • EDTA-CaNa2 the calcium and disodium salt of EDTA
  • the content of calcium sodium edetate is 0.001 mg/ml to 0.1 mg/ml, such as 0.001, 0.01 or 0.1 mg/ml.
  • the pH value of the naloxone hydrochloride injection in the first aspect of the present invention is 3.0 to 6.5, which means that the pH value used in the prior art to stabilize the quality of naloxone hydrochloride injection is 3.0 to 4.0, or the pH value is greater than 4.0 and less than or equal to 6.5, such as 4.1 to 6.5, 4.5 to 6.0 or 5.0 to 6.5.
  • the inventor found that even if the naloxone hydrochloride injection of the first aspect of the present invention adopts a pH value greater than 4.0 and less than or equal to 6.5, under the conditions of high temperature sterilization and long-term storage, the amount of related substances can still be kept extremely low. Level.
  • An injection with a pH closer to a neutral pH usually has lower pain during injection, and is more conducive to the drug delivery compliance of the present invention, which is very beneficial.
  • By adding different amounts of (concentrated) hydrochloric acid those skilled in the art can conveniently adjust the injection solution to the corresponding pH value.
  • the content of naloxone hydrochloride is calculated as naloxone hydrochloride anhydrate.
  • the content of naloxone hydrochloride is 0.02-4 mg/ml, preferably 0.2-2 mg/ml, more preferably 0.4-1 mg/ml, such as 0.4 mg /ml or 1mg/ml.
  • the content of naloxone hydrochloride is 0.4 mg/ml.
  • Sodium chloride is used as an isotonic agent.
  • the content of sodium chloride is 8.5-9.0 mg/ml.
  • the content of sodium chloride is 8.9 mg/ml.
  • the "concentration” and “content” of the ingredients (e.g., naloxone hydrochloride) in the composition can be used interchangeably, and both refer to the composition as a whole.
  • the proportion of can usually be expressed by weight volume concentration (eg, mg/ml).
  • the term "related substances" is well known to those skilled in the art, including impurities and degradation products introduced in the pharmaceutical preparation process.
  • the high and low content of the drug also determines the safety and effectiveness of the pharmaceutical preparation to a certain extent.
  • the amount of related substances is expressed in terms of relative content, which is calculated by the area normalization method of HPLC with the active substance (e.g., naloxone hydrochloride) after deducting known excipients, which is in the composition (
  • the absolute content of the injection solution is basically equal to the product of the content of the active substance (eg, naloxone hydrochloride) and the relative content.
  • the related substances in the naloxone hydrochloride injection of the first aspect of the present invention can still be kept at an extremely low level under the conditions of high temperature sterilization and long-term storage.
  • the amount of related substances in the naloxone hydrochloride injection of the first aspect of the present invention does not exceed 1%, more preferably does not exceed 0.8%, such as does not exceed 0.5% or 0.4%.
  • the amount of related substances in the naloxone hydrochloride injection of the first aspect of the present invention after sterilization at 121°C for 15 minutes does not exceed 0.5%, and more preferably does not exceed 0.4%.
  • the naloxone hydrochloride injection of the first aspect of the present invention is sterilized at 121°C for 15 minutes and placed at 40 ⁇ 2°C for 6 months, and the amount of related substances does not exceed 1%, and more preferably does not exceed 0.8%.
  • Such an extremely low level of related substance content ensures the high quality of the naloxone hydrochloride injection of the first aspect of the present invention, and ensures its safety and effectiveness under the conditions of high temperature sterilization and long-term storage.
  • the present invention provides a preparation method of naloxone hydrochloride injection of the first aspect of the present invention, which comprises:
  • the filtration can be one-step filtration, such as direct fine filtration.
  • the filtration is a two-step filtration. That is, the second intermediate solution of naloxone hydrochloride injection passes through the first step of filtration (coarse filtration, mainly to remove particulate matter) and the second step of filtration (fine filtration, the sterilization efficiency is guaranteed to reach more than 7 logarithmic units), so Prevent the filter membrane from being clogged by particles during fine filtration and improve the filtration efficiency.
  • the first step of the two-step filtration uses a filter membrane with a pore size of 0.4-0.5 ⁇ m
  • the second step uses a filter membrane with a pore size of 0.2-0.25 ⁇ m.
  • the pore size of the filter membrane used in the first step of the two-step filtration is 0.45 ⁇ m
  • the pore size of the filter membrane used in the second step is 0.22 ⁇ m.
  • the inert gas is a gas that has no oxidation reactivity at normal temperature.
  • the inert gas is nitrogen.
  • the present invention provides the use of ethylenediaminetetraacetate in the preparation of sterilized naloxone hydrochloride injection.
  • the sterilized naloxone hydrochloride injection is the sterilized naloxone hydrochloride injection of the first aspect of the present invention.
  • the ethylenediaminetetraacetate is disodium ethylenediaminetetraacetate or calcium sodium ethylenediaminetetraacetate.
  • the present invention provides the application of the naloxone hydrochloride injection of the first aspect of the present invention in the preparation of a medicine for treating diseases that can be treated by naloxone.
  • the diseases that naloxone can treat include toxic diseases, such as acute heroin poisoning, acute alcoholism, acute nitrite poisoning, organophosphorus pesticide poisoning and/or acute carbon monoxide poisoning; central system diseases, such as cerebral infarction (cerebral stroke) , Acute severe cerebral hemorrhage, traumatic diffuse brain swelling, acute severe head injury and/or dizziness; pediatric diseases, such as neonatal hypoxic-ischemic encephalopathy, neonatal asphyxia, primary apnea of premature infants and/or Convulsions persist in children; and, liver disease, schizophrenia, and/or severe myocardial ischemia.
  • toxic diseases such as acute heroin poisoning, acute alcoholism, acute nitrite poisoning, organophosphorus pesticide poisoning and/or acute carbon monoxid
  • the present invention has the following beneficial effects: the naloxone hydrochloride injection of the present invention can be sterilized at 121°C for 15 minutes (microbial survival probability ⁇ 10 -6 ), which is the most efficient method of overkilling with an F0 value of 15.
  • the bacteria redundancy is high, and under the conditions of high temperature sterilization and long-term storage, the related substances can still be maintained at an extremely low level, which ensures the safety and effectiveness of the medication; the naloxone hydrochloride injection of the present invention is at this high temperature.
  • naloxone hydrochloride injection of the present invention is not easy to be combined and used by criminals;
  • the naloxone hydrochloride injection of the invention has few prescription ingredients, low cost, and easy control of the preparation process.
  • Figure 1 is the HPLC chart of naloxone hydrochloride injection containing different concentrations of EDTA-2Na after sterilization at 121°C for 15 minutes, where A, B, C, D, E and F correspond to EDTA-2Na concentrations of 0, 0.0001, 0.0005, 0.001, 0.01 and 0.1 mg/ml.
  • Figure 2 is the HPLC chart of naloxone hydrochloride injection containing different concentrations of EDTA-2Na after sterilization at 115°C for 60 minutes, where A, B, C, D, E, and F correspond to EDTA-2Na concentrations of 0, 0.0001, 0.0005, 0.001, 0.01 and 0.1 mg/ml.
  • Figure 3 is the HPLC chart of naloxone hydrochloride injection containing different concentrations of EDTA-2Na after sterilization at 115°C for 32 minutes, where A, B, C, D, E, and F correspond to EDTA-2Na concentrations of 0, 0.0001, and 0.0005, 0.001, 0.01 and 0.1 mg/ml.
  • Figure 9 is an HPLC chart of naloxone hydrochloride injection containing different concentrations of EDTA-2K after sterilization at 121°C for 15 minutes, where A, B and C correspond to EDTA-2K concentrations of 0.001, 0.01 and 0.1 mg/ml, respectively.
  • Figure 10 is the HPLC chart of naloxone hydrochloride injection containing different concentrations of EDTA-CaNa2 after sterilization at 121°C for 15 minutes, where A, B, and C correspond to EDTA-CaNa2 concentrations of 0.001, 0.01 and 0.1 mg/ml, respectively.
  • Step 1 Weigh naloxone hydrochloride (calculated as anhydrous naloxone hydrochloride), sodium chloride and disodium edetate (an exemplary of disodium edetate in the prescription) The concentration can be respectively 0.001, 0.01 or 0.1mg/ml), add water for injection, mix and stir to make all of them dissolved to obtain the first intermediate solution of naloxone hydrochloride injection;
  • Step 2 Add water for injection to the first intermediate solution of naloxone hydrochloride injection to the prescribed amount, adjust the pH range of 3.0 to 6.5 (for example, 3.5, 4.5 or 6.0) with hydrochloric acid solution to obtain the first intermediate solution of naloxone hydrochloride injection Two intermediate solutions;
  • Step 3 Filter the second intermediate solution of naloxone hydrochloride injection in sequence in two steps, in which the first step has a filter membrane pore size of 0.45 ⁇ m; the second step has a filter membrane pore size of 0.22 ⁇ m to obtain a semi-finished product of naloxone hydrochloride injection;
  • Step 4 Perform visible foreign body inspection on the semi-finished naloxone hydrochloride injection, fill it with inert gas nitrogen, potting, and sterilize at 121°C for 15 minutes to obtain naloxone hydrochloride injection.
  • EDTA-2K dipotassium ethylenediaminetetraacetate
  • EDTA-CaNa2 calcium sodium ethylenediaminetetraacetate
  • the EDTA-2Na in the above preparation method is prepared to obtain naloxone hydrochloride injection containing EDTA-2K and naloxone hydrochloride injection containing EDTA-CaNa2.
  • an Agilent instrument (model: 1200) was used to analyze the naloxone hydrochloride injection (EDTA-2Na concentration of 0.001, 0.01 and 0.1 mg/ ml) and control samples (EDTA-2Na concentration of 0.0005, 0.0001 and 0mg/ml) related substances were detected.
  • the naloxone hydrochloride injection of the present invention is sterilized at 121°C for 15 minutes, and when it contains EDTA-2Na in the concentration range of 0.001 to 0.1 mg/ml, the content of related substances is basically maintained below 0.3%, and When the concentration of EDTA-2Na is lower than 0.001mg/ml, the content of related substances increases greatly, and when the concentration is higher than 0.001mg/ml, the effect tends to passivate or even decrease as the concentration increases; the content of 0.001 ⁇ EDTA-2Na within the concentration range of 0.01mg/ml can also make naloxone hydrochloride injection withstand the equivalent 115°C sterilization for 60 minutes, but the effect of each concentration is worse than the corresponding 121°C sterilization for 15 minutes.
  • the Agilent instrument (model: 1200) was used to sterilize the naloxone hydrochloride injection and the control sample (EDTA- EDTA-) in the prescription of the present invention with different pH values (3.5, 4.5 or 6.0) at 121°C for 15 minutes.
  • 2Na concentration is 0.0001mg/ml) related substances in the detection.
  • the naloxone hydrochloride injection of the present invention is sterilized at 121°C for 15 minutes, and when it contains EDTA-2Na in a concentration range of 0.001 to 0.1 mg/ml, it basically makes The content of related substances is equivalent to that under acidic pH, and when the concentration of EDTA-2Na is lower than 0.001mg/ml, the content of related substances rises greatly, and when the concentration is higher than 0.001mg/ml, as the concentration increases, the effect tends to be Passivation, even reduced.
  • the naloxone hydrochloride injection of the present invention can adopt a pH value that is closer to neutral. At this time, it is still suitable for high-temperature sterilization at 121°C for 15 minutes without increasing the content of related substances, and is closer to the neutral pH value.
  • the injection usually has lower pain during injection, and is more conducive to the drug delivery compliance of the present invention.
  • naloxone hydrochloride injections in the formulation of the present invention sterilized at 121°C for 15 minutes with different pH values (3.5, 4.5 or 6.0), were placed at 40 ⁇ 2°C for 6 months.
  • HPLC detection method Agilent instruments were used (Model: 1200), respectively detect related substances.
  • the related substance detection maps are shown in Figures 6-8, and the results are summarized in Table 3.
  • the naloxone hydrochloride injection of the present invention has undergone an accelerated stability test for 6 months. Compared with the immediately after sterilization, the content of related substances has a slight increase in varying degrees. The pH is closer to neutral and the EDTA-2Na The lower the concentration, the greater the increase, but none of them exceed 0.8%, most of which do not exceed 0.6%.
  • the results show that the naloxone hydrochloride injection of the present invention is suitable for long-term storage, and is expected to be stored for at least 24 months at room temperature, which is convenient for promotion.
  • the naloxone hydrochloride injection of the present invention is sterilized at 121°C for 15 minutes, and when it contains EDTA-2K in a concentration range of 0.001 to 0.1 mg/ml, the content of related substances decreases as the concentration of EDTA-2K increases. But even with the concentration of EDTA-2K of 0.1mg/ml, the content of related substances exceeds 0.5%; when it contains EDTA-CaNa2 in the concentration range of 0.001 ⁇ 0.1mg/ml, the content of related substances is higher than that of using the same amount of EDTA -2Na is even lower.
  • the results show that the naloxone hydrochloride injection of the present invention preferably uses EDTA-CaNa2.

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Abstract

一种盐酸纳洛酮注射液及其制备方法。所述注射液由盐酸纳洛酮、氯化钠、乙二胺四乙酸盐、盐酸、有关物质和水组成，其在121℃灭菌15min后有关物质的量不超过0.5%。所述制备方法包括将盐酸纳洛酮、乙二胺四乙酸盐和氯化钠溶解，用盐酸调节pH至3.0-6.5，过滤，充惰性气体，灌封，经121℃灭菌15min。

Description

盐酸纳洛酮注射液及其制备方法
在先申请
本申请要求中国专利申请第201910654630.3号(申请日：2019年7月19日)的优先权。
技术领域
本发明属于医药技术领域，具体而言，本发明涉及盐酸纳洛酮注射液，其处方使其耐热性强，在高温灭菌和长期存储的条件下有关物质的量保持在极低水平，从而能保持该液体制剂的高质量。另外，本发明还涉及该盐酸纳洛酮注射液的制备方法。
背景技术
纳洛酮，化学名称为17-烯丙基-4,5a-环氧基-3,14-二羟基吗啡喃-6-酮，通常以盐酸盐的形式成药，是阿片受体的拮抗剂，主要用于逆转由于吗啡类物质(毒品)造成的麻醉性镇痛以及呼吸抑制，并且能用于解救乙醇等物质引起的中毒等。
盐酸纳洛酮注射液的处方和制备工艺也有报道。例如，中国专利(申请)CN101590014A采用严格控制pH在3.0至4.0之间并充惰性气体，来防止氧化变质，减少有关物质，但是并不涉及对耐热性方面的关注；中国专利(申请)CN101732313A公开了一种盐酸纳洛酮与聚乙二醇的药物组合物，用于解决盐酸纳洛酮注射液对光不稳定的问题，但是并不涉及对耐热性方面的关注；中国专利(申请)CN104127380A涉及一种盐酸纳洛酮注射液，其包括盐酸纳洛酮、糖类、有机酸和注射用水，但是并不涉及对耐热性方面的关注；中国专利(申请)CN103877016A采用一定量的苹果酸，使得盐酸纳洛酮水溶液的稳定性增加，但是也不涉及对耐热性方面的关注，事实上是使用降低灭菌温度(100℃)的方式来处理；中国专利(申请)CN107485563A在盐酸纳洛酮注射液的制备设备使用时提及“加入依地酸二钠，以调节pH值至3-3.5”，而这是否可行存在着很大的 疑问，当然最终也是采用了降低灭菌温度(100℃)的方式来灭菌。
由于盐酸纳洛酮在水溶液中耐热性差，所以注射液的澄清度与颜色、有关物质和含量等质量指标经高温灭菌或长期放置容易不合格，不利于高温灭菌或长期保存。而且如上所述，面对这一缺陷，没有现有技术能加以有效应对。目前，同行利用降低灭菌温度(如，100℃或115℃)，换用或部分换用灭菌方式(如，辐照灭菌)，低温保存(如，4℃)，甚至直接减少药品有效期等方式来应对，但是，降低灭菌温度和减少灭菌时间直接导致灭菌不彻底，对于注射液制剂来说并不可取；改变灭菌方式和低温保存则直接增加成本，与减少药品有效期等方式一样，都不利于推广。
所以，目前同行都避免开发盐酸纳洛酮的注射用液体制剂，转而开发盐酸纳洛酮粉针剂等非液体制剂，以此避过耐热性方面的难题。例如，中国专利(申请)CN102274196A、CN1562023A、CN1615867A和CN103877578A等均涉及盐酸纳洛酮的冻干粉针剂。
本发明人继在中国专利CN103695497B中公开了一种制备纳洛酮的方法及制备获得的纳洛酮产品后，没有受限于现有技术的发展趋势，并不放弃关注盐酸纳洛酮注射液，研究发现，盐酸纳洛酮粉针剂等固体制剂容易被合并超量使用，会被不法分子利用，所以仍旧有开发新的盐酸纳洛酮注射液的必要；而且，本发明人没有畏于现有技术始终无法解决盐酸纳洛酮注射液耐热性差的难题，迎难而上，经过艰苦的研究，令人意外地开发出一种新的盐酸纳洛酮注射液处方，增强了其耐热性，使其适于高温灭菌和长期存储，可以采用F0值达到15的过度杀灭法灭菌。更令人意想不到的是，该盐酸纳洛酮注射液处方扩展了其适于高温灭菌和长期存储的pH值范围，更接近于中性pH值，有利于改善注射时的顺应性。另外，该盐酸纳洛酮注射液的处方成分少，成本低，制备工艺便于控制，十分利于推广应用。
发明内容
本发明要解决的技术问题在于提供新的制备盐酸纳洛酮注射液及其制备方法，大幅改善盐酸纳洛酮注射液的热稳定性，在高温灭菌和长期存储的条件下，有关物质的量保持在极低水平。
具体而言，在第一方面，本发明提供了经灭菌的盐酸纳洛酮注射液，其由盐酸纳洛酮、氯化钠、乙二胺四乙酸盐、盐酸、有关物质和注射用水组成，其pH值为3.0～6.5。
药物制剂，尤其是注射制剂，无菌保证对于其安全性来说至关重要。优选在本发明第一方面的盐酸纳洛酮注射液中，灭菌指的是121℃灭菌15min。该优选的灭菌方式是是欧盟灭菌方法选择决策树中的首选方式，其F0值达到15。本发明第一方面的盐酸纳洛酮注射液的处方能耐该优选的灭菌方式，仅该方式灭菌后，有关物质的量仍旧保持在极低水平。
本发明人研究发现，乙二胺四乙酸盐可以是乙二胺四乙酸二钠，也可以是乙二胺四乙酸钙钠。乙二胺四乙酸二钠是EDTA的二钠盐，可以简称为EDTA-2Na。优选在本发明第一方面的盐酸纳洛酮注射液中，乙二胺四乙酸二钠的含量为0.001mg/ml～0.1mg/ml，如为0.001、0.01或0.1mg/ml。乙二胺四乙酸钙钠是EDTA的钙和二钠盐，可以简称为EDTA-CaNa2。优选在本发明第一方面的盐酸纳洛酮注射液中，乙二胺四乙酸钙钠的含量为0.001mg/ml～0.1mg/ml，如为0.001、0.01或0.1mg/ml。本发明人发现，这一含量范围内的EDTA-2Na或EDTA-CaNa2有助于本发明第一方面的盐酸纳洛酮注射液在高温灭菌和长期存储的条件下将有关物质的量仍旧保持在极低水平，低于该范围下限，高温灭菌后有关物质的量急剧上升，而且该范围内基本不具有量效关系，浓度高于0.001mg/ml后，随着浓度的增加，效果趋于钝化、甚至有所降低。
本发明第一方面的盐酸纳洛酮注射液的pH值为3.0～6.5，即可以为现有技术中为了稳定盐酸纳洛酮注射液质量而采用的pH＝3.0～4.0，也可以pH值大于4.0且小于等于6.5，如4.1～6.5、4.5～6.0或5.0～6.5。本发明人发现，本发明第一方面的盐酸纳洛酮注射液即使采用大于4.0且小于等于6.5的pH值，在高温灭菌和长期存储的条件下，有关物质的量仍旧能保持在极低水平。更接近于中性pH值的注射液通常注射时的疼痛感更低，更有利于本发明药物的给药顺应性，这是十分有益的。通过加入不同量的(浓)盐酸，本领域技术人员可以方便地调节注射液到相应的pH值。
在本文中，如无相反指示，盐酸纳洛酮的含量以盐酸纳洛酮无水物计。优选在本发明第一方面的盐酸纳洛酮注射液中，盐酸纳洛酮的含量为0.02～4mg/ml， 优选为0.2～2mg/ml，更优选为0.4～1mg/ml，如为0.4mg/ml或1mg/ml。这样低含量的盐酸纳洛酮难以大量合并注射，难以为不法分子通过合并方式来大剂量使用。在本发明的具体实施方式中，盐酸纳洛酮的含量为0.4mg/ml。
氯化钠用于作为等渗剂使用。优选在本发明第一方面的盐酸纳洛酮注射液中，氯化钠的含量为8.5～9.0mg/ml。在本发明的具体实施方式中，氯化钠的含量为8.9mg/ml。
在本文中，如无相反指示，组合物(如，注射液)中成分(如，盐酸纳洛酮)的“浓度”和“含量”可以互换使用，都是指该成分在该组合物整体中所占的比重，通常可以用重量体积浓度(如，mg/ml)等来表示。
在本文中，术语“有关物质”是本领域技术人员所熟知的，包括药物制备工艺中引入的杂质和降解产物等，其含量的高和低也在一定程度上决定了药物制剂安全性和有效性的低和高。在本文中，有关物质的量是以相对含量来表示的，是扣除已知辅料后与活性物质(如，盐酸纳洛酮)通过HPLC的面积归一化法计算出的，其在组合物(如，注射液)中绝对含量基本等于活性物质(如，盐酸纳洛酮)的含量与该相对含量的乘积。
本发明第一方面的盐酸纳洛酮注射液中的有关物质在高温灭菌和长期存储的条件下仍旧能保持在极低水平。优选在本发明第一方面的盐酸纳洛酮注射液中，有关物质的量不超过1％，更优选不超过0.8％，如不超过0.5％或0.4％。优选本发明第一方面的盐酸纳洛酮注射液在121℃灭菌15min后有关物质的量不超过0.5％，更优选不超过0.4％。也优选本发明第一方面的盐酸纳洛酮注射液在121℃灭菌15min后并放置在40±2℃条件下6个月后有关物质的量不超过1％，更优选不超过0.8％。这样极低水平的有关物质含量确保了本发明第一方面的盐酸纳洛酮注射液的高质量，保证了其在高温灭菌和长期存储的条件下的安全性和有效性。
在第二方面，本发明提供了本发明第一方面的盐酸纳洛酮注射液的制备方法，其包括：
(1)将盐酸纳洛酮、乙二胺四乙酸盐和氯化钠混合溶解于注射用水中，得到盐酸纳洛酮注射液第一中间溶液；
(2)用盐酸对盐酸纳洛酮注射液调节pH值至3.0～6.5，得到盐酸纳洛酮注 射液第二中间溶液；
(3)过滤盐酸纳洛酮注射液第二中间溶液，充惰性气体，灌封(即，灌装并密封)，经121℃灭菌15min。
过滤可以一步过滤，如直接精滤。优选在本发明第二方面的制备方法中，过滤为两步过滤。即，盐酸纳洛酮注射液第二中间溶液依次通过第一步过滤(粗滤，主要去除颗粒物)和第二步过滤(精滤，除菌效率保证能达到7个对数单位以上)，这样防止精滤时滤膜被颗粒物堵塞，提高过滤效率。
两步过滤的第一步使用的过滤膜孔径为0.4～0.5μm，第二步使用的过滤膜孔径为0.2～0.25μm。在本发明的具体实施方式中，两步过滤的第一步使用的过滤膜孔径为0.45μm，第二步使用的过滤膜孔径为0.22μm。
惰性气体是在常温下不具有氧化反应性的气体。优选在本发明第二方面的制备方法中，惰性气体是氮气。
在第三方面，本发明提供了乙二胺四乙酸盐在制备经灭菌的盐酸纳洛酮注射液中的应用。优选其中，所述经灭菌的盐酸纳洛酮注射液是本发明第一方面的经灭菌的盐酸纳洛酮注射液。
优选在本发明第三方面的应用中，乙二胺四乙酸盐是乙二胺四乙酸二钠或乙二胺四乙酸钙钠。
在第四方面，本发明提供了本发明第一方面的盐酸纳洛酮注射液在制备用于治疗纳洛酮所能治疗的疾病的药物中的应用。纳洛酮能治疗的疾病包括，中毒性疾病，如急性海洛因中毒、急性酒精中毒、急性亚硝酸盐中毒、有机磷农药中毒和/或急性一氧化碳中毒；中枢系统疾病，如脑梗死(脑中风)、急性重症脑出血、外伤性弥漫性脑肿胀、急性重症颅脑损伤和/或眩晕；儿科疾病，如新生儿缺氧缺血性脑病、新生儿窒息、早产儿原发性呼吸暂停和/或小儿惊厥持续；以及，肝脏病变、精神分裂症和/或重度心肌缺血等。
本发明具有以下有益效果：本发明的盐酸纳洛酮注射液能够采用可以F0值达到15的过度杀灭法中最高效的121℃灭菌15min的方式(微生物残存概率＜10 -6)，灭菌冗余度高，而且在该高温灭菌和长期存储的条件下，有关物质仍旧能保持在极低水平，保证了用药安全性和有效性；本发明的盐酸纳洛酮注射液在该高温灭菌和长期存储的条件下保持高质量的pH值范围广，更接近于中性pH值， 有助于提高顺应性；本发明的盐酸纳洛酮注射液不易为不法分子所合并利用；本发明的盐酸纳洛酮注射液的处方成分少，成本低，制备工艺便于控制。
为了便于理解，以下将通过具体的实施例和附图对本发明进行详细地描述。需要特别指出的是，这些描述仅仅是示例性的描述，并不构成对本发明范围的限制。依据本说明书的论述，本发明的许多变化、改变对所属领域技术人员来说都是显而易见的。另外，本发明引用了公开文献，这些文献是为了更清楚地描述本发明，它们的全文内容均纳入本文进行参考，就好像它们的全文已经在本文中重复而明确记载过一样。
附图说明
图1是含有不同浓度EDTA-2Na的盐酸纳洛酮注射液在121℃灭菌15min后的HPLC图谱，其中A、B、C、D、E和F分别对应EDTA-2Na浓度为0、0.0001、0.0005、0.001、0.01和0.1mg/ml。
图2是含有不同浓度EDTA-2Na的盐酸纳洛酮注射液在115℃灭菌60min后的HPLC图谱，其中A、B、C、D、E和F分别对应EDTA-2Na浓度为0、0.0001、0.0005、0.001、0.01和0.1mg/ml。
图3是含有不同浓度EDTA-2Na的盐酸纳洛酮注射液在115℃灭菌32min后的HPLC图谱，其中A、B、C、D、E和F分别对应EDTA-2Na浓度为0、0.0001、0.0005、0.001、0.01和0.1mg/ml。
图4是含有不同浓度EDTA-2Na的pH＝4.5的盐酸纳洛酮注射液在121℃灭菌15min后的HPLC图谱，其中A、B、C和D分别对应EDTA-2Na浓度为0.0001、0.001、0.01和0.1mg/ml。
图5是含有不同浓度EDTA-2Na的pH＝6的盐酸纳洛酮注射液在121℃灭菌15min后的HPLC图谱，其中A、B、C和D分别对应EDTA-2Na浓度为0.0001、0.001、0.01和0.1mg/ml。
图6是含有不同浓度EDTA-2Na的pH＝3.5的盐酸纳洛酮注射液在121℃灭菌15min后经加速稳定性试验6个月后的HPLC图谱，其中A、B和C分别对应EDTA-2Na浓度为0.001、0.01和0.1mg/ml。
图7是含有不同浓度EDTA-2Na的pH＝4.5的盐酸纳洛酮注射液在121℃灭菌15min后经加速稳定性试验6个月后的HPLC图谱，其中A、B和C分别对应EDTA-2Na浓度为0.001、0.01和0.1mg/ml。
图8是含有不同浓度EDTA-2Na的pH＝6的盐酸纳洛酮注射液在121℃灭菌15min后经加速稳定性试验6个月后的HPLC图谱，其中A、B和C分别对应EDTA-2Na浓度为0.001、0.01和0.1mg/ml。
图9是含有不同浓度EDTA-2K的盐酸纳洛酮注射液在121℃灭菌15min后的HPLC图谱，其中A、B和C分别对应EDTA-2K浓度为0.001、0.01和0.1mg/ml。
图10是含有不同浓度EDTA-CaNa2的盐酸纳洛酮注射液在121℃灭菌15min后的HPLC图谱，其中A、B和C分别对应EDTA-CaNa2浓度为0.001、0.01和0.1mg/ml。
具体实施方式
以下通过实施例进一步说明本发明的内容。如未特别指明，实施例中所用的技术手段为本领域技术人员所熟知的常规手段和市售的常用仪器、试剂，可参见药剂学试验手册以及相应仪器和试剂的厂商说明书等参考。
1，处方(规格：0.4mg/ml)
Figure PCTCN2020078915-appb-000001
2，制备方法
步骤1：称取上述处方量的盐酸纳洛酮(以盐酸纳洛酮无水物计)、氯化钠和乙二胺四乙酸二钠(乙二胺四乙酸二钠在处方中的示例性浓度可以分别为0.001、0.01或0.1mg/ml)，加入注射用水，混合搅拌使其全部溶解，得到盐酸 纳洛酮注射液第一中间溶液；
步骤2：对盐酸纳洛酮注射液第一中间溶液补加注射用水至处方量，用盐酸溶液调节pH值范围3.0～6.5(如，3.5、4.5或6.0)，得到盐酸纳洛酮注射液第二中间溶液；
步骤3：将盐酸纳洛酮注射液第二中间溶液依次进行两步过滤，其中第一步过滤膜孔径为0.45μm；第二步过滤膜孔径为0.22μm，得半成品盐酸纳洛酮注射液；
步骤4：对半成品盐酸纳洛酮注射液进行可见异物检查，并在合格后充惰性气体氮气，灌封，经121℃灭菌15min，即得盐酸纳洛酮注射液。
另外，按照上述方法制备对照样品，所不同的是，乙二胺四乙酸二钠浓度分别为0.0005、0.0001和0(即不加EDTA-2Na)mg/ml；灭菌采用115℃灭菌60min(F0＝15)和115℃灭菌32min(F0＝8)。
另外，用等重量的乙二胺四乙酸二钾(EDTA-2K，CAS No：2001-94-7)和乙二胺四乙酸钙钠(EDTA-CaNa2，CAS No：23411-34-9)代替上述制备方法中的EDTA-2Na，制备获得含EDTA-2K的盐酸纳洛酮注射液和含EDTA-CaNa2的盐酸纳洛酮注射液。
经检测，灭菌前的盐酸纳洛酮注射液中的有关物质含量均在0.1％以下。
3，EDTA-2Na对不同灭菌条件下有关物质的影响
根据HPLC检测法，采用Agilent仪器(型号：1200)，分别对不同灭菌条件下pH＝3.5的本发明处方内的盐酸纳洛酮注射液(EDTA-2Na浓度分别为0.001、0.01和0.1mg/ml)和对照样品(EDTA-2Na浓度分别为0.0005、0.0001和0mg/ml)中的有关物质进行检测。
有关物质检测图谱如图1～3所示，结果汇总于表1中。其中，对本发明的盐酸纳洛酮注射液应用121℃灭菌15min，当其中含有在0.001～0.1mg/ml浓度范围内的EDTA-2Na时，基本上使得有关物质含量维持在0.3％以下，而EDTA-2Na的浓度低于0.001mg/ml后，有关物质含量极具上升，而浓度高于0.001mg/ml后，随着浓度的增加，效果趋于钝化、甚至有所降低；含有0.001～0.01mg/ml浓度范围内的EDTA-2Na也能使盐酸纳洛酮注射液经受住等效的115℃灭菌60min，但 是各浓度效果比相应121℃灭菌15min的都要差。结果表明，本发明的盐酸纳洛酮注射液适宜121℃高温灭菌15min(F0＝15)，比同样F0＝15的115℃灭菌效果还要好，由于该灭菌条件是欧盟灭菌方法选择决策树中的首选，因此这样的特点便于推广应用。
表1 不同浓度EDTA-2Na的注射液灭菌后的有关物质含量(％)
Figure PCTCN2020078915-appb-000002
另外，测试了115℃灭菌32min，其中EDTA-2Na各浓度的效果与相应121℃灭菌15min的相当，但是该灭菌条件仅仅F0＝8，尽管灭菌仍旧符合要求，但是已经几乎没有操作冗余，对灭菌设备和人员要求较高。
4，pH值对高温灭菌条件下有关物质的影响
根据HPLC检测法，采用Agilent仪器(型号：1200)，分别对121℃灭菌15min的不同pH值(3.5、4.5或6.0)的本发明处方内的盐酸纳洛酮注射液和对照样品(EDTA-2Na浓度为0.0001mg/ml)中的有关物质进行检测。
有关物质检测图谱如图1、4和5所示，结果汇总于表2中。其中，在更接近于中性的pH下，对本发明的盐酸纳洛酮注射液应用121℃灭菌15min，当其中含有在0.001～0.1mg/ml浓度范围内的EDTA-2Na时，基本上使得有关物质含量与酸性pH下的相当，而EDTA-2Na的浓度低于0.001mg/ml后，有关物质含量极具上升，而浓度高于0.001mg/ml后，随着浓度的增加，效果趋于钝化、甚至有所降低。结果表明，本发明的盐酸纳洛酮注射液可以采用更接近于中性的pH值，此时仍旧适宜121℃高温灭菌15min而基本不增加有关物质含量，而更接近于中性pH值的注射液通常注射时的疼痛感更低，更有利于本发明药物的给药顺应性。
表2 不同pH值的注射液灭菌后的有关物质含量(％)
Figure PCTCN2020078915-appb-000003
5，本发明的盐酸纳洛酮注射液的稳定性
分别将121℃灭菌15min的不同pH值(3.5、4.5或6.0)的本发明处方内的盐酸纳洛酮注射液放置在40±2℃条件下6个月，根据HPLC检测法，采用Agilent仪器(型号：1200)，分别检测其中的有关物质。
有关物质检测图谱如图6～8所示，结果汇总于表3中。其中，本发明的盐酸纳洛酮注射液经过加速稳定性试验6个月后，相对于刚灭菌后的，有关物质含量有不同程度的微量上升，其中pH越接近中性、EDTA-2Na的浓度越低，上升程度越大，但是均不超过0.8％，其中大部分不超过0.6％。结果表明，本发明的盐酸纳洛酮注射液适宜长期存放，预计在室温下至少能存放24个月，便于推广。
表3 不同pH值的注射液灭菌高温放置后的有关物质含量(％)
Figure PCTCN2020078915-appb-000004
6，EDTA-2K和EDTA-Ca2Na对121℃灭菌条件下有关物质的影响
根据HPLC检测法，采用Agilent仪器(型号：1200)，分别对对121℃灭菌15min、pH＝3.5的含EDTA-2K的盐酸纳洛酮注射液(EDTA-2K浓度分别为0.001、0.01和0.1mg/ml)和含EDTA-CaNa2的盐酸纳洛酮注射液(EDTA-CaNa2浓度分别为0.001、0.01和0.1mg/ml)中的有关物质进行检测。
有关物质检测图谱如图9和10所示，结果汇总于表4中。其中，对本发明的盐酸纳洛酮注射液应用121℃灭菌15min，当其中含有在0.001～0.1mg/ml浓度范围内的EDTA-2K时，有关物质含量随EDTA-2K的浓度增加而降低，但是即使是0.1mg/ml的EDTA-2K浓度，有关物质含量也超过了0.5％；当其中含有在0.001～0.1mg/ml浓度范围内的EDTA-CaNa2时，有关物质含量比使用等量的EDTA-2Na还要低。结果表明，本发明的盐酸纳洛酮注射液优选使用 EDTA-CaNa2。
表4 不同浓度EDTA-2K和EDTA-CaNa2的注射液灭菌后的有关物质含量(％)
Figure PCTCN2020078915-appb-000005
这样的结果出乎预料，因为EDTA-CaNa2中Ca离子是被微弱地络合的，而EDTA-2K与EDTA-2Na的性质更为接近，然而使用EDTA-CaNa2的效果却更好。这暗示了EDTA盐对高温灭菌后有关物质含量的影响不仅仅取决于EDTA本身，与EDTA盐中的金属离子也有关系。

Claims (23)

  1. 经灭菌的盐酸纳洛酮注射液，其由盐酸纳洛酮、氯化钠、乙二胺四乙酸盐、盐酸、有关物质和注射用水组成，其pH值为3.0～6.5，其中，乙二胺四乙酸盐的含量为0.001mg/ml～0.1mg/ml，盐酸纳洛酮的含量为0.2～2mg/ml，氯化钠的含量为8.5～9.0mg/ml，而且其在121℃灭菌15min后有关物质的量不超过0.5％。
  2. 权利要求1所述的盐酸纳洛酮注射液，其中，乙二胺四乙酸盐是乙二胺四乙酸二钠，优选其中，乙二胺四乙酸二钠的含量为0.001、0.01或0.1mg/ml。
  3. 权利要求1所述的盐酸纳洛酮注射液，其中，乙二胺四乙酸盐是乙二胺四乙酸钙钠，优选其中，乙二胺四乙酸钙钠的含量为0.001、0.01或0.1mg/ml。
  4. 权利要求1所述的盐酸纳洛酮注射液，其中，盐酸纳洛酮的含量为0.4～1mg/ml，优选为0.4mg/ml或1mg/ml。
  5. 权利要求1所述的盐酸纳洛酮注射液，其中，氯化钠的含量为8.9mg/ml。
  6. 权利要求1所述的盐酸纳洛酮注射液，其中，有关物质的量不超过1％，优选不超过0.8％，更优选不超过0.5％，例如不超过0.4％。
  7. 权利要求1所述的盐酸纳洛酮注射液，其在121℃灭菌15min后有关物质的量不超过0.4％。
  8. 权利要求1所述的盐酸纳洛酮注射液，其在121℃灭菌15min后并放置在40±2℃条件下6个月后有关物质的量不超过1％，优选不超过0.8％。
  9. 权利要求1～8之一所述的盐酸纳洛酮注射液的制备方法，其包括：
    (1)将盐酸纳洛酮、乙二胺四乙酸盐和氯化钠混合溶解于注射用水中，得到盐酸纳洛酮注射液第一中间溶液；
    (2)用盐酸对盐酸纳洛酮注射液调节pH值至3.0～6.5，得到盐酸纳洛酮注射液第二中间溶液；
    (3)过滤盐酸纳洛酮注射液第二中间溶液，充惰性气体，灌封，经121℃灭菌15min。
  10. 权利要求9所述的制备方法，其中，过滤为两步过滤。
  11. 权利要求10所述的制备方法，其中，两步过滤的第一步使用的过滤膜孔径为0.4～0.5μm，以及第二步使用的过滤膜孔径为0.2～0.25μm。
  12. 乙二胺四乙酸盐在制备经灭菌的盐酸纳洛酮注射液中的应用，其中，所述盐酸纳洛酮注射液由盐酸纳洛酮、氯化钠、乙二胺四乙酸盐、盐酸、有关物质和注射用水组成，所述盐酸纳洛酮注射液pH值为3.0～6.5。
  13. 权利要求12所述的应用，其中，乙二胺四乙酸盐是乙二胺四乙酸二钠。
  14. 权利要求13所述的应用，其中，所述盐酸纳洛酮注射液中的乙二胺四乙酸二钠的含量为0.001mg/ml～0.1mg/ml，如为0.001、0.01或0.1mg/ml。
  15. 权利要求12所述的应用，其中，乙二胺四乙酸盐是乙二胺四乙酸钙钠。
  16. 权利要求15所述的应用，其中，所述盐酸纳洛酮注射液中的乙二胺四乙酸钙钠的含量为0.001mg/ml～0.1mg/ml，如为0.001、0.01或0.1mg/ml。
  17. 权利要求12所述的应用，其中，所述盐酸纳洛酮注射液中的盐酸纳洛酮的含量为0.02～4mg/ml，优选为0.2～2mg/ml，更优选为0.4～1mg/ml，如为0.4mg/ml或1mg/ml。
  18. 权利要求12所述的应用，其中，所述盐酸纳洛酮注射液中的氯化钠的含量为8.5～9.0mg/ml，优选为8.9mg/ml。
  19. 权利要求12所述的应用，其中，所述盐酸纳洛酮注射液中的有关物质的量不超过1％，优选不超过0.8％，如不超过0.5％或0.4％。
  20. 权利要求12所述的应用，其中，所述盐酸纳洛酮注射液在121℃灭菌15min后有关物质的量不超过0.5％，优选不超过0.4％。
  21. 权利要求12所述的应用，其中，所述盐酸纳洛酮注射液在121℃灭菌15min后并放置在40±2℃条件下6个月后有关物质的量不超过1％，优选不超过0.8％。
  22. 权利要求1～8之一所述的盐酸纳洛酮注射液在制备用于治疗纳洛酮所能治疗的疾病的药物中的应用。
  23. 权利要求22所述的应用，所述疾病是急性海洛因中毒、急性酒精中毒、急性亚硝酸盐中毒、有机磷农药中毒、急性一氧化碳中毒、脑梗死、急性重症脑出血、外伤性弥漫性脑肿胀、急性重症颅脑损伤、眩晕、新生儿缺氧缺血性脑病、新生儿窒息、早产儿原发性呼吸暂停、小儿惊厥持续、肝脏病变、精神分裂症或重度心肌缺血。
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