CN1634019A - Carbamaid peroxide freeze dried formulation for injection, its preparation method and uses - Google Patents
Carbamaid peroxide freeze dried formulation for injection, its preparation method and uses Download PDFInfo
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- CN1634019A CN1634019A CN 200410096055 CN200410096055A CN1634019A CN 1634019 A CN1634019 A CN 1634019A CN 200410096055 CN200410096055 CN 200410096055 CN 200410096055 A CN200410096055 A CN 200410096055A CN 1634019 A CN1634019 A CN 1634019A
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Abstract
The disclosed freeze-dried preparation for injection comprises carbamide peroxide and dextran by the mass ratio of 0.001-2 : 0.001-2, the invention also discloses the method for preparing the carbamide peroxide freeze-dried preparation and its use, wherein the preparation is prepared through dissolving carbamide peroxide and dextran in water while keeping the condition of filling nitrogen, filtering, recrystallizing during freeze-drying procedure, and slowing down the release speed during clinical application. The invention can be applied for treating various hypoxemia and fetal distress caused by acute anoxia.
Description
Technical field
The present invention relates to a kind of Carbamaid peroxide freeze dried formulation for injection, Its Preparation Method And Use.
Background technology
The interior oxygen storage of human body is very little, need constantly supply with from the external world.Now having understood oxygen is utilized in mitochondrion and microsome.Therefore, anoxia can be considered to the oxygen supply deficiency, and partial pressure of oxygen reduces in the mitochondrion, and the cellular metabolism obstacle that causes.Treat anoxybiotic basic purpose and be to improve Intramitochondrial partial pressure of oxygen.Gas is to pass through biomembrane with the disperse principle, these films comprise cell membrane, nuclear membrane, endoplasmic reticulum, Golgi complex, mitochondrial membrane and lysosome membrane etc., the gas molecule that is the film both sides is always in a side disperse of being forced down by the high side direction branch of dividing potential drop, therefore, partial pressure is to determine it by biomembranous principal element.Blood oxygen pressure reduces during anoxia, the corresponding reduction of Intramitochondrial partial pressure of oxygen.From oxygen dissociation curve as can be known, during severe depletion of oxygen, the relation of partial pressure of oxygen and saturation is in the steep part of oxygen dissociation curve, and blood oxygen pressure has rising slightly, and blood oxygen saturation just has more increase, and this relation shows that raising partial pressure of oxygen level is significant to the treatment anoxia.
For all kinds of hypoxemia, Therapeutic Method commonly used is an oxygen adsorption method, but curative effect is undesirable, use inconvenience, and intra oxygen injection is a kind of complex, after injecting in the body, decomposite hydrogen peroxide gradually, through the catalytic action of hydrogen peroxide acyl, discharge oxygen again, oxygen combines with hemoglobin in the blood, offers oxygen-starved tissue; Treat and rescue the hypoxemia patient effectively, improve have palpitation, breathe hard, symptom such as uncomfortable in chest, cyanosis, simultaneously, clinical shock, surgical operation are resumed treatment, effect is remarkable, effect is lasting.Clinical common syndromes such as the fetal distress in uterus that causes for anoxia, preeclampsia, fetal rhythm recovers fast, improves obviously after the medication, improve NST (fetus is at the health index of parent) scoring: anemia of pregnant woman's blood oxygen pressure raises significantly, persistent period can reach more than 4 hours, help to reduce the productive rate of cutting open the belly, and rescue fetus for operation and race against time.
The injection Carbamaid peroxide is as a kind of vein oxygen supply preparation, because of it is rapider than the effect of direct suction medical oxygen, is generally accepted and uses.The injection Carbamaid peroxide can decomposite hydrogen peroxide after injecting in the body, discharge oxygen through the hydrogen peroxide enzyme catalysis again, oxygen directly combines with hemoglobin, enters in cell membrane (comprising erythrocyte membrane) and the mitochondrion, thereby improve partial pressure of oxygen and blood oxygen saturation, alleviate anaerobic condition.Carbonic acid amide excretes with original shape by kidney.
The aseptic subpackaged powder of Carbamaid peroxide is only arranged on the domestic market at present, in use, but can't overcome, bring certain difficulty for its application because of the oxygen pain that partial rapid release produces in the injection site.
Summary of the invention
The object of the present invention is to provide a kind of Carbamaid peroxide freeze dried formulation for injection, said preparation has added excipient, avoided the decomposition of Carbamaid peroxide in preparation, Carbamaid peroxide molecule in the component is fully entered in the framework of excipient, the rate of release that when clinical use, slowed down, reduced in the injection process quick decomposition because of Carbamaid peroxide discharge produce oxygen, pain that carbonic acid amide causes.
The object of the present invention is to provide a kind of preparation method of Carbamaid peroxide freeze dried formulation for injection.
The object of the present invention is to provide the purposes aspect the diseases such as fetal distress that a kind of Carbamaid peroxide freeze dried formulation for injection causes in the various hypoxemia of preparation treatment and acute anoxia.
A kind of Carbamaid peroxide freeze dried formulation for injection of the present invention comprises Carbamaid peroxide and dextran, and mass ratio is 0.001～2: 0.001～2.
Wherein, preferred Carbamaid peroxide freeze dried formulation for injection comprises Carbamaid peroxide and dextran, and mass ratio is 0.05～1.5: 0.05～1.5.
Research worker of the present invention is found after deliberation, adopt Carbamaid peroxide to enter the rate of release that to slow down in the framework of macromolecular substances, and injection Carbamaid peroxide patient can feel that intensive pain is that partial rapid release causes in the injection site because of oxygen, so slow down the rate of release of Carbamaid peroxide, can reduce the pain on injection sense.In the freeze-drying prods excipient, belong to having of macromolecule material: dextran or gelatin hydrolysate etc., but preferably use dextran from security consideration clinically, dextran itself also can be made into intravenous injection, and gelatin hydrolysate can not be widely used in intravenous injection, so research worker of the present invention is screened excipient, select to adopt dextran as excipient.
The molecular weight of dextran of the present invention is 10000～42000, is preferably 32000～42000.
At present, the Carbamaid peroxide powder formulation does not generally add excipient, therefore in use partial rapid release can make the patient feel intensive pain in the injection site because of oxygen, the Carbamaid peroxide molecule fully enters in the dextran molecule framework in the Carbamaid peroxide freeze dried formulation for injection of the present invention, in clinical use, slow down Carbamaid peroxide and decomposed the speed that discharges gas, significantly reduced the pain that produces because of rapid release oxygen.
The preparation method of a kind of Carbamaid peroxide freeze dried formulation for injection of the present invention comprises the steps:
By the water for injection of proportioning with 80 ℃～90 ℃ of dextran addings, the injection water yield is 1: 0.01～0.15 with the amount ratio of dextran, boils 20～30 minutes, after cooling is filtered, add Carbamaid peroxide by proportioning, the filtration that stirs, after lyophilization form.
Wherein, after dextran adds entry, can add 0.1～1 ‰ adsorbent, to remove pyrogen, such as active carbon.
Cooling can be adopted progressively falling temperature method, and circulation earlier is cooled to 50 ℃～70 ℃, and then is cooled to 20 ℃～30 ℃.
It is 0.45～0.3 μ m that the dextran aqueous solution filters employed aperture of filter material, and filtering employed aperture of filter material before the lyophilizing fill is 0.1～0.3 μ m.
Lyophilization of the present invention is carried out in freezer dryer, refrigerating process is: the Carbamaid peroxide solution that is made into was kept 1～3 hour at-40 ℃～-35 ℃, be warming up to-10 ℃～0 ℃ then, kept 2～6 hours, be cooled to-40 ℃～-35 ℃ once more and kept 1～2 hour, vacuum maintains below the 15Pa, in 24～36 hours, temperature rises to 15 ℃～35 ℃, and keeps 1～3 hour.
Preparation process of the present invention is all carried out under aseptic condition, can carry out under nitrogen charging device.
Specifically, the preparation method of a kind of Carbamaid peroxide freeze dried formulation for injection of the present invention comprises the steps:
A) by the water for injection of proportioning with 80 ℃～90 ℃ of dextran addings, stir, the acticarbon of adding 0.1～1 ‰ stirs and boiled 20～30 minutes, circulation is cooled to 50～70 ℃, be cooled to 20 ℃～30 ℃ behind the decarbonization filtering, add Carbamaid peroxide by proportioning again, medicinal liquid is stirred;
B) the Carbamaid peroxide solution that is made into was kept 1～3 hour at-40 ℃～-35 ℃, be warming up to-10 ℃～0 ℃ then, kept 2～6 hours, being cooled to-40 ℃～-35 ℃ once more kept 1～3 hour, vacuum maintains below the 15Pa, in 24～36 hours, temperature rises to 15 ℃～35 ℃, and keeps 1～3 hour.
Its preferred preparation process is:
A) by the water for injection of proportioning with 80 ℃～90 ℃ of dextran addings, the injection water yield is 1: 0.01～0.15 with the amount ratio of dextran, stir, the acticarbon of adding 0.5～1 ‰ stirs and boiled 25～30 minutes, circulation is cooled to 50～60 ℃, and with the medicinal liquid decarbonization filtering, logical condensed water makes medicinal liquid is cooled to 20～25 ℃, add Carbamaid peroxide by proportioning again, medicinal liquid is stirred;
B) medicinal liquid was kept 1～2 hour at-40 ℃～-35 ℃, heat up, be warming up to about-10 ℃～-5 ℃ to separate out and to keep temperature to make and separate out fully until the adularescent crystallization, kept 3～6 hours, and be cooled to-40 ℃～-35 ℃ once more and kept 1～2 hour, beginning is distillation slowly, vacuum maintains below the 15Pa, in 26～32 hours, products temperature reaches 20 ℃～30 ℃, keeps 2～3 hours.
Dextran filters through charcoal treatment in the preparation method of Carbamaid peroxide freeze dried formulation for injection of the present invention, Carbamaid peroxide is dissolved in the dextran solution, filtration, fill, whole process for preparation carries out under aseptic condition of filling nitrogen, has avoided the decomposition of the Carbamaid peroxide in the component; Carry out lyophilizing after the fill, adopt the mode of recrystallization in the freeze-drying process, the Carbamaid peroxide molecule is fully entered in the dextran molecule framework, decompose the speed that discharges gas, reduced the pain that produces because of rapid release oxygen thereby in clinical use, slowed down Carbamaid peroxide.
Intravenous drip during injection Carbamaid peroxide of the present invention (lyophilizing) clinical practice.Purposes aspect the diseases such as fetal distress that a kind of Carbamaid peroxide freeze dried formulation for injection of the present invention causes in the various hypoxemia of preparation treatment and acute anoxia.
By the injection Carbamaid peroxide (lyophilizing) that method of the present invention is made, character is white block, and specification can be 0.05g, 0.1g, 0.5g, 1g, and most preferred specification is 0.1g, 1g.
Adult a: 1g, 1～2 time on the one.The child: by per kilogram of body weight 18mg administration, dose is no more than 1g or follows the doctor's advice.Get this product 1g, be diluted to 1ml with 5%, 10% glucose injection or 0.9% sodium chloride injection and contain 2～10mg solution; Or, slowly instil more than 60 minutes with 5%, 10% glucose injection of 100～500ml or 0.9% sodium chloride injection dissolving 1g.Or regulate with 5%, 10% glucose injection or 0.9% sodium chloride injection earlier and drip fastly, add this product again and be diluted to 1ml and contain 2～10mg solution, slowly instil more than 60 minutes.
Injection Carbamaid peroxide of the present invention (lyophilizing) is a Carbamide Peroxide.The hydrogen peroxide that can be decomposed out after injecting in the body discharges oxygen through the hydrogen peroxide enzyme catalysis again.Oxygen directly combines with hemoglobin in the blood, supplies with oxygen-starved tissue.Carbonic acid amide excretes with original shape by kidney.This product LD50 is greater than 324mg/kg.
Research and improvement through process aspect, research worker of the present invention is added excipient in Carbamaid peroxide freeze dried formulation for injection, and employing freeze drying process, not only avoided the decomposition of the Carbamaid peroxide in the component, and the Carbamaid peroxide molecule is fully entered in the framework of dextran, rate of release has slowed down when clinical use, greatly reduce the pain that makes the human body generation in the injection process because of quick generation, the release of injection site oxygen, also do not influence the clinical efficacy of Carbamaid peroxide simultaneously, the clinical practice of being more convenient for; Be used in the medicines such as fetal distress that preparation various hypoxemia of treatment and acute anoxia cause.
The specific embodiment
Following embodiment further describes the present invention, but described embodiment only is used to illustrate the present invention rather than restriction the present invention.
Embodiment 1
A) get the fresh water for injection of 80 ℃ of 200 grams in dense preparing tank, the dextran (molecular weight is 20000) that adds 10 grams, stir, adding 0.1 ‰ active carbon stirs and boiled 20 minutes, circulation is cooled to 50 ℃, with the medicinal liquid decarbonization filtering to dilute preparing tank, logical condensed water makes medicinal liquid is cooled to 20 ℃, adds the Carbamaid peroxide of 10 grams, starts the nitrogen charging device in the compounding system simultaneously, whole process for preparation is carried out in confined conditions, medicinal liquid is stirred standardize solution, intermediate products check, with medicinal liquid through the end-filtration system filtration to basin, to be filled.
B) decide loading amount according to the content of Carbamaid peroxide, liquid medicine filling in cillin bottle, is sent in the freeze drying box.
C) goods were kept 1 hour at-40 ℃, heated up, and were warming up to about-5 ℃ to separate out and to keep temperature to make until the adularescent crystallization to separate out fully, kept 4 hours, were cooled to-40 ℃ once more and kept 1 hour.Beginning is distillation slowly, and vacuum maintains below the 15Pa, and in 24 hours, products temperature reaches 25 ℃ and kept 2 hours.Behind the lyophilizing terminal point, tamponade under fine vacuum is put filtrated air outlet gland, visual inspection, packing promptly after the tamponade.
Embodiment 2
A) get the fresh water for injection of 90 ℃ of 1000 grams in dense preparing tank, the dextran (molecular weight is 10000) that adds 100 grams, stir, adding 0.5 ‰ active carbon stirs and boiled 30 minutes, circulation is cooled to 60 ℃, with the medicinal liquid decarbonization filtering to dilute preparing tank, logical condensed water makes medicinal liquid is cooled to 25 ℃, adds the Carbamaid peroxide of 0.05 gram, starts the nitrogen charging device in the compounding system simultaneously, whole process for preparation is carried out in confined conditions, medicinal liquid is stirred standardize solution, intermediate products check, with medicinal liquid through the end-filtration system filtration to basin, to be filled.
B) decide loading amount according to the content of Carbamaid peroxide, liquid medicine filling in cillin bottle, is sent in the freeze drying box.
C) goods were kept 2 hours at-40 ℃, heated up, and were warming up to about-10 ℃ to separate out and to keep temperature to make until the adularescent crystallization to separate out fully, kept 2 hours, were cooled to-40 ℃ once more and kept 2 hours.Beginning is distillation slowly, and vacuum maintains below the 15Pa, and in 30 hours, products temperature reaches 20 ℃ and kept 3 hours.Behind the lyophilizing terminal point, tamponade under fine vacuum is put filtrated air outlet gland, visual inspection, packing promptly after the tamponade.
Embodiment 3
A) get the fresh water for injection of 85 ℃ of 5000 grams in dense preparing tank, the dextran (molecular weight is 32000) that adds 50 grams, stir, adding 1 ‰ active carbon stirs and boiled 25 minutes, circulation is cooled to 65 ℃, with the medicinal liquid decarbonization filtering to dilute preparing tank, logical condensed water makes medicinal liquid is cooled to 25 ℃, adds the Carbamaid peroxide of 1500 grams, starts the nitrogen charging device in the compounding system simultaneously, whole process for preparation is carried out in confined conditions, medicinal liquid is stirred standardize solution, intermediate products check, with medicinal liquid through the end-filtration system filtration to basin, to be filled.
B) decide loading amount according to the content of Carbamaid peroxide, liquid medicine filling in cillin bottle, is sent in the freeze drying box.
C) goods were kept 1.5 hours at-35 ℃, heated up, and were warming up to about 0 ℃ to separate out and to keep temperature to make until the adularescent crystallization to separate out fully, kept 5 hours, were cooled to-35 ℃ once more and kept 1.5 hours.Beginning is distillation slowly, and vacuum maintains below the 15Pa, and in 26 hours, products temperature reaches 30 ℃ and kept 2.5 hours.Behind the lyophilizing terminal point, tamponade under fine vacuum is put filtrated air outlet gland, visual inspection, packing promptly after the tamponade.
Embodiment 4
A) get the fresh water for injection of 90 ℃ of 6000 grams in dense preparing tank, the dextran (molecular weight is 42000) that adds 900 grams, stir, adding 0.1 ‰ active carbon stirs and boiled 25 minutes, circulation is cooled to 70 ℃, with the medicinal liquid decarbonization filtering to dilute preparing tank, logical condensed water makes medicinal liquid is cooled to 30 ℃, adds the Carbamaid peroxide of 30 grams, starts the nitrogen charging device in the compounding system simultaneously, whole process for preparation is carried out in confined conditions, medicinal liquid is stirred standardize solution, intermediate products check, with medicinal liquid through the end-filtration system filtration to basin, to be filled.
B) decide loading amount according to the content of Carbamaid peroxide, liquid medicine filling in cillin bottle, is sent in the freeze drying box.
C) goods were kept 1 hour at-38 ℃, heated up, be warming up to-10～℃ about separate out and keep temperature to make until the adularescent crystallization and separate out fully, kept 6 hours, be cooled to-38 ℃ once more and kept 2.5 hours.Beginning is distillation slowly, and vacuum maintains below the 15Pa, and in 32 hours, products temperature reaches 35 ℃ and kept 1.5 hours.Behind the lyophilizing terminal point, tamponade under fine vacuum is put filtrated air outlet gland, visual inspection, packing promptly after the tamponade.
Embodiment 5
A) get the fresh water for injection of 80 ℃ of 1000 grams in dense preparing tank, the dextran (molecular weight is 25000) that adds 50 grams, stir, stirring was boiled 20 minutes, circulation is cooled to 70 ℃, with medical filtration to dilute preparing tank, logical condensed water makes medicinal liquid is cooled to 30 ℃, adds the Carbamaid peroxide of 500 grams, starts the nitrogen charging device in the compounding system simultaneously, whole process for preparation is carried out in confined conditions, medicinal liquid is stirred standardize solution, intermediate products check, with medicinal liquid through the end-filtration system filtration to basin, to be filled.
B) decide loading amount according to the content of Carbamaid peroxide, liquid medicine filling in cillin bottle, is sent in the freeze drying box.
C) goods were kept 2.5 hours at-35 ℃.Heat up, be warming up to about-5 ℃ to separate out and to keep temperature to make and separate out fully, kept 3 hours, be cooled to-35 ℃ once more and kept 1 hour until the adularescent crystallization.Beginning is distillation slowly, and vacuum maintains below the 15Pa, and in 36 hours, products temperature reaches 15 ℃ and kept 3 hours.Behind the lyophilizing terminal point, tamponade under fine vacuum is put filtrated air outlet gland, visual inspection, packing promptly after the tamponade.
Experimental example 1
This experimental example is the most preferably detection of relevant every gainer under specification 0.1g, 1g outward appearance, acidity, the injection item of lyophilized formulations injection Carbamaid peroxide of the present invention (lyophilizing).
Character: lyophilized formulations of the present invention is white block, meets the quality standard regulation.
Acidity: get this product 4g, add the cold water 15ml that newly boiled and make dissolving, measure according to two appendix VI of Chinese Pharmacopoeia version in 2000 H, medicine composition injection pH value of the present invention is 2.0～6.0, meets quality standard.
Pyrogen: get this product, add sterilized water for injection and make the solution that contains 7.5mg among every 1ml, inspection (two appendix XI of Chinese Pharmacopoeia version in 2000 D mensuration) dosage is slowly injected 2ml by the every kg of rabbit body weight in accordance with the law, and this product is up to specification.
Aseptic: as to get this product and add sterile saline and make and be equivalent to 0.2% hydrogenperoxide steam generator, draw 5ml, add 1.5% sodium sulfite sterile solution 5ml, mixing, placed 10 minutes, and checked (two appendix XI of Chinese Pharmacopoeia version in 2000 H mensuration) in accordance with the law, this product is up to specification.
Clarity: get this product, every bottle add injection water 4ml dissolving after, check in accordance with the law (two appendix I of Chinese Pharmacopoeia version in 2000 B) that this product is up to specification.
Content uniformity: check in accordance with the law (two appendix I of Chinese Pharmacopoeia version in 2000 B) that this product is up to specification.
Experimental example 2
This experimental example is the most preferably qualitative determination of specification 0.1g, 1g composition of lyophilized formulations injection Carbamaid peroxide of the present invention (lyophilizing).
(1) this product 0.1g adds water 1ml and makes dissolving, adds equivalent nitric acid, and the white crystalline precipitation takes place.
(2) get this product 0.25g, add 2 of dilute sulfuric acids and water 10ml and make dissolving, be divided into two parts, portion adds potassium dichromate test solution number droplet, promptly shows blue (and producing bubble), place and then fade to yellowish-brown, after another part adds isometric ether (or ethyl acetate), add the potassium dichromate test solution, shake up, ether (or ethyl acetate) layer shows blue, and it is faint yellow or almost colourless that lower aqueous solution shows.
(3) get this product 0.1g, add each 1ml of dilute sulfuric acid and water dissolving after, add potassium permanganate test solution number droplet, shake up, purple promptly disappears.
Lyophilized formulations of the present invention is all up to specification with the inspection of beginning a project.
Experimental example 3
This experimental example is the most preferably mensuration of specification 0.1g, 1g physical index of lyophilized formulations injection Carbamaid peroxide of the present invention (lyophilizing).
(1) chloride: get this product 0.2g, check (two appendix VIII of Chinese Pharmacopoeia version in 2000 A) in accordance with the law, with the contrast liquor ratio of standard sodium chloride solution 1.0ml, must not denseer (0.005%).
(2) sulfate: get this product 2g, check (two appendix VIII of Chinese Pharmacopoeia version in 2000 B) in accordance with the law, the contrast liquor ratio made from standard potassium sulfate solution 2.0ml must not denseer (0.01%).
(3) salt: get this product 2g, add water 20ml dissolving after, filter, filtrate is divided into halves, adds dilute sulfuric acid 2ml in the portion, adds water 2ml in another part, leaves standstill 2 hours, two liquid should be clarified equally.
(4) loss on drying: it is an amount of to get this product, is desiccant with the phosphorus pentoxide, under the room temperature dry 2 hours, subtracts weight loss and must not cross 3.0%.
(5) residue on ignition: get this product 2g,, check (two appendix VIII of Chinese Pharmacopoeia version in 2000 N) in accordance with the law, must not cross 0.1% 60 ℃ of dryings 2 hours.
(6) heavy metal: get this product 1g, put in the beaker, after adding liquor ammoniae fortis 15ml and making dissolving, evaporate to dryness in water-bath adds liquor ammoniae fortis 10ml dissolving again, continues evaporate to dryness in water-bath, steamed again 1～2 hour, after adding the suitable quantity of water dissolving then, check (two appendix VIII of Chinese Pharmacopoeia version in 2000 H) in accordance with the law, contain heavy metal and must not cross 10/1000000ths.
(7) arsenic salt: get this product 1g, check the item out-of-date hydrogen oxide of method Ex-all down by heavy metal, from " put in the beaker to revaporization 1～2 hour ", after adding water 23ml and hydrochloric acid 5ml dissolving, check in accordance with the law (two appendix VIII of Chinese Pharmacopoeia version in 2000 J, first method) that arsenic content must not cross 2/1000000ths.
Lyophilized formulations of the present invention is all up to specification with the inspection of beginning a project.
Experimental example 4
This experimental example is the most preferably quantitative assay of specification 0.1g, 1g of lyophilized formulations injection Carbamaid peroxide of the present invention (lyophilizing).
Get this product 0.1g, accurate claim surely, put in the iodine flask, after adding water 25ml and glacial acetic acid 5ml and dissolving, add potassium iodide 2g, 1 of ammonium molybdate test solution, shading was placed 10 minutes, with sodium thiosulfate volumetric solution (0.1mol/L) titration, add starch indicator solution 3ml during to nearly terminal point, continue to drip to blue disappearance, and titrating result is proofreaied and correct with blank experiment, promptly.The sodium thiosulfate volumetric solution (0.1mol/L) of every 1ml is the H of 1.701mg quite
2O
2, this product is pressed dry product and is calculated, and contains hydrogen peroxide (H
2O
2) should be 25.0～35.0%.
Injection of the present invention is through three batches assay, result's following (seeing Table 1):
table 1: content of hydrogen peroxide measurement result (0.1g)
| Lot number | ????％ |
| ????20040101 | ????30.3 |
| ????20040102 | ????29.1 |
| ????20040103 | ????29.5 |
table 2: content of hydrogen peroxide measurement result (1g)
| Lot number | ????％ |
| ????20040301 | ????31.4 |
| ????20040302 | ????29.8 |
| ????20040303 | ????32.1 |
Above experimental example explanation, with injection Carbamaid peroxide (lyophilizing) steady quality of explained hereafter of the present invention, every index all meets the statutory standards content.
Comparative example 1
This comparative example explanation lyophilized formulations of the present invention has identical clinical efficacy with injection Carbamaid peroxide sterilized powder.
2 groups of therapeutic outcome comparative examples of table 3 (%)
Group example number enabledisable
Preparation group 103 103 (100) 0 (0) of the present invention
Sterilized powder group 96 96 (100) 0 (0)
This comparative example explanation, lyophilized formulations of the present invention has identical clinical efficacy with sterilized powder.
Comparative example 2
The untoward reaction in clinical practice of this comparative example explanation lyophilized formulations of the present invention and conventional lyophilized formulations, injection Carbamaid peroxide sterilized powder is compared.
2 groups of therapeutic outcome comparative examples of table 4 (%)
Group example number produces the pain mild pain is not had pain
Conventional lyophilized formulations group 92 82 (89) 7 (8) 3 (3)
This technology preparation group 103 32 (31) 40 (39) 31 (30)
Sterilized powder group 96 86 (90) 6 (6) 4 (4)
The explanation of this comparative example, lyophilized formulations of the present invention lacks in adverse reaction in clinical application than conventional lyophilized formulations, aseptic powdery preparation.
Comparative example 3
This comparative example explanation lyophilized formulations of the present invention and injection Carbamaid peroxide sterilized powder are in the influence of process aspect to product.
The different modes of production of two kinds of preparations of table 5 relatively
| Lyophilized formulations | Sterilized powder | |
| 1 | Fill nitrogen preparation, freezing, vacuum drying, main component is difficult for decomposing. | Room temperature control, main component is easily decomposed at minute process of assembling. |
| 2 | The product quality is loose, and rehydration is good, rapidly dissolving. | Matter is close, dissolves insufficient. |
| 3 | Production process is through filtering with microporous membrane, and finished product speck matter is few. | Powder direct packaging, speck matter are difficult for removing |
Comparative example 4
This comparative example explanation lyophilized formulations of the present invention and general lyophilized formulations are different process aspect.
Table 6 compares with conventional lyophilizing mode
| This technology | Common process | |
| 1 | Fill the nitrogen preparation and avoid the decomposition of main component in technical process. | Process for preparation does not fill nitrogen, and main component is easily decomposed in technical process. |
| 2 | Recrystallization fully enters in the dextran molecule framework Carbamaid peroxide molecule, and the clinical practice untoward reaction is few. | The clinical practice untoward reaction is many. |
Claims (10)
1. a Carbamaid peroxide freeze dried formulation for injection is characterized in that, comprises Carbamaid peroxide and dextran, and mass ratio is 0.001～2: 0.001～2.
2. a kind of Carbamaid peroxide freeze dried formulation for injection according to claim 1 is characterized in that, comprises Carbamaid peroxide and dextran, and mass ratio is 0.05～1.5: 0.05～1.5.
3. a kind of Carbamaid peroxide freeze dried formulation for injection according to claim 1 and 2 is characterized in that the molecular weight of described dextran is 10000～42000, is preferably 32000～42000.
4. a method for preparing the described Carbamaid peroxide freeze dried formulation for injection of claim 1 is characterized in that, comprises the steps:
By the water for injection of proportioning with 80 ℃～90 ℃ of dextran addings, the injection water yield is 1: 0.01～0.15 with the amount ratio of dextran, boils 20～30 minutes, after cooling is filtered, add Carbamaid peroxide by proportioning, the filtration that stirs, after lyophilization form.
5. the preparation method of a kind of Carbamaid peroxide freeze dried formulation for injection according to claim 4 is characterized in that, after dextran adds entry, can add 0.1～1 ‰ adsorbent.
6. the preparation method of a kind of Carbamaid peroxide freeze dried formulation for injection according to claim 4, it is characterized in that, it is 0.45～0.3 μ m that the dextran aqueous solution filters employed aperture of filter material, and filtering employed aperture of filter material before the lyophilizing fill is 0.1～0.3 μ m.
7. the preparation method of a kind of Carbamaid peroxide freeze dried formulation for injection according to claim 4, it is characterized in that, described lyophilization is carried out in freezer dryer, refrigerating process is: the Carbamaid peroxide solution that is made into was kept 1～3 hour at-40 ℃～-35 ℃, be warming up to-10 ℃～0 ℃ then, kept 2～6 hours, being cooled to-40 ℃～-35 ℃ once more kept 1～3 hour, vacuum maintains below the 15Pa, in 24-36 hour, temperature rises to 15 ℃～35 ℃, and keeps 1～3 hour.
8. the preparation method of a kind of Carbamaid peroxide freeze dried formulation for injection according to claim 4 is characterized in that, comprises the steps:
A) by the water for injection of proportioning with 80 ℃～90 ℃ of dextran addings, stir, the acticarbon of adding 0.1～1 ‰ stirs and boiled 20～30 minutes, circulation is cooled to 50～70 ℃, be cooled to 20 ℃～30 ℃ behind the decarbonization filtering, add Carbamaid peroxide by proportioning again, medicinal liquid is stirred;
B) the Carbamaid peroxide solution that is made into was kept 1～3 hour at-40 ℃～-35 ℃, be warming up to-10 ℃～0 ℃ then, kept 2～6 hours, being cooled to-40 ℃～-35 ℃ once more kept 1～3 hour, vacuum maintains below the 15Pa, in 24～36 hours, temperature rises to 15 ℃～35 ℃, and keeps 1～3 hour.
9. the preparation method of a kind of Carbamaid peroxide freeze dried formulation for injection according to claim 4 is characterized in that, comprises the steps:
A) by the water for injection of proportioning with 80 ℃～90 ℃ of dextran addings, the injection water yield is 1: 0.01～0.15 with the amount ratio of dextran, stir, the acticarbon of adding 0.5～1 ‰ stirs and boiled 25～30 minutes, circulation is cooled to 50～60 ℃, and with the medicinal liquid decarbonization filtering, logical condensed water makes medicinal liquid is cooled to 20～25 ℃, add Carbamaid peroxide by proportioning again, medicinal liquid is stirred;
B) medicinal liquid was kept 1～2 hour at-40 ℃～-35 ℃, heat up, be warming up to about-10 ℃～-5 ℃ to separate out and to keep temperature to make and separate out fully until the adularescent crystallization, kept 3～6 hours, and be cooled to-40 ℃～-35 ℃ once more and kept 1～2 hour, beginning is distillation slowly, vacuum maintains below the 15Pa, in 26～32 hours, products temperature reaches 20 ℃～30 ℃, keeps 2～3 hours.
10. the purposes aspect the fetal distress disease that a kind of Carbamaid peroxide freeze dried formulation for injection according to claim 1 causes in the various hypoxemia of preparation treatment and acute anoxia.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1850067B (en) * | 2005-09-08 | 2011-03-16 | 周华英 | In vivo oxygen-supply solution for injection, and its preparing method and use |
| CN103432581A (en) * | 2013-03-22 | 2013-12-11 | 北京海思威科技有限公司 | Application of carbamide peroxide injection in inactivation of viruses for treating diseases |
-
2004
- 2004-11-26 CN CNB2004100960553A patent/CN100404027C/en active Active
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1850067B (en) * | 2005-09-08 | 2011-03-16 | 周华英 | In vivo oxygen-supply solution for injection, and its preparing method and use |
| CN103432581A (en) * | 2013-03-22 | 2013-12-11 | 北京海思威科技有限公司 | Application of carbamide peroxide injection in inactivation of viruses for treating diseases |
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| Publication number | Publication date |
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| CN100404027C (en) | 2008-07-23 |
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