CN1457772A - Injection for curing acute lung injury and acute respirotary distress syndrome - Google Patents
Injection for curing acute lung injury and acute respirotary distress syndrome Download PDFInfo
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- CN1457772A CN1457772A CN 03140852 CN03140852A CN1457772A CN 1457772 A CN1457772 A CN 1457772A CN 03140852 CN03140852 CN 03140852 CN 03140852 A CN03140852 A CN 03140852A CN 1457772 A CN1457772 A CN 1457772A
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Abstract
The injection preparation for treating acute lung injury and acute respiratory distress syndrome is bacteria-free freeze dried powder for injection with Sivelestat as active component, stuffing frame agent, co-solvent and pH regulator. It has improved water solubility of Sivelestat and improved medicine stability.
Description
Technical field
The present invention relates to a kind of injection for the treatment of acute lung injury, adult respiratory distress syndrome; specifically English sivelestat Sodium Hydrate by name; chemistry N-[2-[4-(2 by name; 2-dimethyl propylene acidic group) benzene sulfonamido] benzoyl] the Sodium Glycinate tetrahydrate, structural formula is
Molecular formula is C
20H
21N
2NaO
7S4H
2O, molecular weight are 528.51, the aseptic freeze-dried injectable powder of Chinese sivelestat by name.
Technical background
Acute lung injury (acute lung injury, ALI)/adult respiratory distress syndrome (ALI/ARDS) is meant acute, the respiratory failure of carrying out property anoxia by paathogenic factor caused inside and outside the various lungs beyond the property of heart source.ALI has the identical pathophysiological change of character with ARDS, and the final serious stage of serious ALI or ALI is defined as ARDS.The lung microvascular permeability that is characterized as the main pathology of ALI/ARDS increase and in the alveolar transudate that causes the pulmonary edema of rich in proteins and hyaline membrane form, and with interstitial pulmonary fibrosis.The interior inflammatory reaction of the lung alveolar-capillary membrane damage that causes out of control of being taken as the leading factor by inflammatory cell in the lung (as neutrophilic granulocyte, macrophage) is to form vascular permeability and pulmonary to increase the pathologic basis that causes pulmonary edema.Pathophysiological change reduces with lung compliance, and QS pulmonary shunt increase and ventilation/blood flow are out of proportion to be main.Clinical manifestation is the intractable hypoxemia, breathes frequency and respiratory distress that chest x-ray shows two lung diffuse infiltrating shadows, how concurrent multiple organ dysfunction of later stage.
Since 1967 proposed the ARDS name first, bibliographical information is relevant to cause that the cause of disease of ARDS is increasing.The cause of disease of ARDS can be divided into ten classes, sees the following form.
The infectious fungal infection of the cause of disease 1. shock viral pneumonias 6. medicines, 9. obstetrical and gynecological diseases of table .ARDS and the excessive eclampsia of fungal pneumonia anaesthetic and preeclampsia hemorrhagic rickettsial infection methadone amniotic fluid embolism heart source property tuberculosis colchicin 10. other 2. wounds other infect other acute pancreatitis lungs and the outer wound 4. of chest and inhale behind 7. metabolic disease CTD pulmonary fat embolism gastric content diabetes acid poisoning extracorporal circulatory system drowning, 5. suction pernicious gases, the 8. hematologic disease Cardioversions 3. severe infections and septicopyemia high concentration oxygen other DIC of bacterial pneumonia behind the Cardioversion that repeatedly transfuse blood in a large number by mistake
ARDS is caused that by multiple primary disease pathogenesis is intricate, does not illustrate fully yet so far.Multiple effector lymphocyte and inflammatory mediator have participated in injury of lung, and the pathogenesis of ARDs is played critical effect.These cells and cytokine, inflammatory mediator have constituted ALI/ARDS inflammatory reaction and immunomodulating " cellular network " and " cytokine network ".They are by different signal transduction paths, regulating and control the immunoreation of body, also out of control relevant with inflammatory reaction, the cell that participates in inflammation has polymorphonuclear leukocyte, alveolar epithelial cells, vascular endothelial cell, pulmonary vascular endothelial cell, pulmonary alveolar macrophage, interstitial lung macrophage and lung blood vessel macrophage etc., and wherein macrophage plays a crucial role in damage in polymorphonuclear leukocyte and the lung.They can discharge a large amount of cytokines and inflammatory mediator, expansion that causes inflammation and damage.The inflammatory mediator that participates in inflammatory reaction has oxygen-derived free radicals, arachidonic acid, metabolite leukotriene, prostaglandin, complement system, protease, tumor necrosis factor (TNF), interleukin ILs, platelet activating factor, nitric oxide and pulmonary surfactant etc.Wherein the TNF that monokaryon-the huge system of biting produces is called TNFa, as a kind of pro-inflammatory mediator, may be one of startup factor of injury of lung.ILs is secreted by various kinds of cell, promptly has short scorching used IL-1, IL-6 and IL-8, also has pair inflammation to play the antiinflammatory medium IL-10 and the IL-13 of regulating and controlling effect.With figure brief description ARDS pathogenesis and Pathophysiology characteristics.
The main pathological change sketch map of figure ARDS
Acute lung injury, adult respiratory distress syndrome clinical manifestation:
(1) incubation period, ALI/ARDS all took place in 2～3 days in Most patients after protopathy, therefore very easily thought the aggravation of the protopathy state of an illness by mistake, often lost the opportunity of early diagnosis.
(2) symptom
1. tachypnea and poverty-stricken dyspnea, breathing frequency are respiratory failure the most objective performance the earliest, and be more obvious ALI/ARDS patient.Be generally respiratory frequency above 28 times/minute.Because women, children's and old person's frequency of respiration and respiratory distress are lighter, thus respiratory frequency above 25 times/minute, promptly should enhancing your vigilance property.
2. the early stage cough of cough and expectoration is not obvious, cough in various degree can occur; Also can cough up a small amount of blood, bring up blood and slime sample expectorant is one of classical symptom of ARDS.
3. irritated, staring spells or indifferent
In addition, because of tangible pulmonary edema has appearred in ARDS in early days, the pulmonary infection that occurs together easily has this patient chills and fever can occur, due to easily mistaken diagnosis is primary disease, should be differentiated.
(3) sign
1. cyanosis is difficult to improve because of severe depletion of oxygen and by oxygen uptake, so cyanosis is one of key character of primary disease.
2. the early stage sign of pulmonary's sign pulmonary is less, and middle and advanced stage can be heard dryness or moist sound, as dyspnea occurs, and intercostal and supraclavicular fossa sink when air-breathing.
3. the heart rate heart rate is normal above 100 times/minute.
Acute lung injury, adult respiratory distress syndrome clinical diagnosis:
(1) high risk factor of ALI/ARDS
Directly the serious pulmonary infection of injury of lung factor, gastric content suction, contusion of lung, suction toxic gas, flood weak, oxygen intoxication etc.
2. indirectly injury of lung factor sepsis (sepsis), serious non-thoracic trauma, severe pancreatitis, a large amount of blood transfusion, extracorporeal circulation, DIC etc.
(2) 1. the diagnosis of ALI/ARDS has the high risk factor of morbidity; 2. Acute onset, breathe frequency and (or) respiratory distress; 3. hypoxemia: PaO during ALI
2/ FiO
2≤ 300mmHg; PaO during ARDS
2/ FiO
2≤ 200mmHg; 4. chest X-ray two lungs soak into shade; 5. pulmonary capillary wedge pressure (PCWP)≤18mmHg or clinically can except cardiac pulmonary edema.
All meet above five diagnosable for ALI and ARDS.
Acute lung injury, adult respiratory distress syndrome clinical treatment:
So far still not having specific method, mainly is to carry out specific aim or supportive treatment according to its pathophysiological change and clinical manifestation at present.Cure the Primary Disease, characteristics are control infection, improve ventilation and tissue oxygen confession, prevent further injury of lung and pulmonary edema, are the main principle for the treatment of at present.
(1), Cure the Primary Disease, Cure the Primary Disease takes place in prevention ALI/ARDS, removes inducement as early as possible, is the First Principles of treatment ALI/ARDS.
1. actively the control infection severe infections is the first high risk factor that causes ALI/ARDS, is again the first cause that influences ALI/ARDS.Therefore, in critical patient's rescue process, answer strict sterile working, remove unnecessary catheter in blood vessel and urinary catheter, the prevention skin ulcer is sought and is also handled surgical infection, to reduce nosocomial infection.To the patient of ALI/ARDS accompanying infection sign, should strengthen searching, and should select strong anti-infectives treatment in conjunction with blood, urine, expectorant antibacterial culturing and clinical setting to infection site.
2. positive rescue shock.
3. venous transfusion avoids too much too fast, and crystalloid fluid and colloidal solution were advisable with 1: 1, and reference center venous pressure, blood pressure, pulmonary artery, wedge pressure, pulse pressure difference and urine amount are adjusted the input amount of liquid at any time.
4. use banked blood less as far as possible.
5. the reduction of the fracture timely, maintenance.
6. the critical patient robs the aid and support oxygen uptake, but should avoid the oxygen of long time high concentration to suck, and general concentration of oxygen inhalation 40%～50% is kept PaO
260mmHg.
(2), improve ventilation and organize the severe depletion of oxygen of oxygen supply ALI/ARDS, use nose conduit and mask oxygen-inspiration and be difficult to prove effective, Failure Treated with Mechanical Ventilation is to correct anoxybiotic major measure.As fraction of inspired oxygen (FiO
2)＞0.5, and PaO
2＜60mmHg should mechanical ventilation, and its most frequently used ventilating mode is PEEP.
(3), the strict control input of strict control input amount of liquid amount of liquid, should keep body fluid balance, go out every day people's amount of liquid generally the amount of being controlled at lack about 500ml than output.Can place the Swan-Ganz conduit in case of necessity, the dynamic monitoring pulmonary capillary wedge pressure is adjusted the input amount of liquid at any time.
(4), too many levels alleviates the damage of lung and whole body and has attempted both at home and abroad at present to carry out Drug therapy, to alleviate lung and systemic inflammatorome at its link of mainly falling ill.
1. the glucocorticoid glucocorticoid can act on a plurality of morbidity links of ALI/ARDS.Promptly be used for the treatment of ALI/ARDS very early.At present domestic scholars does not advocate that the conventional glucocorticoid of using prevents and treats ALI/ARDS.But, advocate that still the application glucocorticoid treats to concurrent ALI/ARDS such as the concurrent ALI/ARDS of multiple long bone and fracture of pelvis, acute pancreatitis, mistake suction.
2. non-this type of medicine of hydrocortisone antiinflammatory drugs mainly includes the lipoxygenase and the cyclooxygenase pathway inhibitor of prostaglandin metabolism, as ibuprofen, indomethacin and acidum clofenamicum etc.The early stage application can be proved effective.
3. this type of medicine of oxygen free radical scavenger and antioxidant has N-acetylcystein, vitamin E, superoxide dismutase (SOD) etc.The experience of using clinically is few at present.
4. vasodilation in theory, vasodilation can reduce pulmonary vascular resistance, improves the lung blood flow, and in fact it has also reduced hypoxia contraction of physiological lung blood vessel and peripheral vascular resistance, with the periphery shunting, reduce oxygenate in the lung that had existed already when further strengthening ARDS.Therefore, at present most scholar does not advocate to use the nimble treatment of vasodilation ARDS.But the report of using Anisodamine treatment ARDS is arranged.Its method is: 1. be applied as early as possible; 2. measuring should not be excessive, general each 10～20mg, and every 6h intravenous drip once after the state of an illness is improved, is promptly taken the circumstances into consideration decrement or inactive, in order to avoid blood vessel is further expanded, it is out of proportion to increase the weight of ventilation/blood flow.
5. pulmonary surfactant (pulmonary surfactant, PS) replacement therapy
(1) promote synthesizing and secretion of PS: glucocorticoid, adrenal gland's energy and cholinergic agonist all have this effect.So have the people to design: the ARDS therapeutic scheme of aminophylline+glucocorticoid+isoproterenol in order to following scheme.Ambroxol is the metabolite of expectorant bromhexine hydrochloride, and alternative hormone is used for the control of ARDS.
(2) surfactant alternative medicine: four kinds of treatment surfactant preparations are arranged at present.Nature extract: through centrifugal gained, contain whole apoproteins with bronchoalveolar lavage fluid or amniotic fluid; The improvement natural medicine; Artificial preparation; Reconstituted surfactants.But Clinical Experience is few, still needs and furthers investigate at raising usefulness, minimizing anaphylaxis and aspects such as medication and preparation source.
6. alleviate pulmonary edema and mainly should control amount infused, particularly the colloid liquid measure in order to avoid the pulmonary circulation fluid pressure increases or the alveolar-capillary membrane that passes through the permeability increase of a large amount of plasma proteins, is gathered at an alveolar and a matter, increases the weight of pulmonary edema.Under the hemodynamic state stable case,, can drink and use a small amount of diuretic for alleviating pulmonary edema.
7. strengthen nutritional support ARDS patient body and be in the hypermetabolism state, energy expenditure increases, even also continue the long period in convalescent period.Therefore, must give strong nutritional support as soon as possible.
Sivelestat (Sivelestat Sodium Hydrate) is an elastase inhibitor, can optionally suppress neutrophilic granulocyte and discharge NE, improve respiratory function, shorten the time that patient uses respiratory organ, the pressure that reduction installation respiratory organ causes and the coincidence of respiratory tract infection disease.In addition, this product can also make patient get out of danger as early as possible, withdraws from from intensive care unit(ICU) (ICU), has reduced medical treatment cost.
Sivelestat (Sivelestat Sodium Hydrate) can improve SIRS and idiopathic pulmonary fibrosis (idiopathic pulmonary fibrosis, IPF) acute lung injury (the ALI)/adult respiratory distress syndrome (ARDS) of initiation such as grade.
The sivelestat pharmacological research
The mechanism of action: neutrophil elastase is a kind of of protease, is to be separated by the neutrophilic granulocyte that accumulates in pulmonary, and it can make pulmonary vascular permeability increase, and brings out acute lung injury.Can also promote the neutrophilic granulocyte migration factor in addition, the exacerbate inflammation reaction.Noticeable especially in the injury of lung of systemic inflammatory response.And sivelestat is a kind of neutrophil elastase selective depressant.
Pharmacological action: the 1. inhibitory action of pair neutrophil elastase: sivelestat has very big inhibitory action to the activity of the neutrophil elastase of people and various animals.Its form is the antagonism blocking effect.Sivelestat does not have the blocking-up effect substantially and only optionally blocks neutrophil elastase serine protease, cysteine proteinase and metalloproteases; Biological intravital elastoser BF be easy to plain destruction of active acid that produced by neutrophilic granulocyte and forfeiture to the blocking effect of elastoser, but sivelestat is not subjected to the influence of these active acid elements to the blocking effect of elastoser.
2. to the action effect of acute pulmonary function injury model: in the acute pulmonary function injury model of the Mus that the neutrophil elastase of personnel selection brings out, after vein gives sivelestat continuously, the blood volume that is penetrated in the bronchovesicular perfusate with inhibition is an index, has shown that sivelestat has better action; In the Mus acute lung injury model that causes by cobratoxin or endotoxin, after giving sivelestat with continuous vein, be that index has shown that sivelestat has better action with the elastase activity suppression ratio in the blood plasma or in the bronchoalveolar washing liquid.
3. to the improvement effect of pulmonary function: in to the Mus imbedibility injury of lung model that causes by hydrochloric acid, suppressed the decline of pulmonary function behind the continuous intravenous injection sivelestat.The Mus survival rate is greatly improved.
4. to the effect of neutrophil elastase in ethanol mediation rat pipe film injury: neutrophil elastase latent effect as a kind of key substance in the acute gastric mucosal lesion of ethanol mediation has obtained confirmation in the Mus experiment.Result of study shows that sivelestat can show and suppress the acute injury effect of neutrophil elastase to gastric mucosa of rat, effectively protects gastric mucosa.
5. to the latent effect of polymorphonuclear elastoser in dog law during ischemia damage model: polymorphonuclear elastoser (RMN-E) is a kind of circulatory mediator that comes from neutrophilic granulocyte.Yet its effect research in the law during ischemia damage is less.We to PMN-E the effect in dog law during ischemia damage model study.Along with the prolongation of Ischemia Time, 30 minutes ischemia group and 120 minutes ischemia group relatively, PMN-E especially PMN-E index and liver function injury has significant increase.Ischemia group was divided into the PMN-E rising and the group that do not raise in 60 minutes.
Behind the ischemia-reperfusion, do not raise group relatively with PMN-E, the PMN-E index and the m-GOT of rising group have significant increase, and in addition, PMN-E does not increase that group is poured into back hepatic tissue blood flow again and liver function recovery is better.After giving PMN-E inhibitor sivelestat, PMN-E and PMN-E index do not see obvious increase but hepatic tissue blood flow and liver function are obviously recovered, and Histological research shows does not see cell injury.The result that this research obtains show that PMN-E has played potential effect in the law during ischemia damage and also treat with PMN-E inhibitor sivelestat after can improve liver function injury.
The research of sivelestat general pharmacology
(1) to the influence of animal general signs
ICR is that (intravenous injection gives sivelestat to male mice, observes in 6,24,48 and 72 hours after administration for 5 ages in week, body weight 27.0～31.5g).As a result, do not see that sivelestat produces obviously influence to the animal general signs.
(2) to central nervous system's influence
1. to the effect of independent activity of animals: ICR is that (intravenous injection gives sivelestat to male mice for 5 ages in week, body weight 28.0～35.7g).As a result, do not see that sivelestat produces obviously influence to the mice autonomic activities.
2. barbital being brought out the influence of animal sleep effect: ICR is that (intravenous injection gave sivelestat after 1 minute to male mice, lumbar injection barbital 100mg/kg for 5～6 ages in week, body weight 28.5～37.9g).As a result, do not see that sivelestat causes mice sleep to barbital and produces obviously influence.
3. to the influence of spasm effect: ICR is male mice (6 ages in week, a body weight 27.7～40.2g).
1. electric shock is brought out the influence of mice spasm effect: the intravenous injection sivelestat is after 1 minute, with electric shock (50mA, 0.2 second).As a result, sivelestat does not have obvious influence to spasm effect and the mortality rate that the electric shock mice produces.
2. pentylenetrazol is brought out the effect of mice spasm: mouse mainline gives sivelestat subcutaneous injection pentylenetrazol after 1 minute.As a result, sivelestat brings out the mice spasm to pentylenetrazol and death effect does not have bright influence.
4. to the influence of pain sensation effect: ICR is male mice (7 ages in week, a body weight 31.8～42.7g).
1. acetic acid stimulates writhing method: mouse mainline gives 1 minute pneumoretroperitoneum of sivelestat and injects 0.6% acetum.As a result, the sivelestat Dichlorodiphenyl Acetate stimulates the mouse writhing effect not have obvious influence.
2. Haffner method: mouse mainline give sivelestat after 1 minute the mouse tail root add 500g gravity.As a result, sivelestat does not have obvious influence to the mice pain effect that the Haffner method produces.
5. to the influence of body temperature: SD is male rat (7 ages in week, a body weight 289.1～350.8g).Intravenous injection gives sivelestat, 30,60,120,180,240 and 300 minutes survey rat rectal temperatures after administration.As a result, sivelestat does not have obvious influence to rat temperature.
(3) to the influence of smooth muscle self-disciplining
1. to the influence of the ileum contraction of exsomatizing: Hartley is male guinea pig (11-12 age in week, a body weight 510.6～722.6g).As a result, sivelestat does not have obvious influence to the contraction of guinea pig ileum.
2. to the influence of myocardium vessel contraction: Hartley is male guinea pig (8～9 ages in week, a body weight 464.6～495.2g).As a result, sivelestat does not have obvious influence to the contraction of guinea pig in vitro blood vessel.
3. to the influence of isolated tracheal contraction: Hartley is male guinea pig (8～9 ages in week, a body weight 464.6～495.2g).As a result, sivelestat does not have obvious influence to the contraction of guinea-pig isolated trachea.
(4) to the neural influence of periphery
SD is male rat (12 ages in week, a body weight 433.3～494.2g).As a result, sivelestat does not have obvious effect to the rat peripheral nervous system.
(5) to breathe, the influence of blood circulation
1. to breathing, blood pressure, the rhythm of the heart, blood flow and Electrocardiographic influence: male and female beagle dog, body weight 7.46～11.25kg, intravenous injection gives sivelestat.As a result, sivelestat does not have obvious influence to breathing, blood pressure, the rhythm of the heart, blood flow and the electrocardiogram of dog.
2. to the influence of Mesenteric artery blood flow: male beagle dog, body weight 10.34～14.63kg, intravenous injection gives sivelestat.As a result, sivelestat does not have obvious influence to dog Mesenteric artery blood flow.
3. to the influence of blood pressure drops effect due to the various factors: male and female beagle dog, body weight 7.46～14.46kg, intravenous injection gives sivelestat.As a result, sivelestat does not have obvious influence to the dog blood pressure drops effect due to the various factors.
4. to the effect of isolated heart: Hartley is male guinea pig (7～9 ages in week, a body weight 340.1～588.7g).As a result, sivelestat does not have obvious effect to guinea pig isolated heart.
(6) to the influence of digestive system
ICR is male mice (7～8 ages in week, a body weight 30.1～37.6g).As a result, sivelestat does not have obvious influence to the wriggling of the stripped intestinal of mice.
(7) to the influence of water and electrolyte metabolism effect
SD is male rat (7 ages in week, a body weight 224.3～272.7g).Intravenous injection gives sivelestat.As a result, sivelestat does not have obvious influence to water and the electrolyte metabolism of rat.
(8) other effects
1. to the influence of blood and hematopoietic function: SD male rat (8 ages in week, body weight 268.5～305.0g).As a result, sivelestat does not have obvious influence to rat blood and hematopoietic function.
2. haemolysis: adult male, 26-41 year.As a result, sivelestat does not have obvious hemolytic reaction.
The sivelestat toxicological study
(1) acute toxicity test
1. rat and dog intravenous list agent administration toxicity research: the SD rat, male and female are not limit, and the intravenous single dose gives sivelestat 150,300 and 450mg/kg.The result shows, when dosage during more than or equal to 300mg/kg, rat appearance activity reduces, breathe phenomenon such as slow down, extremity and auricle bleach.Especially in the 450mg/kg group, there is 1 to show chronic tic and death in 6 female rats.The surviving animals above-mentioned symptom is disappearance in 3 hours after administration, and each treated animal is not seen weight increase.Dead rat postmortem finds that bronchus has few foam sample liquid, the visible petechia of right side articular muscle, tendon and pulmonary.
Beale dog intravenous single dose gives sivelestat 75 and 15mg/kg, does not see that clinical symptoms, body weight, food ration, the blood biochemical to dog learned obviously influence of index generation.
Research thinks that sivelestat intravenous single dose administration is about 450mg/kg to the lethal dose of rat, to the lethal dose of dog greater than 150mg/kg.
2. single dose administration toxicity research in the mouse vein: the KM mice, male and female half and half, the intravenous single dose gives sivelestat 327.67,409.6,512,640,800,1000 and 1250mg/kg.The result shows, twitches immediately after the administration of 1250mg/kg dosage group mice, and is all dead after about 1 minute, dead mice extremity and perioral cyanosis, and its breast abdominal part of postmortem shows no obvious abnormalities.LD50 is 561.71mg/kg, and the 95% fiducial limit scope of LD50 is 495.42mg/kg～636.82mg/kg.
3. single dose administration toxicity research in the mouse peritoneal: the KM mice, male and female half and half, the intraperitoneal single dose gives sivelestat 554.63,652.51,767.66,903.13,1062.5 and 1250mg/kg.The result shows that movable immediately the minimizing reposes after the administration of 1250mg/kg dosage group mice, and is all dead in 5 hours, dead mice extremity and perioral cyanosis, and its breast abdominal part of postmortem shows no obvious abnormalities.LD
50Be 822.44mg/kg, LD
5095% fiducial limit scope be 752.50mg/kg～898.85mg/kg.
(2) long term toxicity test
1. repetitively administered 4 all toxicity tests and 4 all restorative tests in the rat vein: SD rat, male and female are not limit, intravenous gives sivelestat O (excipient contrast and saliferous contrast), 18.75,37.5,75 and 150mg/kg every day, and continuous 4 weeks are 4 weeks of convalescent period afterwards.The result shows, each dosage of sivelestat does not all have obvious influence to clinical symptoms, body weight, food ration, ophthalmology's inspection, urinalysis, hematology, blood biochemical, organ weight, postmortem and the histopathology of rat, and the dosage that the male and female rat can give is 150mg/kg/ days.
2. dog intravenous repetitively administered 4 all toxicity tests and 4 weeks are recovered test: the beagle dog, and male and female are not limit, and intravenous gives sivelestat 0 (excipient contrast), 7.5,15 and 30mg/kg, 4 weeks of convalescent period after continuous 4 weeks every day.The result shows that 15mg/kg of short duration movable the minimizing and ataxic gait (appearance of these symptoms is relevant with the pharmacological effect of sivelestat) occur with 30mg/kg dosage group male and female dog.The equal visible red cell of 30mg/kg dosage group male and female dog, hematocrit and hemoglobin reduce, and male dogs lung weight increases, but histopathological study shows and do not see that any organ that comprises lung changes.Each dosage is not seen the variation of the body weight, food ration, ophthalmology, feces, urine, hematology, blood biochemical, electrocardiogram, blood pressure, body temperature, pulsation, liver and renal function and the postmortem that cause the dog relevant with treatment, and the dosage that the male and female dog can give is 15mg/kg/ days.
3. repetitively administered 24 all toxicity tests and 4 weeks are recovered test in the rat vein: the SD rat, and male and female are not limit, and intravenous gives sivelestat O (excipient contrast), 18.75,37.5 and 75mg/kg 4 weeks of convalescent period after continuous 24 weeks every day.The result shows that each dosage does not have obvious influence to clinical symptoms, body weight, food ration, ophthalmology, urine, hematology, blood biochemical, organ weight, postmortem and the histopathology of rat.The dosage that the male and female rat can give is 75mg/kg/ days.
4. dog intravenous repetitively administered 24 all toxicity tests and 4 weeks are recovered test: the beagle dog, and male and female are not limit, and intravenous gives sivelestat O (excipient contrast), 7.5,15 and 300mg/kg, 4 weeks of convalescent period after continuous 24 weeks every day.The result shows, in the above dosage group of 15mg/kg and 15mg/kg, observing the existing transient activity of dog reduces and ataxic gait (these symptoms are relevant with the pharmacological effect of sivelestat), the visible big or small hemorrhagic speckle in treatment group dog drug administration by injection position, but these phenomenons may be relevant with prolonged and repeated administration, and be not to be that toxicity changes.Do not see the body weight, food ration, ophthalmology's urine, hematology, blood biochemical, electrocardiogram, blood pressure and the organ weight's that cause the dog relevant variation with treatment.The dosage that the male and female dog can give is 30mg/kg/ days.
(3) reproductive toxicity test
1. rat reproductive toxicity test: SD rat, male and female are not limit, male rat all through intravenous every day gave sivelestat 18.75,37.5 and 70mg/kg in back 7 days from preceding 64 days of copulation during to mating season to postmortem, female rats from preceding 15 days of copulation to pregnancy, observed the influence that sivelestat is grown the reproduction of male and female rat and offspring thereof.The result shows, in the male and female rat, does not see the change of the general signs relevant with sivelestat, body weight, food ration or postmortem, does not also observe the change of oestrous cycle, copulation and the reproduction index of the male and female rat relevant with sivelestat.The hypophysis weight of each administration treated animal all descends to some extent, but does not see tissue pathologies change.
Pregnant Mus finds that through laparotomy inspection sivelestat is to corpus luteum number, fetal survival number, embryo's implantation rate, absorption and still birth rate, tire Mus and the placental weight of pregnant Mus, and the outward appearance of tire Mus, skeleton or internal organs are not seen obvious influence.Show that the sivelestat vein gives general and genotoxicity and the offspring's thereof of male and female rat growth not had overt toxicity in 75mg/kg/ days.
2. rat fetus is in utero grown and the effect of female function the back: the SD rat, to dividing the 20th day puerperium, every day, vein gave sivelestat 18.75,37.5 and 75mg/kg from conceived the 7th day of pregnant Mus.The result, institute's equal spontaneous labor of Mus of being pregnant, sivelestat to clinical sign, body weight, the food ration of pregnant Mus, become pregnant, give a birth and the suckling overall process is not had obvious influence, the perinatal growth of tire Mus is comprised the overall process of growth, motion, emotion audition and the fertility of natality, survival rate, physiology and function does not have obvious influence.Show that the sivelestat vein gives pregnant Mus and offspring thereof not had obvious influence in 75mg/kg/ days.
3. to the teratogenesis of rabbit: the Kb1:NWZ rabbit, day every day, intravenous gave sivelestat 0 (excipient contrast), 7.5,15 and 30mg/kg in the 6th of pregnancy～18th, and all rabbit were put to death at conceived the 29th day, checked the tire Mus.As a result, do not see that the clinical symptoms relevant with sivelestat and the phenomena of mortality occur.Have in the matched group 3 pregnant rabbit miscarriages are arranged in 1 pregnant rabbit, the 300mg/kg dosage group.During the administration, 15 and the body weight of 30mg/kg dosage group rabbit and food ration reduce, these variations all are restored after the off-test.30mg/kg dosage group rabbit kidney weight increases to some extent.Do not find that the sivelestat of arbitrary dosage has any influence to pregnant rabbit after the row laparotomy, do not see any carrying out property toxic reaction yet, the result shows, but pregnant rabbit intravenous gives sivelestat 7.5mg/kg/ days, but and young rabbit intravenous gives sivelestat 30mg/kg/ days.
(4) mutagenicity test
Do not see that sivelestat has mutagenic action.
(5) anaphylaxis, zest and hemolytic test
Result of study shows, the sivelestat intravenous administration is not seen anaphylaxis, zest and hemolytic reaction.
The sivelestat pharmacokinetic:
1. blood drug level: healthy adult man, with 0.5mg/kg/ speed at one hour rating intravenous injection sivelestat, blood drug level is that 11.678 μ g/ml, area under curve (AUC) are 61.113 μ ghr/ml after 2 hours, T
1/2It is 2～6 hours.(131.4 minutes), 6～10 hours (199.9 minutes)
| AUC(μg·hr/ml) | ??T 1/2(2～6hr) ??(min) | T 1/2(6～10hr) (min) | ?C 2hr(μg/ml) |
| 61.113 | ??131.4 | 199.9 | ?11.678 |
2. metabolism: sivelestat main metabolic organ in vivo is a liver, combines with glucuronic acid and hydrosulphate earlier, and mainly be the Carboxylesterase hydrolysis by esterase.Sivelestat metabolism and cytochrome P in vivo
450(CytP
450) irrelevant.
3. drain: sivelestat mainly is to excrete through urine, healthy adult man, with 0.5mg/kg/ speed at one hour rating intravenous injection sivelestat, there is 81% metabolite to discharge after 24 hours in 2 hours, has 84.5% metabolite from urine, to discharge after 48 hours from urine.
The sivelestat clinical research
1, the clinical trial of carrying out according to the international test method(s) of double-blind trial and ARDS Network shows that sivelestat is to the pulmonary function injury patient of systemic inflammatory response symptom effectively (3 internal organs impaired subjects uses of other before the administration except that lung sivelestats 14 days).
| The internal organs of damage | Diagnostic criteria |
| Heart | Circulation volume is undesired, influences the myocardial contraction factor and increases, blood pressure is on the low side (SBP＜100mmHg) |
| Liver | Serum mesobilirubin＞5mg/dL, Salt (GPT) 200IU/L |
| Kidney | Blood urea nitrogen in the serum＞50mg/dL inosine＞3mg/dL |
| Digestive tract hemorrhage | The digestive tract hemorrhage that need transfuse blood |
| The central nervous system | Press the 3.3.9 grade standard and judge that disturbance of consciousness is person more than 2 grades |
| The blood coagulation system | By Japanese Health and human services department disseminated inravascular coagulation (DIC) diagnostic criteria is judged |
2, carry out in the case of double blinding clinical trial in 234 examples, sivelestat has been obtained curative effect preferably to the pulmonary function improvement with the systemic inflammatory response symptom, and reaching the moderate above patient who improves is 70.5% (165/234).
3, in double-blind trial research, sivelestat administration in pulmonary dysfunction 72 hours, reaching the moderate above patient who improves is 72.5% (66/91); The patient who reaches moderate above improvement of administration is 54.5% (12/22) after 72 hours.
4, in carrying out 14 days clinical research of double-blind trial administration, with administration after 5 days pulmonary function be improved as benchmark, the sivelestat administration after 10 days and 14 days pulmonary function to reach the moderate result of improvement as shown in the table:
A unconverted example is because side effect and drug withdrawal does not detect after 14 days again after 5 days.
| Pulmonary function improves degree after 5 days | Pulmonary function improves degree (medium improvement) after 10 days | Pulmonary function improves degree (medium improvement) after 14 days |
| Significantly improve | 100.0% (56/56 example) | 100.0% (56/56 example) |
| Medium improvement | 90.0% (36/40 example) | 90.0% (36/40 example) |
| The slight improvement | 64.5% (20/31 example) | 80.6% (25/31 example) |
| Constant | 27.8% (10/36 example) | 34.3% (12/35 example) |
| Worsen | 0.0% (0/12 example) | 0.0% (0/12 example) |
| Amount to | 69.7% (122/175 example) | 74.1% (129/174 example) |
5, in the research of the II clinical trial phase that carries out, contain before the administration lung General Symptoms after the patient that interior 3 following internal organs damage uses sivelestat improve reach moderate above improver be after 63.2% (24/38 example) contains 4 above internal organs and damages patients and use sivelestat the General Symptoms improvement to reach moderate above improver be 33.3% (5/15).
In sum, sivelestat is acute lung injury, an adult respiratory distress syndrome medicine safely and effectively.
Goal of the invention
The present invention reaches and improves the sivelestat water solublity by the aseptic freeze-dried injectable powder of preparation sivelestat, improves the purpose of medicine stability.
Summary of the invention
For achieving the above object, the present invention by the following technical solutions:
Active component sivelestat and filling bracket agent, pH regulator agent, solubilizing agent are made aseptic freeze-dried injectable powder, and concrete preparation process is as follows:
1. get in the water for injection of filling bracket agent adding prepared fresh, add active carbon, be heated to and boil 10 minutes, filter carbon removal, filtrate is chilled to room temperature.
2. get active component sivelestat and solubilizing agent, add in the above-mentioned filling bracket agent solution, with pH to 7.5～8.5 of pH regulator agent regulator solution, make the sivelestat dissolving, add active carbon, stirred 10 minutes, microporous filter membrane fine straining after the core coarse filtration, packing behind the detection fine straining liquid.
3. the sample after the packing carried out pre-freeze, drying bu sublimation, jump a queue, roll lid promptly after the drying again.
Filling bracket agent in the injection of the present invention includes but not limited to mannitol, sorbitol, lactose, aminoacid, amino acid salts, amino acid derivativges, sodium chloride, glucose, sucrose, xylitol etc.
PH regulator agent in the injection of the present invention includes but not limited to sodium carbonate, sodium bicarbonate, phosphate, acetate, citrate salt, amino acid salts etc.
Solubilizing agent in the injection of the present invention includes but not limited to polyoxyethylene sorbitan monoleate, polysorbate 60, polysorbate 40, polysorbate 20 etc.
Below through detecting explanation beneficial effect of the present invention
Detect index and method
1. water content detection: sample thief, measure according to aquametry (two appendix VIII of Chinese Pharmacopoeia version in 2000 M, the first method A), contain moisture and must not cross 5.0%.
2.pH detect: sample thief an amount of (suitable approximately sivelestat 0.1g), add after the water 10ml dissolving mensuration (two appendix VI of Chinese Pharmacopoeia version in 2000 H) in accordance with the law, pH value should be 7.5～8.5.
3. the color of solution and clarity detect: 5 parts of sample thiefs, respectively be equivalent to sivelestat 0.1g, add water 10ml dissolving respectively after, solution should be clarified colourless; As showing muddy, compare with No. 1 turbidity standard (two appendix IX of Chinese Pharmacopoeia version in 2000 B), all must not be denseer; As colour developing, compare with yellow No. 2 standard color solutions (two appendix IX of Chinese Pharmacopoeia version in 2000 A, first method), all must not be darker.
4. detection of bacterial endotoxin: sample thief is an amount of, and water is made the solution that contains sivelestat 0.02mg among every 1ml, checks (two appendix XI of Chinese Pharmacopoeia version in 2000 E) in accordance with the law, and containing the endotoxin amount in every 1mg sivelestat should be less than 25EU.
5. aseptic detection: sample thief, add respectively in 100ml 0.9% aseptic sodium chloride solution and dissolve, check (two appendix XI of Chinese Pharmacopoeia version in 2000 H) in accordance with the law, should be up to specification.
6. related substance detects: sample thief an amount of (being equivalent to sivelestat 0.1g), and add 10ml water and make dissolving, precision is measured 1ml and is put in the 100ml measuring bottle, is diluted to scale with the mobile phase under the assay item, shakes up, as need testing solution; The accurate absorption in above-mentioned need testing solution 1ml to the 100ml measuring bottle, above-mentioned mobile phase is diluted to scale, shakes up, in contrast solution.According to the method test under the assay item, get contrast solution 20 μ l and inject chromatograph of liquid, regulate the instrument detection sensitivity, make main constituent chromatograph peak height be about 10%～20% of monitor full scale, get each 20 μ l of need testing solution and contrast solution again, inject chromatograph of liquid respectively, the record chromatogram is to 3 times of the retention time at main constituent peak, the chromatogram of need testing solution is as showing impurity peaks, desolventize outside the peak, each impurity peak area sum must not be greater than 4 times (4.0%) of contrast solution main peak area.
7. assay: measure according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2000).
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica; Be mobile phase with phosphoric acid solution (phosphoric acid 5.5ml, adding water to 1000ml triethylamine adjusting pH is a 3.2) methanol (30: 70); The detection wavelength is 220nm.Number of theoretical plate calculates by the sivelestat peak should be not less than 2000, and the separating degree of sivelestat peak and adjacent impurity peaks should be up to specification.
Get the content under the content uniformity item, precision takes by weighing in right amount (being equivalent to sivelestat 20mg approximately), put in the 50ml measuring bottle, it is an amount of to add methanol, supersound process makes the sivelestat dissolving, and is diluted to scale with methanol, shakes up, filter, precision is measured in subsequent filtrate 5ml to the 50ml measuring bottle, adds mobile phase and is diluted to scale, shakes up, get 20 μ l and inject chromatograph of liquid, the record chromatogram, other gets the about 20mg of sivelestat reference substance that measures moisture, measures with method, press external standard method with calculated by peak area, promptly.
Testing result
One, example 1 sample detection result
1. moisture: 2.8%
2.pH value: 8.2
3. the color of solution and clarity: meet the requirements
4. bacterial endotoxin: meet the requirements
5. aseptic: as to meet the requirements
6. related substance: 2.1%
7. content: 100.3%
Two, example 1 sample detection result
1. moisture: 3.1%
2.pH value: 8.1
3. the color of solution and clarity: meet the requirements
4. bacterial endotoxin: meet the requirements
5. aseptic: as to meet the requirements
6. related substance: 2.8%
7. content: 97.6%
Three, example 3 sample detection results
1. moisture: 3.5%2.pH value: the color of 8.13. solution and clarity: 4. bacterial endotoxins meet the requirements: it is 5. aseptic to meet the requirements: 6. related substances meet the requirements: 4.2%7. content: 96.5%
The specific embodiment one, example 1
Sivelestat 100g
Mannitol 200g
Polyoxyethylene sorbitan monoleate 50g
Sodium carbonate is an amount of
Water for injection adds to 3000ml
Be distributed into 1000 bottles, lyophilization.Two, example 2
Sivelestat 100g
Mannitol 200g
Polyoxyethylene sorbitan monoleate 50g
Sodium bicarbonate is an amount of
Water for injection adds to 3000ml
Be distributed into 1000 bottles, lyophilization.Three, example 3
Sivelestat 100g
Lactose 200g
Polyoxyethylene sorbitan monoleate 50g
Sodium carbonate is an amount of
Water for injection adds to 3000ml
Be distributed into 1000 bottles, lyophilization
Claims (5)
1. the injection of treatment acute lung injury, adult respiratory distress syndrome, it is characterized in that: it is the aseptic freeze-dried injectable powder made from active component sivelestat and filling bracket agent, solubilizing agent and pH regulator agent.
2. the preparation process of the injection of the described treatment acute lung injury of claim 1, adult respiratory distress syndrome is in the water for injection of 1. getting filling bracket agent adding prepared fresh, add active carbon, be heated to and boil 10 minutes, filter carbon removal, filtrate is chilled to room temperature.
2. get active component sivelestat and solubilizing agent, add in the above-mentioned filling bracket agent solution, with pH to 7.5～8.5 of pH regulator agent regulator solution, make the sivelestat dissolving, add active carbon, stirred 10 minutes, microporous filter membrane fine straining after the core coarse filtration, packing behind the detection fine straining liquid.
3. the sample after the packing carried out pre-freeze, drying bu sublimation, jump a queue, roll lid promptly after the drying again.
3. the described filling bracket agent of claim 1 includes but not limited to mannitol, sorbitol, lactose, aminoacid, amino acid salts, amino acid derivativges, sodium chloride, glucose, sucrose, xylitol etc.
4. the described pH regulator agent of claim 1 includes but not limited to sodium carbonate, sodium bicarbonate, phosphate, acetate, citrate salt, amino acid salts etc.
5. the described solubilizing agent of claim 1 includes but not limited to polyoxyethylene sorbitan monoleate, polysorbate 60, polysorbate 40, polysorbate 20 etc.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03140852 CN1457772A (en) | 2003-06-02 | 2003-06-02 | Injection for curing acute lung injury and acute respirotary distress syndrome |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03140852 CN1457772A (en) | 2003-06-02 | 2003-06-02 | Injection for curing acute lung injury and acute respirotary distress syndrome |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1457772A true CN1457772A (en) | 2003-11-26 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 03140852 Pending CN1457772A (en) | 2003-06-02 | 2003-06-02 | Injection for curing acute lung injury and acute respirotary distress syndrome |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100448442C (en) * | 2005-11-29 | 2009-01-07 | 重庆医药工业研究院有限责任公司 | Use of elastic protease inhibitor for preparing medicine for protecting cerebral hemorrhage |
| JP2012188421A (en) * | 2011-02-25 | 2012-10-04 | Ono Pharmaceut Co Ltd | Preparation for injection containing sivelestat sodium salt or hydrate thereof |
| JP2014037378A (en) * | 2012-08-16 | 2014-02-27 | Nipro Corp | Pharmaceutical preparation and method for producing the same |
| CN104107172A (en) * | 2013-04-18 | 2014-10-22 | 上海汇伦生命科技有限公司 | Preparation method of sivelestat sodium lyophilized powder for injection |
| CN104473915B (en) * | 2014-11-25 | 2016-08-24 | 李亚军 | Sivelestat is as the application for the treatment of epilepsy medicament |
| CN106902353A (en) * | 2015-12-22 | 2017-06-30 | 江苏万邦生化医药股份有限公司 | The application of peptide boric acid esters protease inhibitors or its composition in the medicine for the treatment of PUD D |
-
2003
- 2003-06-02 CN CN 03140852 patent/CN1457772A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100448442C (en) * | 2005-11-29 | 2009-01-07 | 重庆医药工业研究院有限责任公司 | Use of elastic protease inhibitor for preparing medicine for protecting cerebral hemorrhage |
| JP2012188421A (en) * | 2011-02-25 | 2012-10-04 | Ono Pharmaceut Co Ltd | Preparation for injection containing sivelestat sodium salt or hydrate thereof |
| JP2014037378A (en) * | 2012-08-16 | 2014-02-27 | Nipro Corp | Pharmaceutical preparation and method for producing the same |
| CN104107172A (en) * | 2013-04-18 | 2014-10-22 | 上海汇伦生命科技有限公司 | Preparation method of sivelestat sodium lyophilized powder for injection |
| CN104107172B (en) * | 2013-04-18 | 2017-11-28 | 上海汇伦生命科技有限公司 | The preparation method of sivelestat sodium injection freeze-dried powder |
| CN104473915B (en) * | 2014-11-25 | 2016-08-24 | 李亚军 | Sivelestat is as the application for the treatment of epilepsy medicament |
| CN106902353A (en) * | 2015-12-22 | 2017-06-30 | 江苏万邦生化医药股份有限公司 | The application of peptide boric acid esters protease inhibitors or its composition in the medicine for the treatment of PUD D |
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