CN104721808A - Pharmaceutical composition for treating neonatal jaundice - Google Patents
Pharmaceutical composition for treating neonatal jaundice Download PDFInfo
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Abstract
The invention discloses a pharmaceutical composition for treating neonatal jaundice. Each preparation unit of the pharmaceutical composition contains 0.3-0.5g of L-ornithine L-aspartate component and contains ascorbic acid to contribute to drug stability. By means of pharmaceutical technical means, the pharmaceutical composition is prepared into powder to be used for treating neonatal jaundice.
Description
Technical field
The present invention relates to the pharmaceutical composition containing aspartic acid ornithine being used for the treatment of neonatal jaundice, belong to technical field of medicine, be specifically related to the aspartic acid ornithine powder being suitable for neonate oral administration, be used for the treatment of neonatal jaundice.
Background technology
Jaundice is a kind of clinical common disease performance, in adult, jaundice is more common in liver and gall pathological changes patient, and the dysfunctions such as the reduction of Adult Liver gallbladder disease Patients ' Hepatocytes function or bile secretion cause blood mesobilirubin to cause accumulation raise and occur skin, sclera and mucosa xanthochromia by Metabolism Excretion.
Although neonatal jaundice blood parameters also shows as bilirubin and raises, but the cause of disease has the different of essence from adult's jaundice, after neonate birth, in body, erythrocyte all there will be destruction in various degree, because erythrocytic destruction produces haemachrome, haemachrome enters enterohepatic circulation increase and changes bilirubin into, blood mesobilirubin is raised, simultaneously because neonatal hepatocytes absorbs and the hypofunction of conjugated bilirubin, hepatocyte excretion conjugated bilirubin function is more weak, blood mesobilirubin is raised, comprehensively causes neonatal jaundice.
To be that non-neonate bilirubin metabolism is abnormal cause blood mesobilirubin to raise and occur the clinical picture of skin, sclera and mucosa xanthochromia neonatal jaundice, both physiological phenomenon, again the main manifestations of various diseases.Neonatal jaundice pathogenic factor is comparatively complicated, severity extent is also different, and blood parameters shows as bilirubin and raises, therefore also known as hyperbilirubinemia, bilirubin has neurotoxicity, control not in time, bilirubin encephalopathy (bilirubin encephalopathy) may be caused, cause nervous lesion and functional disability, as cerebral palsy etc., even threat to life, brings considerable distress to infant and family thereof, causes larger burden to society.
Neonatal jaundice caused by many reasons, can need clinicist carefully to assess, and appropriately, effectively processes, to reduce the incidence rate of severe hyperbilirubinemia and bilirubin encephalopathy.Physiologic jaundice is because neonatal hepatocytes is not yet ripe, to bilirubin picked-up and delivery, function is poor causes, according to statistics, be about 70% in its incidence rate term infant of neonatal jaundice, occur jaundice in 3-20 days after birth, be everlasting and peak for 3-7 days, decline immediately after 1 week, premature infant's incidence rate is about 90%, and pathological jaundice accounts for the 30-50% of neonatal jaundice, for neonate inpatient is the first.Because neonatal jaundice is difficult to distinguish physiological or pathologic in early days, therefore in order to avoid causing consequence, usually namely carry out conservative therapeutic intervention in early days.
Neonatal jaundice is different from Adult Onset's reason, and treatment neonatal jaundice is also different from the method for adult's jaundice, simply the medication of adult's jaundice or adult's hepatoprotective can not be carried out inference and be used for neonate.The current treatment for neonatal jaundice is main mainly with blue-light treatment, and be aided with the Chinese patent medicine of some adult's uses, chemotherapy, serious uses exchange transfusion.
Blue light illumination is a kind of Therapeutic Method by fluorescence irradiation treatment neonatal jaundice disease, its Main Function makes unconjugated bilirubin change water solublity isomer into, easily excrete from bile and urine, its light source has blue light, green glow, daylight lamp or sunlight etc., the most effective with blue light, mostly adopt two-sided even four sides blue-ray radiation therapy hyperbilirubinemia of newborn clinically, but find in use for many years because of, neonate thermotaxic centre is grown not yet ripe, blue light box fluorescent lamp long-time continuous is irradiated the heat effect produced and is easily caused heating, perspire, dehydration, erythra, cry, eye hides not plenary session and to affect one's power of vision the situations such as growth, need meticulous nurse, to observe with or without rebound phenomenon simultaneously, when knock-on value exceedes level before phototherapy, need phototherapy again.
The medicines such as bacillus subtilis bigeminy viable bacteria granular, bacillus bifidus tetragenous viable bacteria sheet, have and accelerate bilirubin decomposition and stop the re-absorbed effect of bilirubin, form associativity bilirubin through biliary system excretion to enteral, heavily do not absorbed at little enteral, thus reduced bilirubin level, but offer limited effectiveness, in this type of package insert, indication does not have regulation and is applicable to treatment neonatal jaundice disease, only just applying from simple theory analysis, belong to Use overrun, is non-rational use of drug.
Clinical also have the situation adopting the preparation for treating neonatal jaundices such as Yinzhihuang oral liquid, said preparation consists of Herba Artemisiae Scopariae, Fructus Gardeniae, Radix Scutellariae, there is the effects such as heat clearing away, removing toxic substances, dampness removing, jaundice eliminating, by induction liver drug enzyme system, promote that liver is to bilirubinic picked-up, combination and excretion.But this quasi drugs also belongs to adult's medication, in package insert, indication does not specify to be applicable to treatment neonatal jaundice disease equally, there is non-rational use of drug phenomenon equally, and neonate dosage and adult human dose distinguish very large, the uncontrollable dosage of infants ' parents, easily cause excessive use or wrongly take, causing untoward reaction to occur.And neonate natural endowment is not enough, internal organs function is on the weak side, the cold and cool medical material of the many genus of this quasi drugs, and easily injury internal organs function, causes the untoward reaction such as diarrhoea, and meanwhile, mouthfeel is pained, and neonate is difficult to accept.
When neonatal jaundice is serious, exchange transfusion energy Rapid replacement is adopted to go out the harmful substances such as bilirubin, antibody and sensitized erythrocyte in blood, abnormal level of serum total bilirubin is declined rapidly, avoid the generation of bilirubin encephalopathy, there is limitation in this method, neonate blood vessel comparatively thin, unintelligible in use, operation easier is comparatively large, easily causes cross infection blood class disease simultaneously.
For the treatment of neonatal jaundice, Therapeutic Principle is different from adult's jaundice, needs to reduce bilirubin level fast on the one hand, avoids high bilirubin level to damage organism normal cell, needs enhance hepatocyte function to protect hepatocyte to avoid on the other hand impaired simultaneously.Have not yet to see this type of neonatal jaundice marketing drugs, for many years, market is badly in need of the medicine being exclusively used in neonatal jaundice.
(chemical name is (S)-2 to aspartic acid ornithine, 5-diaminovaleric acid (s)-2-aminosuccinic acid salt), 20 century 70s go on the market in Germany, within 1991, record Deutscher Arzneibucs, within 2000, import injection goes on the market at home, within 2006, domestic manufacturer produces granule and injectable powder listing, all belongs to adult's medication.
Aspartic acid ornithine can promote glutamine synthesis system in liver and tricarboxylic acid cycle in vivo, thus promote function of detoxification and the energy synthesis of liver, reduce liver damage, participate in the synthesis of nucleic acid in hepatocyte, be beneficial to hepatocyte to repair, accelerate the recovery of liver function, therefore aspartic acid ornithine can be developed to the medicine of neonatal jaundice.
Patent CN1383815A, CN1582912A, CN1679941A, CN103239434A all relate to the therapeutic combination of hepatopathy, hepatic encephalopathy, constituent and the present composition have the difference of essence, and have nothing to do with treatment neonatal jaundice, although patent CN102274166A refer in the claims for Neonatal jaundice therapy, but concrete dosage is not described, also confirm to reduce neonatal bilirubin without any data, therefore practical significance be there is no for neonatal jaundice medication.Above-mentioned patent is tangible different from tool of the present invention.
So far, there is not yet the open use for the oral drug preparation containing winter propylhomoserin ornithine composition of Neonatal jaundice therapy or open report both at home and abroad.
Be well known that at present, the pharmaceutical preparation containing aspartic acid ornithine composition of existing commercially available use, there are aspartic acid ornithine granule, powder ampoule agent for injection and injection 3 kinds of preparation formulations, specify only indication in its package insert to be applicable to treat the hyperammonemia that causes of hepatic lesions, do not have regulation to be applicable to neonatal jaundice, belong to adult's medication category.Therefore, need to solve Problems existing, the strict dosage controlling aspartic acid ornithine, is made into applicable neonate and makes pharmaceutical composition, make it in the prevention and therapy of neonatal jaundice, be able to extensive use.
Summary of the invention
The present invention's object is to provide the aspartic acid ornithine pharmaceutical composition of stable, capable of being industrialized a, low cost.The present inventor is through a large amount of creationary work, by selecting the carrier auxiliary material be suitable for, pharmaceutical technology means are adopted to make the oral powder being applicable to neonate and taking, in water-soluble or milk, use nursing device administration, be convenient to take medicine, improve the compliance of neonate medication, belong to neonate special medicament, have substantial different compared with existing known technology.
Another object of the present invention is to provide the purposes that aspartic acid ornithine is used for the treatment of neonatal jaundice, specify that neonate dosage, guarantee neonate drug safety and effectiveness, aspartic acid ornithine pharmaceutical composition is used for the treatment of neonatal jaundice, to existing medication system be one breakthrough perfect, there is the progress of significance compared with current known technology.
The pharmaceutical composition being used for the treatment of neonatal jaundice of the present invention, containing aspartic acid ornithine, ascorbic acid in compositions, the ratio of preferred aspartic acid ornithine and ascorbic acid is 3-5: 0.18-0.22, and more excellent both choosings ratio is 3-5: 0.2.
Also containing wherein one or both the combination of mannitol, xylitol in pharmaceutical composition of the present invention, the combination of preferred mannitol and xylitol 1: 1.
Containing aspartic acid ornithine 3 to 5 parts, 0.9 part, mannitol, xylitol 0.9 part, 0.2 part, ascorbic acid in pharmaceutical composition of the present invention, preferred aspartic acid ornithine 3 parts or 5 parts.
Pharmaceutical composition of the present invention, calculates by each preparation unit, and each preparation unit contains aspartic acid ornithine 0.3 to 0.5g, and more excellent contains aspartic acid ornithine 0.3g or 0.5g.
Pharmaceutical composition of the present invention, after adopting pharmaceutical technology means to make preparation, each preparation unit contains aspartic acid ornithine 0.3g or 0.5g, xylitol 0.09g and/or mannitol 0.09g, ascorbic acid 0.02g.
The purposes of pharmaceutical composition of the present invention in preparation treatment neonatal jaundice medicine is the medicine for taking to neonate, is dissolved in by medicine in the water of 20-50ml volume or milk and uses when taking.
Pharmaceutical compositions method of the present invention is proportionally weighed each component, and mixing, pulverized 150 mesh sieves, carries out a point packaging, preferably make the powder of oral administration according to single dosage.
The aspartic acid ornithine pharmaceutical composition being used for the treatment of neonatal jaundice of the present invention, amino-acid analyzer can be adopted to detect wherein aspartic acid ornithine content fast, do not use the derivatization reagent of severe toxicity in testing process, determination method is more easy.
Aspartic acid ornithine pharmaceutical composition of the present invention, by a large amount of creative works, with the stability of preparation formability (granularity, angle of repose), taste, main constituent for evaluation index, preferably obtain powder composite, containing aspartic acid ornithine 0.3g or 0.5g, mannitol 0.09g, xylitol 0.09g, ascorbic acid 0.02g in each preparation unit.
Each preparation unit of the present invention refers to powder according to unit dosage form through a point packaging, and often bag or every bag of powder packaging represent each preparation unit.
Provided by the invention can the aspartic acid ornithine pharmaceutical composition being used for the treatment of neonatal jaundice of industrialization, tool has the following advantages:
The present inventor proves through a large amount of research work, the ascorbic acid (vitamin C) contained in pharmaceutical composition, except there is flavored action, also there is stabilizer function, aspartic acid ornithine composition can be made more stable in pharmaceutical composition, unexpected discovery simultaneously, vitamin C and aspartic acid ornithine coupling, produce synergism, strengthen aspartic acid ornithine and reduce transaminase's effect, be more conducive to protect hepatocyte function, simultaneously, vitamin C is as one of necessary vitamin of neonate, be conducive to newborn nutrition equilibrium, this combination can improve immunity of organisms, be beneficial to and improve neonate resistance against diseases.
Pharmaceutical composition containing aspartic acid ornithine of the present invention, dissolubility is good, moderate taste, in water soluble or milk, adopts nursing device administration, is more conducive to neonate and takes.
Pharmaceutical composition containing aspartic acid ornithine of the present invention, adopt pharmaceutical technology means to make powder, production process is simple, and without high energy consumption links such as dryings, production cost is low, and clinical application can be made more economical.
Of the present invention containing in the pharmaceutical composition of aspartic acid ornithine contains xylitol, except there is sweeting agent effect, also there is bacteriostasis, to make in aspartic acid ornithine pharmaceutical composition of the present invention not bacteriostatic agent or antiseptic, be more conducive to ensureing neonate drug safety.
Pharmaceutical composition containing aspartic acid ornithine of the present invention, contained aspartic acid ornithine composition is decomposed into Aspartic Acid in vivo and ornithine works, amino acid preparation is compared with other class ingredient, for needed by human body, safety is higher, is breakthrough perfect to existing medication system by aminoacid treatment neonatal jaundice.
The pharmaceutical composition of aspartic acid ornithine of the present invention, according to embodiment method, be prepared into powder, according to method inspection under the Pharmacopoeia of the People's Republic of China 2010 editions (two annex I P powder) item, this product granularity and appearance uniform degree etc. all conform with the regulations, and dissolubility is good; Adopting fixed funnel method to measure angle of repose is 38.5 °, and this product mobility can meet pharmacy machine and divide reload request to powder.
Detailed description of the invention
Below by way of specific embodiment, this explanation is described in more detail, but the present invention is not limited only to these embodiments.
Embodiment 1
[prescription]
[method for making]
Get mannitol and the xylitol mixing of recipe quantity, add the aspartic acid ornithine of recipe quantity, ascorbic acid mixing, pulverized 150 mesh sieves, aluminum-plastic composite membrane bag subpackage, product inspection, warehouse-in.
[specification] often comprises aspartic acid ornithine 0.5g.
[usage and dosage] every day 3 times, each 1 bag.In water soluble or administration in milk, be used for the treatment of neonatal jaundice.
Embodiment 2
[prescription]
[method for making]
Get mannitol and the xylitol mixing of recipe quantity, add the aspartic acid ornithine of recipe quantity, ascorbic acid mixing, pulverized 150 mesh sieves, aluminum-plastic composite membrane bag subpackage, product inspection, warehouse-in.
[specification] often comprises aspartic acid ornithine 0.3g.
[usage and dosage] every day 3 times, each 1 bag.In water soluble or administration in milk, be used for the treatment of neonatal jaundice.
Experimental example 1 ascorbic acid is on the impact of pharmaceutical composition stability
Utilize hot test and exposure experiments to light to compare containing ascorbic acid component and not containing the stability of the compositions of ascorbic acid component, after carrying out high temperature 60 DEG C and 4500LX ± 500 illumination process in 10 days respectively, measure the aspartic acid ornithine component content in compositions.
Result of study shows, the compositions containing ascorbic acid is to light, well thermally-stabilised, and ascorbic acid creates the effect of stabilizing agent.
Experimental example 2 xylitol is on the impact of pharmaceutical composition stability
Compositions 1: aspartic acid ornithine 5 parts, 0.9 part, mannitol
Compositions 2: aspartic acid ornithine 5 parts, 0.9 part, mannitol, xylitol 0.9 part
Under same operating environment, each 100g of preparation compositions, places compositions at 25 ± 2 DEG C of condition lower open mouths, compares containing xylitol component and not containing the microbial limit measurement result of the compositions of xylitol component.
Get this product 10g, check (Chinese Pharmacopoeia version in 2010 two annex XI J) in accordance with the law, bacterial population inspection adopts membrane-filter procedure process, and the inspection of yeast and mold number adopts conventional method process, with the bacterium colony number of single culture dish for count results.
Result of study shows, the compositions microorganism containing xylitol is almost without breeding, and be beneficial to product and preserve, the compositions containing xylitol need not add antibacterial or antiseptic.
Experimental example 3 aspartic acid ornithine pharmaceutical composition is to young Mus Jaundice Model drug efficacy study
1, modeling and administration
1.1 grouping
Wistar male rat children Mus 70 (15-20 age in days), must open eyes, body weight (38-43) g, is divided into blank young Mus group (10) and model group (60) at random.
1.2 modeling method
Young Mus fasting 6h before modeling, the gavage pure water process respectively of blank group 10, model group (60) prepares rat acute hyperbilirubinemia model with the disposable gavage of 4%ANIT (α-ANIT) salad oil solution 3mL/kg, after ANIT gavage 48h, ANIT processed group is divided into model group, low dose group, middle dosage group and high dose group at random, not containing ascorbic acid powder group, Yin Zhi Huang contrast medicine group, often organizes 10.
1.3 medicine process
The composition sample of embodiment 1 is adopted to configure to drug solns.
1.3.1 low dose group: be equivalent to aspartic acid ornithine converts young Mus according to surface area method dosage by neonate each consumption 0.3g/ (3.5kg body weight), and dissolve with purified water, be mixed with the drug solution of each gavage 0.3ml.
1.3.2 middle dosage group: be equivalent to aspartic acid ornithine converts young Mus according to surface area method dosage by neonate each consumption 0.5g/ (3.5kg body weight), and dissolve with purified water, be mixed with the drug solution of each gavage 0.3ml.
1.3.3 high dose group: be equivalent to the dosage of aspartic acid ornithine by each consumption 0.3g/ of neonate (3.5kg body weight) 5 times, the dosage of young Mus is converted according to surface area method, and dissolve with purified water, be mixed with the drug solution of each gavage 0.5ml.
1.3.4 not containing ascorbic acid group: composition components ratio is (aspartic acid ornithine 5 parts, 0.9 part, mannitol, xylitol 0.9 part), the dosage of young Mus is converted according to surface area method, and dissolve with purified water, be mixed with the drug solution of each gavage 0.3ml.
1.3.5 Yinzhihuang oral liquid matched group: with reference to adult's consumption, convert the dosage of young Mus according to surface area method, to young Mus gastric infusion.
1.4 medications:
Blank group gavage pure water, model group gavage pure water, aspartic acid ornithine three dosage groups, not containing ascorbic acid component group and Yin Zhi Huang matched group, respectively according to corresponding dosage gastric infusion, successive administration 3 days.
2, sample collecting and process
After gastric infusion the 4th day, young Mus, with after 7% chloral hydrate intraperitoneal injection of anesthesia, faced upward position and fixes, open abdominal cavity, observed the situation such as color, matter, form of liver spleen.Through postcava blood sampling, win liver spleen, weigh.After blood 4 DEG C of standing 3h, the centrifugal 30min of 5000r/min, separation of serum, detects liver function index with fully automatic blood bio-chemical detector.
3, observation index
3.1 ordinary circumstance
Comprise the death condition of young Mus, inhale newborn behavior, weight, liver general form, liver and spleen weight etc.Calculate liver index (liver/body ratio)=liver weight/weight (%), spleen index (spleen/body ratio)=spleen weight/weight (‰).
3.2 serum liver Function detection
Total bilirubin (TBIL) content and liver function index glutamate pyruvate transaminase (ALT), glutamic oxaloacetic transaminase, GOT (AST), alkali phosphatase (ALP) activity.
4, statistical method: measurement data carries out one factor analysis of variance with SPSS software, represents result with mean ± standard deviation, is that difference has statistical significance with P<0.05.
5, result
5.1 young Mus general status
5.1.1 general status is in Table.Dead 6 of model group, wherein 2 death after modeling the 2nd day, all the other 4 all appear at administration the 3rd, inhale newborn behavior 1 time average day, and young Mus tolerance is poor, does not give any treatment, and food-intake is few and occur dead; In administration the 3rd day, there is diarrhoea in various degree, inhale newborn behavior 3 times average day in 2 death of Yin Zhi Huang matched group children Mus.Aspartic acid ornithine three dosed administration groups and not containing ascorbic acid group, all without dead without diarrhoea phenomenon, inhale newborn behavior average day 6 times and blank organizes indistinction.
5.1.2 model group children Mus is compared with normal group children Mus, model group body weight significantly alleviates (P<0.01), the liver of model group is heavy and liver body ratio is remarkable raises (P<0.01), spleen heavily changes not obvious, because model group body weight obviously alleviates, cause spleen body than raising obvious (P<0.05).
5.1.3 low dose group, middle dosage group, high dose group and containing ascorbic acid group compared with blank group, body weight, liver is heavy, spleen heavy and liver body ratio, spleen body do not have statistical significance, with normal mice indifference than change.
5.1.4 low dose group, middle dosage group, high dose group and containing ascorbic acid group compared with model group, remarkable reduction liver body ratio (P<0.01), spleen body reduces obviously (P<0.05) than compared with model group, illustrates that ornithine aspartate composition has better therapeutical effect.
5.15 low dose group, middle dosage group, high dose group and containing comparing between ascorbic acid group, body weight, liver is heavy, spleen is heavy, when spleen body is than without significant change for liver body, and therapeutic effect no significant difference, without pronounced amount effect relationship.Not high than slightly relative to other three dosage group liver bodies containing ascorbic acid group, be not slightly inferior to other three dosage groups containing ascorbic acid group therapeutic effect.
5.1.6 low dose group, middle dosage group, high dose group and containing ascorbic acid group compared with Yin Zhi Huang group, significantly reduce liver body ratio (P<0.05), spleen heavily changes not obvious, and drug effect is better than Yin Zhi Huang group.
5.1.7 Yin Zhi Huang group compares with normal group children Mus, body weight significantly alleviates (P<0.05), liver is heavy and liver body ratio is remarkable raises (P<0.01), spleen heavily changes not obvious, because losing weight, cause spleen body than raising apparently higher than blank group (P<0.05).Compared with model group, body weight, liver weight, spleen weight, spleen body are than no significant difference, and liver body ratio has reduction (P<0.05).
Note: compare with blank group, * P<0.01; Compare with model group, #P<0.05, ##P<0.01, △ P<0.05 compared with Yin Zhi Huang group.
5.2 young Hepar Mus changes of function
5.2.1ANIT young Hepar Mus dysfunction is caused, compared with blank group, model group total bilirubin (TBIL) content and the active obviously rising (P<0.01) of ALT, AST, ALP, model modeling successfully can be used for assessing drug effect.
5.2.2 compared with model group children Mus, low dose group, middle dosage group, high dose group and not containing ascorbic acid group, obviously alleviate jaundice children Mus serum T BIL content (P<0.01), obviously reduce ALT, AST, ALP activity (P<0.01).Basic, normal, high dosage group and not containing no significant difference between ascorbic acid group, effective dose relation is not obvious, low, middle dosage has good therapeutical effect to young Mus Jaundice Model, do not contain ascorbic acid group with compared with dosage group in equivalent aspartic acid ornithine, be not weaker than the compositions containing ascorbic acid containing ascorbic acid group reduction content of bilirubin and ALT, AST, ALP active function, the compositions of aspartic acid ornithine and ascorbic acid has synergism advantage.
5.2.3 compared with Yin Zhi Huang group, low dose group, middle dosage group and high dose group obviously reduce jaundice children's Mus serum T BIL content and ALT, AST activity (P<0.01), reduce ALP activity (P<0.05), therapeutical effect is better than Yin Zhi Huang group.
Note: compare with blank group, * P<0.01; Compare with model group, #P<0.01, △ P<0.05, ▲ P<0.01 compared with Yin Zhi Huang group.
Experimental example 4 aspartic acid ornithine pharmaceutical composition is to Jaundice Model of Rat drug efficacy study
1, modeling and administration
1.1 grouping
Wistar male rat 70, body weight (180-220) g, is divided into blank group (10) and model group (60) at random.
1.2 modeling method
Rat Fast 12h before modeling, the gavage pure water process respectively of blank group 10, model group (60) prepares rat acute hyperbilirubinemia model with the disposable gavage of 4%ANIT (α-ANIT) salad oil solution 3mL/kg, after ANIT gavage 48h, ANIT processed group is divided into model group, low dose group, middle dosage group and high dose group at random, not containing ascorbic acid powder group, Yin Zhi Huang contrast medicine group, often organizes 10.
1.3 medicine process
The composition sample of embodiment 1 is adopted to configure to drug solns.
1.3.1 low dose group: be equivalent to aspartic acid ornithine by the dosage of each consumption 0.3g/ of neonate (3.5kg body weight) according to surface area method conversion rat, and dissolve with purified water, be mixed with the drug solution of each gavage 0.5ml.
1.3.2 middle dosage group: be equivalent to aspartic acid ornithine by the dosage of each consumption 0.5g/ of neonate (3.5kg body weight) according to surface area method conversion rat, and dissolve with purified water, be mixed with the drug solution of each gavage 0.5ml.
1.3.3 high dose group: be equivalent to the dosage of aspartic acid ornithine by each consumption 0.3g/ of neonate (3.5kg body weight) 5 times, according to the dosage of surface area method conversion rat, and dissolve with purified water, be mixed with the drug solution of each gavage 1ml.
1.3.4 not containing ascorbic acid group: composition components ratio is (aspartic acid ornithine 0.5g, mannitol 0.09g, xylitol 0.09g), according to the dosage of surface area method conversion rat, and dissolve with purified water, be mixed with the drug solution of each gavage 0.5ml.1.3.5 Yinzhihuang oral liquid matched group: according to the dosage of surface area method conversion rat, to rat oral gavage administration.
1.4 medications:
Blank group gavage pure water, model group gavage normal saline, aspartic acid ornithine three dosage groups, not containing ascorbic acid component group and Yin Zhi Huang matched group, respectively according to corresponding dosage gastric infusion, successive administration 3 days.
2, sample collecting and process
After gastric infusion the 4th day, rat, with after 7% chloral hydrate intraperitoneal injection of anesthesia, faced upward position and fixes, open abdominal cavity, observed the situation such as color, matter, form of liver spleen.Through postcava blood sampling, win liver spleen, weigh.After blood 4 DEG C of standing 3h, the centrifugal 30min of 5000r/min, separation of serum, detects liver function index with fully automatic blood bio-chemical detector.
3, observation index
3.1 ordinary circumstance
Comprise the death condition of rat, weight, liver general form, liver and spleen weight etc.Calculate liver index (liver/body ratio)=liver weight/weight (%), spleen index (spleen/body ratio)=spleen weight/weight (‰).
3.2 serum liver Function detection
Total bilirubin (TBIL) content and liver function index glutamate pyruvate transaminase (ALT), glutamic oxaloacetic transaminase, GOT (AST), alkali phosphatase (ALP) activity.
4, statistical method: measurement data carries out one factor analysis of variance with SPSS software, represents result with mean ± standard deviation, is that difference has statistical significance with P<0.05.
5, result
5.1 rat general status
5.1.1 general status is in Table.Model group 1 death after modeling the 4th day, average daily inleting appetite 6.6 ± 1.4g is less than blank group (P<0.01); Yin Zhi Huang matched group is without death, and occur diarrhoea in various degree, average daily inleting appetite 9.4+2.2g is less than blank group (P<0.01).Aspartic acid ornithine three dosage groups and not containing ascorbic acid group, all without dead without diarrhoea phenomenon, average daily inleting appetite 15.7 ± 3.1g and blank organize 18.5 ± 2.1g indistinction.
5.1.2 model group rats compares with normal rats, model group body weight significantly alleviates (P<0.01), the liver of model group is heavy and liver body ratio is remarkable raises (P<0.01), spleen heavily changes not obvious, because model group body weight obviously alleviates, cause spleen body than raising obvious (P<0.05).
5.1.3 low dose group, middle dosage group, high dose group and containing ascorbic acid group compared with blank group, body weight, liver is heavy, spleen heavy and liver body ratio, spleen body do not have statistical significance, with normal mice indifference than change.
5.1.4 low dose group, middle dosage group, high dose group and containing ascorbic acid group compared with model group, remarkable reduction liver body ratio (P<0.01), spleen is heavy unchanged, because body weight and model group change variant, causing spleen body than reducing (P<0.05), illustrating that ornithine aspartate composition has better therapeutical effect.
5.15 low dose group, middle dosage group, high dose group and containing comparing between ascorbic acid group, body weight, liver is heavy, spleen is heavy, when spleen body is than without significant change for liver body, and therapeutic effect no significant difference, without pronounced amount effect relationship.Not high than slightly relative to other three dosage group liver bodies containing ascorbic acid group, be not slightly inferior to other three dosage groups containing ascorbic acid group therapeutic effect.
5.1.6 low dose group, middle dosage group, high dose group and containing ascorbic acid group compared with Yin Zhi Huang group, significantly reduce liver body ratio (P<0.05), spleen heavily changes not obvious, and drug effect is better than Yin Zhi Huang group.
5.1.7 Yin Zhi Huang group compares with normal group, and body weight significantly alleviates (P<0.05), and liver is heavy and liver body ratio is remarkable raises (P<0.05), and spleen heavily changes not obvious.Compared with model group, body weight, liver weight, spleen weight, spleen body are than no significant difference, and liver body ratio has reduction (P<0.05).
Note: compare with blank group, * P<0.05; Compare with model group, #P<0.05, ##P<0.01, △ P<0.05 compared with Yin Zhi Huang group.
5.2 Liver Function changes
5.2.1ANIT cause Liver Function abnormal, compared with blank group, model group total bilirubin (TBIL) content obviously raises (P<0.01), and model modeling successfully can be used for assessing drug effect.
5.2.2 compared with model group rats, low dose group, middle dosage group, high dose group and not containing ascorbic acid group, obviously alleviate jaundice rat blood serum TBIL content (P<0.01), obviously reduce ALT, AST, ALP activity (P<0.01).Basic, normal, high dosage group and not containing ascorbic acid group no significant difference, effective dose relation is not obvious, low, middle dosage has good therapeutical effect to Jaundice Model of Rat, do not contain ascorbic acid group compared with dosage group in equivalent aspartic acid ornithine, be not weaker than the compositions containing ascorbic acid containing ascorbic acid group reduction content of bilirubin and ALT, AST, ALP active function, the compositions of aspartic acid ornithine and ascorbic acid has synergism advantage.
5.2.3 compared with Yin Zhi Huang group, low dose group, middle dosage group and high dose group obviously reduce jaundice rat blood serum TBIL content and ALT, AST are active, and P<0.01 reduces ALP active, P<0.05, therapeutical effect is better than Yinzhihuang oral liquid.
Note: compare with blank group, * P<0.01; Compare with model group, #P<0.01, △ P<0.05, ▲ P<0.01 compared with Yin Zhi Huang group.
Claims (11)
1. be used for the treatment of the pharmaceutical composition of neonatal jaundice, containing aspartic acid ornithine, ascorbic acid in compositions.
2. pharmaceutical composition as claimed in claim 1, containing aspartic acid ornithine, ascorbic acid in compositions, the ratio of preferred aspartic acid ornithine and ascorbic acid is 3-5: 0.18-0.22, and more excellent both choosings ratio is 3-5: 0.2.
3. pharmaceutical composition according to claim 2, is characterized in that in compositions also containing xylitol and/or mannitol.
4. pharmaceutical composition according to claim 3, is characterized in that in compositions containing aspartic acid ornithine 3 to 5 parts, xylitol 0.9 part and/or 0.9 part, mannitol.
5. pharmaceutical composition according to claim 4, is characterized in that more excellent selects aspartic acid ornithine 3 parts or 5 parts containing aspartic acid ornithine 3 to 5 parts, 0.9 part, mannitol, xylitol 0.9 part, 0.2 part, ascorbic acid in compositions.
6. pharmaceutical composition according to claim 4, is characterized in that simultaneously containing mannitol and xylitol in compositions, the more excellent combination selecting mannitol and xylitol 1: 1.
7. pharmaceutical composition according to claim 5, it is characterized in that described compositions calculates by each preparation unit, each preparation unit contains aspartic acid ornithine 0.3 to 0.5g, more excellent in aspartic acid ornithine 0.3g or 0.5g.
8. pharmaceutical composition according to claim 5, after it is characterized in that said composition adopts pharmaceutical technology means to make preparation, each preparation unit contains aspartic acid ornithine 0.3g or 0.5g, xylitol 0.09g and/or mannitol 0.09g, ascorbic acid 0.02g.
9. the purposes of the pharmaceutical composition described in claim 1-8 any one in preparation treatment neonatal jaundice medicine.
10. purposes according to claim 9, it is characterized in that the medicine for taking to neonate, and described medicine is dissolved in the water of 20-50ml volume or milk using.
Pharmaceutical composition method described in 11. preparation claim 1-8 any one, it is characterized in that each component proportionally to weigh, mixing, pulverized 150 mesh sieves, carries out a point packaging, preferably make the powder of oral administration according to single dosage.
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| CN112870234A (en) * | 2021-01-27 | 2021-06-01 | 四川九章生物科技有限公司 | Application of pharmaceutical composition containing chlorogenic acid in preparation of medicines for treating pathological jaundice |
| CN112870234B (en) * | 2021-01-27 | 2023-06-02 | 四川九章生物科技有限公司 | Application of pharmaceutical composition containing chlorogenic acid in preparation of medicine for treating pathological jaundice |
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