WO2023097706A1 - 一种聚合血红蛋白在制备防治呼吸衰竭药物中的应用 - Google Patents

一种聚合血红蛋白在制备防治呼吸衰竭药物中的应用 Download PDF

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WO2023097706A1
WO2023097706A1 PCT/CN2021/135696 CN2021135696W WO2023097706A1 WO 2023097706 A1 WO2023097706 A1 WO 2023097706A1 CN 2021135696 W CN2021135696 W CN 2021135696W WO 2023097706 A1 WO2023097706 A1 WO 2023097706A1
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drug
polymerized hemoglobin
sodium
group
oxygen
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French (fr)
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游可为
李剑波
张彦鹏
石松
王文刚
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润方（北京）生物医药研究院有限公司
润方(北京)生物科技有限公司
游可为
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Publication of WO2023097706A1 publication Critical patent/WO2023097706A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/41—Porphyrin- or corrin-ring-containing peptides
    • A61K38/42—Haemoglobins; Myoglobins
    • 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
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention belongs to the technical field of medicine, and in particular relates to the application of polymerized hemoglobin in the preparation of medicines for preventing and treating respiratory failure.
  • Asthma (Bronchial Asthma, BA) and chronic obstructive pulmonary disease (COPD) are common respiratory diseases characterized by progressive airflow limitation and destructive lung disease.
  • Acute lung injury (acute lung injury, ALI) is acute hypoxic respiratory insufficiency caused by the progression of diffuse lung lesions, while pulmonary fibrosis (PF) is a group of destructive lung diseases with different etiologies and common pathological features. One of the leading causes of death from disease.
  • BA, ALI, COPD and PF are four different diseases, there is an inseparable relationship between them. They are all relatively serious lung diseases that cause respiratory failure.
  • PF pulmonary fibrosis
  • the lung is the main organ of the respiratory system.
  • the metabolic processes of the human body include external respiration/pulmonary respiration (gas exchange between the lungs and the external environment and lung ventilation-gas exchange between the alveoli and the blood) and internal respiration/tissue respiration (gas transport through the blood Gas exchange between blood and tissue cells or interstitial fluid after reaching the tissue)
  • respiration/tissue respiration gas transport through the blood Gas exchange between blood and tissue cells or interstitial fluid after reaching the tissue
  • Oxygen therapy is a means of treatment in BA, ALI, COPDPF, or IF without exacerbating lung disease.
  • Oxygen therapy can increase blood oxygen saturation, thereby improving the patient's cardiopulmonary function, reducing blood viscosity, increasing oxygen supply to the heart, and delaying the progression of the disease.
  • To avoid potential heart failure in patients with lung disease early low-flow oxygen inhalation is necessary.
  • the ultimate goal of oxygen inhalation is to maintain proper tissue oxygen supply with minimal cardiopulmonary work, increase blood oxygen saturation, correct hypoxemia, and ensure that tissue cells receive moderate oxygen to restore and maintain their functions.
  • the percutaneous oxygen saturation can be maintained above 90%, and some injuries caused by hypoxia, such as pulmonary hypertension and pulmonary vascular resistance, can be improved, and the quality of life has been improved, but the time of inhaling low-flow oxygen every day is longer. For a long time, the quality of life of patients has not been effectively improved.
  • the pulmonary blood vessels are ischemic due to the influence of the disease, or vascular occlusion caused by inflammation. Therefore, oxygen therapy is not simply inhalation of oxygen. It is necessary to formulate different oxygen therapy plans according to different conditions in a reasonable and standardized manner under the guidance of doctors.
  • the present invention provides an application of polymerized hemoglobin in the preparation of a drug for preventing and treating respiratory failure, and the respiratory failure is selected from asthma, acute lung injury, chronic pulmonary obstruction or pulmonary fibrosis.
  • the medicament containing polymerized hemoglobin of the present invention is an isotonic colloid solution, which can correct the viscosity of blood vessels in the lungs and alleviate pulmonary blood ischemia, ischemia and hypoxia and the inflammatory damage caused by it when used in small doses.
  • the medicine is prepared by adding medically acceptable auxiliary materials to polymerized hemoglobin.
  • the medicament contains 12.0-140.0 g of polymerized hemoglobin per 1 L of the medicament.
  • neuroprotective agents can also be added to the drug.
  • the said excipients are prepared by dissolving in 1L of water for injection by weight, and the specific proportions are as follows: 5.6-6.6g of sodium chloride, 0.3-0.48g of potassium chloride, 0.2-0.4g of calcium chloride dihydrate, acetyl Cysteine 2.0 ⁇ 2.14g, bis-3,5-dibromosalicylic acid fumarate 0 ⁇ 2.08g, sodium acetate trihydrate 0 ⁇ 7.47g, sodium hydroxide 0 ⁇ 0.48g, sodium lactate 0 ⁇ 3.0g .
  • the clinically commonly used neuroprotective agent is prepared by dissolving one or more of the following substances in 1L of water for injection by weight, and the specific ratio is 0.15-60.0 mg of edaravone and 0.60-60 mg of ganglioside 55.0mg, butylphthalide 3.0 ⁇ 315.0mg, vinpocetine 0.15 ⁇ 125.0mg, citicoline 3.0 ⁇ 520.0mg.
  • the drug is the following substances dissolved in 1L of water for injection, and the specific ratio is as follows: the specific ratio is as follows: 65.0 g of polymerized hemoglobin, 6.6 g of sodium chloride, 0.3 g of potassium chloride, and 0.2 g of calcium chloride dihydrate , 0.4 g of sodium hydroxide, 3.0 g of sodium lactate, and 2.0 g of acetylcysteine.
  • the drug is the following substances dissolved in 1L of water for injection, and the specific ratio is as follows: the specific ratio is as follows: 65.0 g of polymerized hemoglobin, 6.6 g of sodium chloride, 0.3 g of potassium chloride, and 0.2 g of calcium chloride dihydrate , Sodium Hydroxide 0.35g, Sodium Lactate 3.0g, Acetylcysteine 2.0g, Edaravone 3.24mg.
  • the drug is that the following substances are dissolved in 1L of water for injection, and the specific proportions are as follows: 65.0g of polymerized hemoglobin, 5.6g of sodium chloride, 0.48g of potassium chloride, 0.4g of calcium chloride dihydrate, acetylcysteine Amino acid 2.1g, bis-3,5-dibromosalicylic acid fumarate 2.08g, sodium acetate trihydrate 7.47g.
  • the respiratory failure is selected from asthma, acute lung injury, chronic pulmonary obstruction or pulmonary fibrosis.
  • the polymerized hemoglobin in the present invention is derived from human or animal hemoglobin after modification to form a stable molecular polymer, thereby prolonging the half-life of natural hemoglobin in blood and avoiding its depolymerization into dimers in vivo.
  • Drugs prepared from polymerized hemoglobin have the characteristics of non-toxicity, low immunogenicity, good rheological properties, longer circulation residence time and normal physiological metabolic pathways.
  • the polymerized hemoglobin of the present invention is prepared according to the preparation method of cross-linked hemoglobin in the publication number CN110563836A.
  • the drug administration routes described in the present invention include, but are not limited to, intravenous injection and arterial injection.
  • the medicine described in the present invention is a colloidal solution, and small dose perfusion will not bring damage caused by reperfusion to the lungs, but can slow down the ischemia caused by the impact of the disease on the lung blood vessels, or the vascular occlusion caused by inflammation caused by ischemia;
  • the medicine described in the present invention is a red blood cell substitute, which can increase the total hemoglobin concentration in plasma, thereby increasing the arterial oxygen content. Wide temperature range (2 ⁇ 40°C), no blood coagulation risk and other advantages;
  • the drug of the present invention is an oxygen-carrying drug, in which the particle size of polymerized hemoglobin is only one-thousandth of that of red blood cells, but its oxygen-carrying capacity is as high as 7 to 9 times that of red blood cells, which can provide oxygen to relieve lung cancer.
  • short-term administration can be maintained for a long period of time, improving the quality of life of patients with lung damage caused by diseases;
  • Neuroprotective agents can be added to the medicine of the present invention, which can synergistically and effectively regulate inflammatory mediators, adjust the balance of anti-inflammatory mediators, and reduce the effect of inflammatory mediators, so as to exert a better protective effect on lung tissue.
  • Polyhemoglobin in the following examples is prepared according to the method of Example 1 in CN110563836A.
  • the drug containing polymerized hemoglobin in this embodiment is that the following substances are dissolved in 1L of water for injection, and the specific ratios are as follows: polymerized hemoglobin 140.0g, sodium chloride 6.0g, potassium chloride 0.48g, dihydrate chloride Calcium 0.27g, sodium hydroxide 0.31g, sodium lactate 1.75g, acetylcysteine 2.14g.
  • the drug containing polymerized hemoglobin in this embodiment is that the following substances are dissolved in 1L of water for injection, and the specific ratios are as follows: polymerized hemoglobin 65.0g, sodium chloride 6.6g, potassium chloride 0.3g, dihydrate chloride Calcium 0.2g, sodium hydroxide 0.4g, sodium lactate 3.0g, acetylcysteine 2.0g.
  • the drug containing polymerized hemoglobin in this embodiment is that the following substances are dissolved in 1L of water for injection, and the specific ratios are as follows: polymerized hemoglobin 65.0g, sodium chloride 6.6g, potassium chloride 0.3g, dihydrate chloride Calcium 0.2g, sodium hydroxide 0.35g, sodium lactate 3.0g, acetylcysteine 2.0g, edaravone 3.24mg.
  • the drug containing polymerized hemoglobin in this embodiment is that the following substances are dissolved in 1L of water for injection, and the specific ratios are as follows: polymerized hemoglobin 65.0g, sodium chloride 5.6g, potassium chloride 0.48g, dihydrate chloride Calcium 0.4g, acetylcysteine 2.1g, bis-3,5-dibromosalicylic acid fumarate 2.08g, sodium acetate trihydrate 7.47g.
  • the drug containing polymerized hemoglobin in this embodiment is that the following substances are dissolved in 1L of water for injection, and the specific ratios are as follows: polymerized hemoglobin 65.0g, sodium chloride 5.6g, potassium chloride 0.48g, dihydrate chloride Calcium 0.4g, acetylcysteine 2.1g, bis-3,5-dibromosalicylic acid fumarate 2.08g, sodium acetate trihydrate 7.47g, citicoline 37.14mg.
  • the drug containing polymerized hemoglobin in this embodiment is that the following substances are dissolved in 1L of water for injection, and the specific ratios are as follows: polymerized hemoglobin 12.0g, sodium chloride 6.2g, potassium chloride 0.35g, dihydrate chloride Calcium 0.4g, acetylcysteine 2.0g, bis-3,5-dibromosalicylic acid fumarate 1.2g, sodium acetate trihydrate 5.7g.
  • Test drug the drug comprising polymerized hemoglobin prepared in Example 4, wherein the hemoglobin content is 65.0 g/L;
  • mice 32 male Wistar rats of SPF grade, weighing 180-220g, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., and the experimental animals were kept in sterile cages with independent air supply, and the litter was 60Co radiation. Disinfected corn cob litter, particle size 4 ⁇ 6mm. Rats were fed with sterilized feed specially formulated for mice, and purified water was freely available to drink. The temperature in the animal laboratory is kept at about 25°C, the relative humidity is kept at 40-70%, and the light is 12 hours a day.
  • the grouping and dosage of Wistar rats are shown in Table 1, and the administration began on the second day after the model was established, once a day.
  • Each calibration point on the pre-defined master curve is adjusted (recalibrated) to a new, instrument-specific measurement level, ie the working curve, by assaying the high and low calibrator.
  • the measuring instrument automatically calculates the content of HA, LN, PIIIP and CIV of each sample by means of a working curve obtained by calibration of the main curve through two points, and the results are expressed in ng/ml.
  • Test drug the drug containing polymerized hemoglobin prepared in Example 2, wherein the hemoglobin content is 65.0 g/L;
  • Test animals Wistar rats, weighing 200-250 g, male, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., the test animals were kept in sterile cages with independent air supply, and the litter was corn sterilized by 60Co radiation. Core padding, particle size 4 ⁇ 6mm. Rats were fed with sterilized feed specially formulated for mice, and purified water was freely available. The temperature in the animal laboratory is kept at about 25°C, the relative humidity is kept at 40-70%, and the light is 12 hours a day.
  • Wistar rats were ear-marked
  • the rats were anesthetized by intraperitoneal injection of 2% pentobarbital (40mg/kg), and the three groups were randomly divided into three groups, 4 rats in each group, which were administered through the dorsal vein of the penis.
  • the protective drug was given first, and the toxic substance was given 10 minutes later. , executed 6 hours after administration.
  • the rats were weighed 6 hours after administration.
  • Serum supernatant and alveolar lavage fluid IL-1 ⁇ was detected by radioimmunoassay, and the measurement range was 0.03-8.1 ng/ml.
  • the rats in the NS group had no obvious limitation by clinical visual inspection. After the injury, the LPS group and the HBOC group successively developed shortness of breath, individual rats had wheezing, and cyanosis of limbs and lips.
  • the pathological changes of the lungs were mainly widening of the alveolar septa, exudation and aggregation of a large number of white blood cells, atrophy of some alveoli, and exudate and hemorrhage in the alveolar cavity.
  • the degree of injury in the LPS group gradually increased over time, while the extent and degree of lesion in the HBOC group were significantly reduced compared with the LPS group.
  • Test drug the drug comprising polymerized hemoglobin prepared in Example 3, wherein the hemoglobin content is 65.0 g/L, and Edaravone is 3.24 mg;
  • Positive drug the drug containing polymerized hemoglobin prepared in Example 2, wherein the hemoglobin content is 65.0 g/L.
  • mice 16 SPF male SD rats, weighing 180-220g, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., and the experimental animals were kept in sterile cages with independent air supply, and the litter was 60Co radiation Disinfected corn cob litter, particle size 4 ⁇ 6mm. Rats were fed with sterilized feed specially formulated for mice, and purified water was freely available to drink. The temperature in the animal laboratory is kept at about 25°C, the relative humidity is kept at 40-70%, and the light is 12 hours a day.
  • Rats in the normal group were anesthetized by intraperitoneal injection of 10% chloral hydrate on the 1st and 14th day and then fixed, pressed the base of the tongue with a tongue depressor, and gently inserted into the trachea of the rat with a curved gavage needle to feel the tracheal cartilage Ring, thickening of the breath sound of the rat is the standard for successful insertion, and then slowly inject 200 ⁇ l of 1 ⁇ g/ml lipopolysaccharide. The two lungs were distributed as evenly as possible. After the completion, the rats were reared individually, and put back into the original cage after the consciousness, behavior, and activities were completely restored.
  • the rats were put into a closed passive smoking box at 8:00 p.m. every day from the 2nd to 13th day and the 15th to 28th day (the top is a cigarette lighter box, and only the side wall is left with a 1 cm diameter channel).
  • Model group, positive control group and drug group were established by passive smoking.
  • the method was the same as that of the normal group, except that the rats were put into the airtight passive smoking box at 8:00 p.m. every day from the 2nd to 13th day and the 15th to 28th day, 2 cigarettes/time/10min, continuous passive smoking for 4 times, the interval between changing cigarettes is 5min/time.
  • the right upper lung and right lower lung were taken, rinsed with normal saline, fixed in 10% neutral formalin solution, dehydrated, embedded in paraffin and sectioned, and the condition of lung tissue and bronchi were observed by HE staining , and the expression of matrix metalloproteinase-9 (MMP-9) and matrix metalloproteinase-12 (MMP-12), immunohistochemical cysteine protease protein (Caspase-12) and enhancer binding protein homologous protein ( CHOP) expression.
  • MMP-9 matrix metalloproteinase-9
  • MMP-12 matrix metalloproteinase-12
  • CHOP enhancer binding protein homologous protein
  • the F and RI values of the positive control group and the drug group were significantly decreased, and the PIF and Cdyn values were significantly increased, indicating that the compound drug containing polymerized hemoglobin and neuroprotective agent (drug group) and the drug containing polymerized hemoglobin alone (Positive control group) has a significant curative effect on improving clinical symptoms such as airflow limitation and dyspnea caused by obstructive ventilatory disorder, and the curative effect of the compound drug containing neuroprotective agent is more significant.
  • MMP has a prominent effect on smoke-induced COPD, and is closely related to the physiological process of airway remodeling inflammatory response.
  • the expression of MMP-9 and MMP-12 in the model group was high, and the expression of MMP-9 and MMP-12 were significantly weakened after the application of single or compound drugs containing polymerized hemoglobin drugs, and the expression of the drug group had obvious advantages.
  • Caspase-12 and CHOP as important factors in immunohistochemical endoplasmic reticulum stress response, are closely related to lung tissue apoptosis.
  • the expressions of Caspase-12 and CHOP in rats treated with single or compound drugs containing polymerized hemoglobin were significantly lower than those in the model group, and the expression of the drug group had a clear advantage.
  • the present inventor also conducted the above tests on other embodiments, and the results are basically the same, and will not be listed one by one due to limited space.

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Abstract

一种聚合血红蛋白在制备防治呼吸衰竭药物中的应用。所述的药物是一种载氧药物，也是一种胶体溶液。具有良好的流变学性质，较长的循环停留时间和正常的生理代谢途径等特点，与同样具有载氧功能的全血或红细胞相比，无需配型，工作温度范围为2～40℃，无凝血风险、稳定时长达36个月等优势。其中聚合血红蛋白粒径尺寸仅为红细胞的千分之一，但载氧能力却高达红细胞的7～9倍，小剂量的灌注可缓解组织缺血状况和减轻炎症反应，并能到达红细胞不可及的微循环末端有效供氧。也可加入神经保护剂制备成复方药物，更有助于降低呼吸衰竭患者的炎症状态，减少氧自由基损伤。

Description

一种聚合血红蛋白在制备防治呼吸衰竭药物中的应用 技术领域
本发明属于医药技术领域，具体涉及一种聚合血红蛋白在制备防治呼吸衰竭药物中的应用。
背景技术
哮喘(Bronchial Asthma，BA)和慢肺阻(chronic obstructive pulmonary diseases，COPD)是一种以气流逐渐受限的破坏性肺部疾病为特征的常见性呼吸系统疾病，急性肺损伤(acute lung injury，ALI)是肺部弥漫性病变进展导致的急性低氧性呼吸功能不全，而肺纤维化(pulmonary fibrosis，PF)是一组病因各异且具有共同病理特征的一类肺破坏性疾病，是肺脏疾病致死的主要原因之一。BA、ALI、COPD和PF虽是四个不同的疾病，但四者之间有密不可分的关系，都是比较严重的肺部疾病，造成呼吸衰竭。BA反复发作易导致肺部感染，进而出现肺炎、ALI、COPD等相关疾病，进展累积可成PF。PF典型的病理特征表现为肺泡上皮细胞损伤、成纤维细胞过度增生、细胞外基质沉积、肺组织结构变形、肺功能衰竭等。PF常指特发性肺纤维化，是特发性间质性肺炎中最常见的一种，占47％～71％。
BA、ALI或COPDPF进展累积均可导致PF，多在40～50岁发病，大部分PF患者发病3～8年后死亡，平均生存时间只有2.5～3年，目前尚无有效的治疗手段，支持治疗以延长其生存期。进行性呼吸困难是BA、ALI、COPD或PF的主要症状之一，且常伴有低氧血症。吸氧可以缓解病情，改善生存质量。
肺脏是呼吸系统的主要器官，人体新陈代谢过程有外呼吸/肺呼吸(肺与外界环境的气体交换和肺换气-肺泡与血液之间的气体交换)和内呼吸/组织呼吸(气体经过血液运输到达组织后血液与组织细胞或组织液之间的气体交换) 两种，肺脏除了主管呼吸功能外，与心血管系统也有着密切的联系。
氧疗是治疗BA、ALI、COPDPF或IF中的一种手段，不会加重肺部疾病。氧疗可使血氧饱和度增加，进而改善患者的心肺功能，使血液粘稠度降低，增加心脏供氧，延缓病情的发展。为避免肺疾病患者潜在心衰的发生，早期低流量吸氧是有必要的。吸氧的最终目的是在心肺做功最小的情况下维持适当的组织氧供，提高血氧饱和度，纠正低氧血症，保证组织细胞得到适度的氧气以恢复和维持其功能。通过吸氧使经皮血氧饱和度维持在90％以上，并且能够改善肺动脉高压和肺血管阻力等一些因缺氧造成的损伤，使生活质量有所改善，但每天吸入低流速的氧气时间较长，患者生活质量感并未得以有效改善。而且肺部血管因病症影响引起缺血，或炎症引起的血管闭塞而缺血。所以氧疗并非简单吸入氧气，需要在医师指导下合理、规范的根据不同的病情制定不同的氧疗方案。
鉴于以上原因，特提出本发明。
发明内容
为了解决现有技术存在的以上问题，本发明提供了一种聚合血红蛋白在制备防治呼吸衰竭药物中的应用，呼吸衰竭选自哮喘、急性肺损伤、慢肺阻或肺纤维化病症。本发明的含有聚合血红蛋白药物为等渗的胶体溶液，小剂量使用可以纠正肺部血管血液的粘稠度和缓解肺部血光缺血，以及缺血缺氧及其带来的炎症损伤。
为了实现上述目的，本发明采用如下技术方案：
一种聚合血红蛋白在制备防治呼吸衰竭药物中的应用。
进一步的，所述的药物为聚合血红蛋白加入医学上可接受的辅料制成。
进一步的，所述的药物中每1L药物中含聚合血红蛋白为12.0～140.0g。
进一步的，所述的药物中还可加入临床常用的神经保护剂。
进一步的，所述的辅料以重量计溶解在1L注射用水中制成，具体比例如 下：氯化钠5.6～6.6g、氯化钾0.3～0.48g、二水氯化钙0.2～0.4g、乙酰半胱氨酸2.0～2.14g、双3,5-二溴水杨酸富马酸酯0～2.08g、三水乙酸钠0～7.47g、氢氧化钠0～0.48g、乳酸钠0～3.0g。
进一步的，所述的临床常用的神经保护剂为以下一种或几种物质以重量计溶解在1L注射用水中制成，具体比例为依达拉奉0.15～60.0mg、神经节苷脂0.60～55.0mg、丁苯酞3.0～315.0mg，长春西汀0.15～125.0mg、胞磷胆碱3.0～520.0mg。
进一步的，所述的药物为以下各物质溶解在1L注射用水中，具体比例如下：具体比例如下：聚合血红蛋白65.0g、氯化钠6.6g、氯化钾0.3g、二水氯化钙0.2g、氢氧化钠0.4g、乳酸钠3.0g、乙酰半胱氨酸2.0g。
进一步的，所述的药物为以下各物质溶解在1L注射用水中，具体比例如下：具体比例如下：聚合血红蛋白65.0g、氯化钠6.6g、氯化钾0.3g、二水氯化钙0.2g、氢氧化钠0.35g、乳酸钠3.0g、乙酰半胱氨酸2.0g、依达拉奉3.24mg。
进一步的，所述的药物为以下各物质溶解在1L注射用水中，具体比例如下：聚合血红蛋白65.0g、氯化钠5.6g、氯化钾0.48g、二水氯化钙0.4g、乙酰半胱氨酸2.1g、双3,5-二溴水杨酸富马酸酯2.08g、三水乙酸钠7.47g。
进一步的，所述的呼吸衰竭选自哮喘、急性肺损伤、慢肺阻或肺纤维化病症。
本发明的中的聚合血红蛋白来源于人源或动物源的血红蛋白经修饰后形成一种稳定的分子聚合物，从而延长天然血红蛋白在血液中的半衰期，并避免其在体内解聚成二聚体。以聚合血红蛋白制备的药物具有无毒性，低免疫原性，并且具有良好的流变学性质，较长的循环停留时间和正常的生理代谢途径等特点。
本发明的聚合血红蛋白按照公开号CN110563836A中交联血红蛋白的制备方法制成而成。
本发明中所述的药物给药途径包括但不限于静脉注射、动脉注射途径。
与现有技术相比，本发明的有益效果为：
(1)本发明所述的药物是一种胶体溶液，小剂量灌注不会给肺部带来再灌注导致的损伤，反而能够缓肺部血管因病症影响引起缺血，或炎症引起的血管闭塞造成的缺血；
(2)本发明所述的药物是一种红细胞代用品，可增加血浆中总血红蛋白浓度，从而增加动脉含氧量，与同样具备载氧功能的全血或红细胞相比，无需配型，工作温度范围广(2～40℃)，无凝血风险等优势；
(3)本发明所述的药物是一种载氧药物，其中聚合血红蛋白粒径尺寸仅为红细胞的千分之一，但载氧能力却高达红细胞的7～9倍，可以提供氧气以缓解肺功能损伤程度和减轻炎症反应，并能到达红细胞不可及的微循环末端有效供氧，同时较短时间给药可以维持较长一段时间，改善肺因疾病损伤患者的生活质量；
(4)本发明所述的药物中可加入神经保护剂，可协同有效地调节炎症介质，调节抗炎症介质平衡,并减轻炎症介质作用，发挥对肺部组织的较好的保护作用。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚，下面将对本发明的技术方案进行详细的描述。显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动的前提下所得到的所有其它实施方式，都属于本发明所保护的范围。
以下实施例中的聚合血红蛋白按照CN110563836A中实施例1的方法制备而成。
实施例1
本实施例的包含聚合血红蛋白的药物，所述的药物为以下各物质溶解在1L注射用水中，具体比例如下：聚合血红蛋白140.0g、氯化钠6.0g、氯化钾 0.48g、二水氯化钙0.27g、氢氧化钠0.31g、乳酸钠1.75g、乙酰半胱氨酸2.14g。
实施例2
本实施例的包含聚合血红蛋白的药物，所述的药物为以下各物质溶解在1L注射用水中，具体比例如下：聚合血红蛋白65.0g、氯化钠6.6g、氯化钾0.3g、二水氯化钙0.2g、氢氧化钠0.4g、乳酸钠3.0g、乙酰半胱氨酸2.0g。
实施例3
本实施例的包含聚合血红蛋白的药物，所述的药物为以下各物质溶解在1L注射用水中，具体比例如下：聚合血红蛋白65.0g、氯化钠6.6g、氯化钾0.3g、二水氯化钙0.2g、氢氧化钠0.35g、乳酸钠3.0g、乙酰半胱氨酸2.0g、依达拉奉3.24mg。
实施例4
本实施例的包含聚合血红蛋白的药物，所述的药物为以下各物质溶解在1L注射用水中，具体比例如下：聚合血红蛋白65.0g、氯化钠5.6g、氯化钾0.48g、二水氯化钙0.4g、乙酰半胱氨酸2.1g、双3,5-二溴水杨酸富马酸酯2.08g、三水乙酸钠7.47g。
实施例5
本实施例的包含聚合血红蛋白的药物，所述的药物为以下各物质溶解在1L注射用水中，具体比例如下：聚合血红蛋白65.0g、氯化钠5.6g、氯化钾0.48g、二水氯化钙0.4g、乙酰半胱氨酸2.1g、双3,5-二溴水杨酸富马酸酯2.08g、三水乙酸钠7.47g、、胞磷胆碱37.14mg。
实施列6
本实施例的包含聚合血红蛋白的药物，所述的药物为以下各物质溶解在1L注射用水中，具体比例如下：聚合血红蛋白12.0g、氯化钠6.2g、氯化钾0.35g、二水氯化钙0.4g、乙酰半胱氨酸2.0g、双3,5-二溴水杨酸富马酸酯1.2g、三水乙酸钠5.7g。
试验例1包含聚合血红蛋白的药物对肺纤维化大鼠静脉注射有效性研究
受试药物：实施例4制备的包含聚合血红蛋白的药物，其中血红蛋白含量为65.0g/L；
试验动物：32只SPF级雄性Wistar大鼠，体重180～220g，购自北京维通利华实验动物技术有限公司，受试动物饲养于无菌的独立送风的笼中，垫料为60Co辐射消毒的玉米芯垫料，粒径4～6mm。饲以专门为小鼠配制的消毒饲料，自由饮用纯净水。动物实验室内温度保持在25℃左右，相对湿度保持在40-70％，每日光照12h。
1.实验方法
1.1建模
Wistar大鼠均打耳标。
取体重为180～220的Wistar大鼠32只，大鼠自然饲养3天以适应环境。按体重分为3组，即正常组、模型组、药物组，每组8只；除正常组大鼠外，其余2组大鼠用异氟烷呼吸麻醉后，仰卧面定，颈部消毒后逐层分离并暴露气管，注射器经气管软骨环间隙朝向心端刺入气管，缓慢注入博莱霄素5mg/kg，注射后立即将大鼠直立并左右旋转，使药液在肺内均匀分布。
1.2分组及给药剂量
Wistar大鼠分组及给药剂量见表1，自造模后第2天开始给药，每天1次。
表1 分组及给药剂量
组别 受试药物 剂量
模型组 生理盐水 12.31ml/kg
药物组 聚合血红蛋白药物 800mg/kg
正常组 生理盐水 12.31ml/kg
2.评估指标
纤维化四项化学发光法检测
在造模后分别于第7天和第14天大鼠尾静脉采血进行纤维化四项指标检测。
实验开始前，各试剂均应平衡至室温，试剂不能直接在37℃溶解；试剂或样品配制时，均需充分混匀，混匀时尽量避免起泡，步骤如下：
(1)检测步骤
A.测试前准备
检查测定仪所处温度是否在20℃以上，温度波动是否在5℃以内；实验前各种试剂需置室温平衡、混匀；加样器、分配器使用前要调准刻度；固定混匀器的转数不变，混匀时间设为30s；校准温育设备温度；检查测定仪内化学发光激发物、工作洗液、反应杯是否充足，废物收集袋和废液桶已清空，打印机和纸张充足。
B.移液和温育
准自动化学发光移液步骤
a.分别将校准品、标本加40μl，发光标记物40μl，荧光素标记物40μl，磁性微球溶液加20μl，混匀，37℃温育15min。上磁分离器分离4min，倒去上清液。
b.不取掉磁分离器，轻轻沿试管壁加入工作液400μl，静置60s，倒去上清液。
c.重复步骤b。
d.上机测试。
(2)定标
通过测定高、低校准品，将预先定义的主曲线上的每个定标点调整(重新定标)为一个新的、仪器特异的测量水平亦即工作曲线。
(3)计算和结果
测定仪借助于主曲线经两点定标而得到的一条工作曲线，自动计算每一个标本的HA、LN、PIIIP及CIV含量，结果以ng/ml表示。
3.实验结果
造模后第7天和第14天对所有大鼠进行采集尾静脉血，检测透明质酸酶(HA)、层粘连蛋白(LN)、III型前胶原(PIIIP)和IV型胶原蛋白 (CIV)含量，结果见表2。
表2 大鼠HA、LN、PIIIP和CIV含量比较
Figure PCTCN2021135696-appb-000001
结果表明，药物组与模型组相比，大鼠7天及14天HA、LN、PIIIP和CIV含量均较低；药物组与正常组相比，大鼠7天及14天HA、LN、PIIIP和CIV含量均较高，具有统计学意义。
试验例2包含聚合血红蛋白的药物对急性肺损伤(ALI)大鼠静脉注射预防作用的研究
受试药物：实施例2制备的包含聚合血红蛋白药物，其中血红蛋白含量65.0g/L；
试验动物：Wistar大鼠，体重200～250g，雄性，购自北京维通利华实验动物技术有限公司，受试动物饲养于无菌的独立送风的笼中，垫料为60Co辐射消毒的玉米芯垫料，粒径4～6mm。饲以专门为小鼠配制的消毒饲料，自由饮用纯净水。动物实验室内温度保持在25℃左右，相对湿度保持在40～70％，每日光照12h。
1.实验方法
1.1给药方法
Wistar大鼠均打耳标
大鼠腹腔注射2％戊巴比妥(40mg/kg)麻醉，三组随机分为三组，每组4只，分别经阴茎背静脉注射给药，先给予保护药物，10min后给予致毒物质，给药6h后处死。
1.2分组及给药剂量
大鼠分组及给药剂量见表3。
表3 大鼠分组及给药剂量
Figure PCTCN2021135696-appb-000002
2.评估指标
2.1体重称定
给药6h后对大鼠体重称定。
2.2大鼠临床
大鼠致伤后，观察大鼠身体暴露部位出现的病理特征。
2.3血气分析
大鼠致伤后2h、6h分别动脉采血进行血气分析。
2.4病理分析
抽大鼠1ml静脉血2500转/分钟离心10min，上清与-20℃保存待测。打开大鼠胸腔，游离气管和肺，结扎右侧支气管，左侧支气管插管后用2ml生理盐水进行灌洗，待30s后回抽，反复2次，最后抽取灌洗液约1.8ml，2000转/分钟离心10min，上清液于-20℃保存待测，取右下肺进行常规病理。
2.5 IL-1β测定
血清上清液和肺泡灌洗液IL-1β采用放免法测定，测定范围为0.03～8.1ng/ml。
3.结果
3.1体重称定
大鼠致伤后6h体重称定结果见表4。
表4 大鼠致伤后6h体重称定结果
分组 NS组 LPS组 HBOC组
致伤后6h平均体重 229g 221g 227g
结果表明，大鼠致伤后6h体重为NS组、LPS组与HBOC组的组间大鼠体重无明显差异。
3.2大鼠致伤后临床比较
临床目测NS组大鼠无明显受限，LPS组与HBOC组在致伤后先后出现呼吸急促，个别大鼠有喘鸣音，四肢、口唇紫绀。
3.3血气分析
血气分析结果见表5。
表5 血气分析结果
Figure PCTCN2021135696-appb-000003
结果表明，血气PaO 2、PaCO 2和pH值，LPS组和HBOC组在致伤后2h、6h均显著低于NS组，HBOC组在致伤后2h、6h均显著高于LPS组。说明含聚合血红蛋白的药物能有效提高健康大鼠的PaO 2，这主要与药物具有高携氧有关。
3.4病理结果
病理损伤评分结果见表6。
表6 病理损伤评分结果
Figure PCTCN2021135696-appb-000004
结果表明，LPS组和HBOC组在致伤后2h、6h均显著高于NS组， HBOC组在致伤后2h、6h均显著低于LPS组。
肺病理的改变主要为肺泡间隔变宽，有大量的白细胞渗出、聚集，部分肺泡萎缩，肺泡腔内可见有渗出液、出血。LPS组损伤程度随时间逐步加重，HBOC组相对LPS组病变范围和病变程度明显减轻。
3.5 IL-1β测定
血清与肺泡灌洗液中IL-1β浓度测定结果分别见表7、表8。
表7 血清中IL-1β浓度测定结果(ng/ml)
Figure PCTCN2021135696-appb-000005
结果表明，LPS组和HBOC组在致伤后2h、6h，血清中IL-1β均显著高于NS组，HBOC组在致伤后2h、6h，血清中IL-1β与LPS组无显著差别。
表8 肺泡灌洗液中IL-1β浓度测定结果(ng/ml)
Figure PCTCN2021135696-appb-000006
结果表明，LPS组和HBOC组在致伤后2h、6h，肺泡灌洗液中IL-1β均显著高于NS组，HBOC组在致伤后2h、6h，肺泡灌洗液中IL-1β显著低于LPS组。说明含聚合血红蛋白药物对脏器损伤具有一定的保护作用。
试验例3包含聚合血红蛋白的药物对慢肺阻大鼠静脉注射有效性研究
受试药物：实施例3制备的包含聚合血红蛋白的药物，其中血红蛋白含量为65.0g/L，依达拉奉3.24mg；
阳性药物：实施例2制备的包含聚合血红蛋白的药物，其中血红蛋白含量为65.0g/L。
试验动物：16只SPF级雄性SD大鼠，体重180～220g，购自北京维通利华实验动物技术有限公司，受试动物饲养于无菌的独立送风的笼中，垫料为60Co辐射消毒的玉米芯垫料，粒径4～6mm。饲以专门为小鼠配制的消毒饲 料，自由饮用纯净水。动物实验室内温度保持在25℃左右，相对湿度保持在40-70％，每日光照12h。
1.实验方法
1.1建模
SD大鼠均打耳标。
取体重为180～220的SD大鼠16只，大鼠自然饲养3天以适应环境。按体重分为4组，即正常组、模型组、阳性对照组和受试药物组，每组4只；
正常组大鼠在第1d和第14d用10％水合氯醛腹腔注射麻醉后进行固定，以压舌板压住舌根，以弯头灌胃针轻轻插入大鼠气管，以感觉触到气管软骨环，大鼠呼吸音增粗为插入成功标准，随后缓慢注入1μg/ml脂多糖200μl，听诊见湿罗音后将固定大鼠连同固定板竖起，轻微左右摇晃3次，使注入的脂多糖在两肺尽可能的均匀分布，完成后大鼠单独饲养，待意识、行为、活动完全恢复后放回原饲养笼中。根据大鼠的昼夜节律在第2～13d和第15～28d的每日于晚8时开始将大鼠放入密闭被动吸烟箱体中(顶端为点烟盒，仅侧壁留置直径约1cm通气孔)55min。
模型组、阳性对照组和药物组被动吸烟造模。方法同正常组，不同之处为在第2～13d和第15～28d的每日于晚8时开始将大鼠放入密闭被动吸烟箱体中，2支/次/10min，连续被动吸烟4次，换烟间隔5min/次。
每日密闭前，每组分别给予受试药物。
1.2分组及给药剂量
分组及给药剂量见表9。
表9 分组及给药剂量
Figure PCTCN2021135696-appb-000007
2.评估指标
2.1肺功能检测
大鼠于造模28d后，麻醉固定大鼠，采用无束缚全身体积描记系统检测大鼠的静息呼吸频率(F)、吸气峰流速(PIF)、气道阻力(RI)以及肺动态顺应性水平(Cdyn)。
2.2肺组织检测
支气管肺泡灌洗后，取右上肺和右下肺，生理盐水冲洗后浸泡于10％中性福尔马林溶液中固定，经组织脱水、石蜡包埋切片，采用HE染色观察肺组织和支气管情况，并对基质金属蛋白酶-9(MMP-9)和基质金属蛋白酶-12(MMP-12)表达情况、免疫组化学半胱胺酸蛋白酶蛋白(Caspase-12)和增强子结合蛋白同源蛋白(CHOP)表达。
3.结果
3.1肺功能检测
肺功能检测结果见表10。
表10 肺功能检测结果
Figure PCTCN2021135696-appb-000008
结果表明，模型组相比正常组，F、RI值均显著增高，而PIF、Cdyn值均显著降低，说明造模后存在明显气流受限和通气障碍，促使炎性细胞的释放和聚集，表明造模成功。与模型组相比，阳性对照组和药物组的F、RI值均显著降低，PIF、Cdyn值均显著增高，表明含聚合血红蛋白和神经保护剂的复方药物(药物组)和单纯含聚合血红蛋白药物(阳性对照组)对于改善气流受限、阻塞性通气障碍所导致的呼吸困难等临床症状均有显著疗效，而含神经保护剂的复方药物的疗效更显著。
3.2肺组织检测
肺组织检测结果见表11。
表11 肺组织检测结果
  MMP-9 MMP-12 Caspase-12 CHOP
正常组 6.31 6.08 1557.66 1217.82
模型组 145.46 123.74 10418.63 10271.29
阳性对照组 60.07 50.58 7295.39 7208.45
药物组 53.12 42.21 6223.67 6226.35
结果表明：MMP对于烟雾引起的慢阻肺疾病具有突出作用，与气道重塑炎症反应的生理过程密切相关。模型组MMP-9和MMP-12均高表达，应用含聚合血红蛋白的药物的单药或复方药物后MMP-9和MMP-12的表达均显著减弱，药物组的表达更具有明显优势。
Caspase-12和CHOP作为免疫组化内质网应激反应中的重要因子，与肺组 织细胞凋亡有密切关系。经含聚合血红蛋白的单药或复方药物治疗后大鼠Caspase-12和CHOP的表达均显著低于模型组，并且药物组的表达更具有明显优势。
表明含聚合血红蛋白和神经保护剂的复方药物(药物组)与单纯含聚合血红蛋白药物(阳性对照组)均能够抑制并减轻炎症带来的损伤，含有神经保护剂的复方药物在治疗炎症损伤方面更具有明显优势。
本发明人对其他实施例也做了上述试验，结果基本一致，由于篇幅有限，不再一一列举。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本发明揭露的技术范围内，可轻易想到变化或替换，都应涵盖在本发明的保护范围之内。因此，本发明的保护范围应以所述权利要求的保护范围为准。

Claims (10)

  1. 一种聚合血红蛋白在制备防治呼吸衰竭药物中的应用。
  2. 根据权利要求1所述的应用，其特征在于，所述的药物为聚合血红蛋白加入医学上可接受的辅料制成。
  3. 根据权利要求1或2所述的应用，其特征在于：所述的药物还可加入临床常用的神经保护剂。
  4. 根据权利要求1或2所述的应用，其特征在于，所述的药物中每1L药物中含聚合血红蛋白为12.0～140.0g。
  5. 根据权利要求2所述的应用，其特征在于，所述的辅料以重量计溶解在1L注射用水中制成，具体比例如下：氯化钠5.6～6.6g、氯化钾0.3～0.48g、二水氯化钙0.2～0.4g、乙酰半胱氨酸2.0～2.14g、双3,5-二溴水杨酸富马酸酯0～2.08g、三水乙酸钠0～7.47g、氢氧化钠0～0.48g、乳酸钠0～3.0g。
  6. 根据权利要求3所述的应用，其特征在于：所述的临床常用的神经保护剂为以下一种或几种物质以重量计溶解在1L注射用水中制成，具体比例为依达拉奉0.15～60.0mg、神经节苷脂0.60～55.0mg、丁苯酞3.0～315.0mg，长春西汀0.15～125.0mg、胞磷胆碱3.0～520.0mg。
  7. 根据权利要求1～6任意一项所述的应用，其特征在于，所述的药物为以下各物质溶解在1L注射用水中，具体比例如下：聚合血红蛋白65.0g、氯化钠6.6g、氯化钾0.3g、二水氯化钙0.2g、氢氧化钠0.4g、乳酸钠3.0g、乙酰半胱氨酸2.0g。
  8. 根据权利要求1～6任意一项所述的应用，其特征在于，所述的药物为以下各物质溶解在1L注射用水中，具体比例如下：聚合血红蛋白65.0g、氯化钠6.6g、氯化钾0.3g、二水氯化钙0.2g、氢氧化钠0.35g、乳酸钠3.0g、乙酰半胱氨酸2.0g、依达拉奉3.24mg。
  9. 根据权利要求1～6任意一项所述的应用，其特征在于，所述的药物为 以下各物质溶解在1L注射用水中，具体比例如下：聚合血红蛋白65.0g、氯化钠5.6g、氯化钾0.48g、二水氯化钙0.4g、乙酰半胱氨酸2.1g、双3,5-二溴水杨酸富马酸酯2.08g、三水乙酸钠7.47g。
  10. 根据权利要求1所述的应用，其特征在于，所述的呼吸衰竭选自哮喘、急性肺损伤、慢肺阻或肺纤维化病症。
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