CN102440968A - More stable desmopressin (DDAVP) polypeptide drug freeze-dried powder injection - Google Patents
More stable desmopressin (DDAVP) polypeptide drug freeze-dried powder injection Download PDFInfo
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Abstract
The invention relates to a more stable desmopressin (DDAVP) polypeptide drug freeze-dried powder injection. The injection mainly comprises main medicines of desmopressin acetate, osmotic pressure regulator, pH regulator, antioxidizer and local analgesic, wherein the antioxidizer is added to improve the stability of the injection, and the local analgesic is added so that the pain of a patient can be relieved and the main medicines are not influenced. The preparation technology of the injection main comprises weighing, dissolving, heat source adsorbing by activated carbon, filtering, end filtering, split charging, vacuum drying, plug and cap pressing. The injection is used for treating renal and urogenital disorder, and has the characteristics of stronger and more lasting antidiuresis function and less or nearly no pressure increasing function. The injection has the stable quality, exact curative effect and is beneficial to patients to accept.
Description
Technical field:
The present invention relates to formulation art, specifically is a kind of more stable DDAVP polypeptide drugs lyophilized injectable powder.
Background technology:
Desmopressin (Desmopressin) is a kind of synthetic analogues of natural hormone arginine vasopressin, has the inhibition activity of urinating of height, is used to treat diseases of urinary system.The natural human arginine vasopressin is 9 peptides, and 1 links to each other with cystine linkage with 6 cysteine and forms loop configuration, and 1 and 9 has an amino, and 8 is the L-arginine.Desmopressin has the transformation of two places to the structure of natural molecule, the one, remove 1 amino, the 2nd, replace 8 L-arginine with the D-arginine, promptly the 1-desmopressin (1-deamino-8-D-arginine vasoprssin, DDAVP).This structure of modification has strengthened the ability of molecule antagonism enzymatic degradation greatly, and antidiuretic activity strengthens, and prolong action time, and the blood vessel pressurization significantly reduces.The big 2000-3000 of the active odds ratio parent molecule of the diuresis/pressurization of Desmopressin times, drug effect can be kept 10-12 hour, and parent molecule has only 2-3 hour.In addition, heavy dose of vassopressin can also improve the level of blood coagulation factor VIII, and anastalsis is arranged.
The clinical practice in more than 20 year proves, no matter is that its nasal cavity drop, spray or oral tablet have all been obtained good curative effect, and side effect seldom takes place, consistent generally acknowledge Desmopressin be the treatment central diabetes insipidus choice drug.Though existing desmopressin preparation can reach patient's demand, but still need to improve.Tablet usually need be with water delivery service, and the treatment of Desmopressin must the limit fluid picked-up, and when absorbing with tablet form, the bioavailability of Desmopressin is equivalent to intravenous 0.1% approximately.Intranasal administration can obtain high bioavailability, but patient's acceptance is lower.And intranasal administration may have harmful effect to cilium, causes virus and antibacterial to be prone to get into mucosa.
The acetic acid desmopressin injection prescription that has gone on the market includes 4.0 μ g/ml or 15.0 μ g/ml desmopressin acetates, 9.0mg/ml sodium chloride.Its poor stability is only in 2 ℃～8 ℃ preservations of refrigerator temperature; It is during to patient's subcutaneous injection, and the injection site produces pain, is unfavorable for that the patient accepts.The present invention is directed to these problems and propose, add antioxidant to improve stability of formulation, adding the local analgesia agent does not have influence with the pain that alleviates the patient to principal agent.The said preparation steady quality, determined curative effect is beneficial to the patient and accepts.
Summary of the invention:
The objective of the invention is to prepare a kind of is the lyophilized injectable powder of active component with the desmopressin acetate, has steady quality, and determined curative effect is beneficial to advantages such as patient's acceptance.
The present invention has prepared a kind of lyophilized injectable powder that contains the desmopressin acetate medicine, and it comprises principal agent desmopressin acetate, osmotic pressure regulator, pH value regulator, antioxidant and local analgesic.
The present invention has prepared a kind of lyophilized injectable powder that contains the desmopressin acetate medicine, and its osmotic pressure regulator is selected from sodium chloride, glucose, glycerol, mannitol, sorbitol, boric acid, Borax etc.; Its pH value regulator is selected from hydrochloric acid, acetic acid, sodium acetate, sulphuric acid, lactic acid, malic acid, citric acid, phosphoric acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydrogen phosphate etc.; Its antioxidant is selected from sodium sulfite, sodium pyrosulfite, ascorbic acid, sodium thiosulfate, sodium sulfite, glutathion, thiourea, TGA, vitamin E etc.; Its local analgesia agent is selected from benzyl alcohol, chlorobutanol and procaine hydrochloride etc.
Through a large amount of optimization experiment, the present invention has found that most preferably prescription is formed.Wherein, The preferred 0.1-50 μ of the concentration of its principal agent desmopressin acetate g/ml; The preferred 0.1-100mg/ml sodium chloride of its osmotic pressure regulator; Its pH value regulator preferably uses hydrochloric acid to transfer pH to be 3.5-5.5, preferred 0.01-2%w/v sodium sulfite of its antioxidant and 0.01-2%w/v sodium pyrosulfite, preferred 0.1-5%w/v benzyl alcohol of its local analgesia agent and 0.03-2%w/v chlorobutanol.
In addition, the present invention also provides preparation to contain the method for the lyophilized injectable powder of desmopressin acetate medicine.Its technology is following:
1 precision takes by weighing the above-mentioned material of recipe quantity to sterilization container;
2 add an amount of water for injection dissolves fully;
3 usefulness hydrochloric acid are regulated pH value to 3.5 between 5.5;
4 water for injection standardize solution;
5 activated carbon adsorption pyrogens;
6 0.45 μ m filtering with microporous membranes;
7 0.22 μ m filtering with microporous membranes;
Fill is in sterilized cillin bottle after 8 passed examinations, vacuum lyophilization, tamponade, outlet, Zha Gai;
Labeling packing after 9 passed examinations.
The specific embodiment:
The present invention comprises but is not limited to following examples.
Embodiment 1:
4.0 μ g/ml desmopressin acetate, 9.0mg/ml sodium chloride, the 0.1%w/v sodium sulfite, the 2%w/v benzyl alcohol, using hydrochloric acid to transfer pH is 4.0, its preparation technology is following:
Under aseptic condition, take by weighing desmopressin acetate 0.004g, sodium chloride 9.0g, sodium sulfite 1g and 20g benzyl alcohol; Place sterilization container, add recipe quantity 80% water for injection, stir and make dissolving; Transfer pH to 4.0 with hydrochloric acid, add the injection water, stir to 1000ml.Add 25g injection active carbon and stir 30min, the sterilization filter coarse filtration is taken off charcoal, with 0.45 μ m filtering with microporous membrane, uses 0.22 μ m filtering with microporous membrane at last; Filtrating detect qualified after, fill in 2ml sterilization cillin bottle (1ml/ bottle), lyophilisation; The vacuum tamponade, outlet rolls lid.Make every bottle to be equivalent to 4.0 μ g desmopressin acetates.
Make 1000 bottles of desmopressin acetate lyophilized injectable powders (containing desmopressin acetate 4.0 μ g) by present embodiment; Through stable accelerated test and animal blood vessels zest, muscle irritation, haemolysis and anaphylaxis experiment, its stability and clinical drug safety property are investigated.
The stability accelerated test:
The a collection of test sample that will go on the market respectively and to put into temperature by a collection of sample of commercially available back be that 40 ± 2 ℃, relative humidity are that 75% ± 5% climatic chamber is investigated, 0,1,2,3 and sampling and measuring 6 months the time, the result sees table 1-1 and table 1-2 respectively.
Table 1-1 listing reference substance accelerated test result
Table 1-2 self-control sample accelerated test result
Can find out through table 1-1 and table 1-2; Investigate 6 months through accelerated test; The desmopressin acetate lyophilized injectable powder of the present invention's preparation compares with the acetic acid desmopressin injection that has gone on the market, and appearance luster, acidity, clarity of solution do not have significant change, and the impurity of the test sample of listing increases, content descends obviously; Show that the desmopressin acetate lyophilized injectable powder that the present invention prepares can preserve under room temperature, stability increases.
Blood vessel irritation, muscle irritation, haemolysis and anaphylaxis experiment:
Blood vessel irritation:
Choose 6 of the undamaged healthy rabbits of ears, left side auricular vein injection embodiment 1 solution 1ml, capacity 5% glucose solutions such as auris dextra injection, were injected 7 days continuously at every day 1 time.
During the injection, regularly observe the irritative response of auricular vein every day.Put to death rabbit on the 8th day, and got bilateral auricular vein and surrounding tissue, use formaldehyde fixed, do the conventional organization section at the proximal part of injection site, light microscopic is observed down and is had or not pathological change.Observation index and criterion are seen table 1-3.
Table 1-3 blood vessel irritation scoring and criterion
The result shows that the zest of rabbit auricular vein injection embodiment 1 solution compares no significant difference with 5% glucose solution.Inflammatory reactions such as the congestion of blood vessel, surrounding tissue edema are not seen in perusal.Tissue slice inspection does not see that blood vessel structure is unusual, endothelial injury, thrombosis and other pathological change.The blood vessel of its naked eyes and om observation, the cumulative score of surrounding tissue show nonirritant all less than 0.5.
Muscle irritation:
Get 6 of healthy rabbits, injection embodiment 1 solution 1ml in every rabbit left side quadriceps femoris, inject with the volume normal saline on the right side.The injection back is observed injection site muscle and is had or not reactions such as hyperemia, edema, and (the 3rd day) sacrificed by exsanguination behind the Half animals 48h is vertically cut skin, and injection site, perusal both sides has or not reactions such as hyperemia, edema, and gets its tissue and do pathologic finding.Then by the IR of showing this medicine of standard evaluation among the 1-4.Remaining animal continues to observe 14d, repeats aforesaid operations in the 18th day after the sacrificed by exsanguination, and evaluation criterion is seen table 1-4.
Table 1-4 muscular irritation reaction evaluating standard
The result shows; After injecting embodiment 1 solution in the quadriceps femoris of rabbit left side; Perusal injection site muscle does not have reactions such as hyperemia, edema, and explicitly IRs such as tissue degeneratiaon or necrosis are not also seen in the pathological tissue inspection, compare no significant difference with the normal saline side.
Sensitization to Cavia porcellus:
Choose 6 of healthy guinea pigs, every lumbar injection embodiment 1 solution 0.5ml, the next day, inject 1 time, injects altogether 3 times.Be divided into 2 groups then at random, after the 1st administration 14 or 21 days respectively, quiet notes embodiment 1 solution 1ml.Observe Cavia porcellus and have or not allergic symptoms such as excited uneasiness, dyspnea.
Two groups of Cavia porcelluss of result are all movable normal, do not see adnormal respiration etc.
External hemolytic test:
Prepare 2% rabbit red cell suspension.Get 7 in test tube, 1-5 adds various liquid by table.Each test tube is shaken up gently, put in 37 ℃ of waters bath with thermostatic control and hatch, observe 0.5,1,2,3,6 hour result.Erythrocyte agglutination in vitro and hemolytic criterion are seen table 1-6.
The outer hemolytic test application of sample table of table 1-5 desmopressin acetate solution body
Outer haemolysis of table 1-6 red cell body and agglutination test criterion
As a result, the distilled water control tube was complete hemolysis in 0.5 hour.Normal saline did not all have haemolysis with each desmopressin acetate solution in 6 hours.Jolting gently, the erythrocyte of normal saline and each concentration desmopressin acetate solution pipe bottom sediments all can disperse fully, shows that desmopressin acetate solution does not have red cell agglutination.
Blood vessel irritation, muscle irritation, external hemolytic and anaphylaxis experiment show that embodiment 1 solution does not have tangible zest, anaphylaxis, can not cause hemolytic reaction yet.Show that the desmopressin acetate lyophilized injectable powder safety that the present invention prepares is good, can supply clinical vein injection and intramuscular injection to use.
Embodiment 2:
4.0 μ g/ml desmopressin acetate, 9.0mg/ml sodium chloride, the 0.1%w/v sodium pyrosulfite, the 0.4%w/v chlorobutanol, using hydrochloric acid to transfer pH is 4.0, its preparation technology is following:
Under aseptic condition, take by weighing desmopressin acetate 0.004g, sodium chloride 9.0g, sodium pyrosulfite 1g and 4g chlorobutanol; Place sterilization container, add recipe quantity 80% water for injection, stir and make dissolving; Transfer pH to 4.0 with hydrochloric acid, add the injection water, stir to 1000ml.Add 25g injection active carbon and stir 30min, the sterilization filter coarse filtration is taken off charcoal, with 0.45 μ m filtering with microporous membrane, uses 0.22 μ m filtering with microporous membrane at last; Filtrating detect qualified after, fill in 2ml sterilization cillin bottle (1ml/ bottle), lyophilisation; The vacuum tamponade, outlet rolls lid.Make every bottle to be equivalent to 4.0 μ g desmopressin acetates.
Make 1000 bottles of desmopressin acetate lyophilized injectable powders (containing desmopressin acetate 4.0 μ g) by present embodiment; Through stable accelerated test and animal blood vessels zest, muscle irritation, haemolysis and anaphylaxis experiment, its stability and clinical drug safety property are investigated.
The stability accelerated test:
The a collection of test sample that will go on the market respectively and to put into temperature by a collection of sample of commercially available back be that 40 ± 2 ℃, relative humidity are that 75% ± 5% climatic chamber is investigated, 0,1,2,3 and sampling and measuring 6 months the time, the result sees table 2-1 and table 2-2 respectively.
Table 2-1 listing reference substance accelerated test result
Table 2-2 self-control sample accelerated test result
Can find out through table 2-1 and table 2-2; Investigate 6 months through accelerated test; The desmopressin acetate lyophilized injectable powder of the present invention's preparation compares with the acetic acid desmopressin injection that has gone on the market, and appearance luster, acidity, clarity of solution do not have significant change, and the impurity of the test sample of listing increases, content descends obviously; Show that the desmopressin acetate lyophilized injectable powder that the present invention prepares can preserve under room temperature, stability increases.
Blood vessel irritation, muscle irritation, haemolysis and anaphylaxis experiment:
Blood vessel irritation:
Choose 6 of the undamaged healthy rabbits of ears, left side auricular vein injection embodiment 2 solution 1ml, capacity 5% glucose solutions such as auris dextra injection, were injected 7 days continuously at every day 1 time.
During the injection, regularly observe the irritative response of auricular vein every day.Put to death rabbit on the 8th day, and got bilateral auricular vein and surrounding tissue, use formaldehyde fixed, do the conventional organization section at the proximal part of injection site, light microscopic is observed down and is had or not pathological change.Observation index and criterion are seen table 2-3.
Table 2-3 blood vessel irritation scoring and criterion
The result shows that the zest of rabbit auricular vein injection embodiment 2 solution compares no significant difference with 5% glucose solution.Inflammatory reactions such as the congestion of blood vessel, surrounding tissue edema are not seen in perusal.Tissue slice inspection does not see that blood vessel structure is unusual, endothelial injury, thrombosis and other pathological change.The blood vessel of its naked eyes and om observation, the cumulative score of surrounding tissue show nonirritant all less than 0.5.
Muscle irritation:
Get 6 of healthy rabbits, injection embodiment 2 solution 1ml in every rabbit left side quadriceps femoris, inject with the volume normal saline on the right side.The injection back is observed injection site muscle and is had or not reactions such as hyperemia, edema, and (the 3rd day) sacrificed by exsanguination behind the Half animals 48h is vertically cut skin, and injection site, perusal both sides has or not reactions such as hyperemia, edema, and gets its tissue and do pathologic finding.Then by the IR of showing this medicine of standard evaluation among the 2-4.Remaining animal continues to observe 14d, repeats aforesaid operations in the 18th day after the sacrificed by exsanguination, and evaluation criterion is seen table 2-4.
Table 2-4 muscular irritation reaction evaluating standard
The result shows; After injecting embodiment 2 solution in the quadriceps femoris of rabbit left side; Perusal injection site muscle does not have reactions such as hyperemia, edema, and explicitly IRs such as tissue degeneratiaon or necrosis are not also seen in the pathological tissue inspection, compare no significant difference with the normal saline side.
Sensitization to Cavia porcellus:
Choose 6 of healthy guinea pigs, every lumbar injection embodiment 2 solution 0.5ml, the next day, inject 1 time, injects altogether 3 times.Be divided into 2 groups then at random, after the 1st administration 14 or 21 days respectively, quiet notes embodiment 2 solution 1ml.Observe Cavia porcellus and have or not allergic symptoms such as excited uneasiness, dyspnea.
Two groups of Cavia porcelluss of result are all movable normal, do not see adnormal respiration etc.
External hemolytic test:
Prepare 2% rabbit red cell suspension.Get 7 in test tube, 2-5 adds various liquid by table.Each test tube is shaken up gently, put in 37 ℃ of waters bath with thermostatic control and hatch, observe 0.5,1,2,3,6 hour result.Erythrocyte agglutination in vitro and hemolytic criterion are seen table 2-6.
The outer hemolytic test application of sample table of table 2-5 desmopressin acetate solution body
Outer haemolysis of table 2-6 red cell body and agglutination test criterion
As a result, the distilled water control tube was complete hemolysis in 0.5 hour.Normal saline did not all have haemolysis with each desmopressin acetate solution in 6 hours.Jolting gently, the erythrocyte of normal saline and each concentration desmopressin acetate solution pipe bottom sediments all can disperse fully, shows that desmopressin acetate solution does not have red cell agglutination.
Blood vessel irritation, muscle irritation, external hemolytic and anaphylaxis experiment show that embodiment 2 solution do not have tangible zest, anaphylaxis, can not cause hemolytic reaction yet.Show that the desmopressin acetate lyophilized injectable powder safety that the present invention prepares is good, can supply clinical vein injection and intramuscular injection to use.
Embodiment 3:
15.0 μ g/ml desmopressin acetate, 9.0mg/ml sodium chloride, the 0.1%w/v sodium pyrosulfite, the 2%w/v benzyl alcohol, using hydrochloric acid to transfer pH is 4.0, its preparation technology is following:
Under aseptic condition, take by weighing desmopressin acetate 0.015g, sodium chloride 9.0g, sodium pyrosulfite 1g and 20g benzyl alcohol; Place sterilization container, add recipe quantity 80% water for injection, stir and make dissolving; Transfer pH to 4.0 with hydrochloric acid, add the injection water, stir to 1000ml.Add 25g injection active carbon and stir 30min, the sterilization filter coarse filtration is taken off charcoal, with 0.45 μ m filtering with microporous membrane, uses 0.22 μ m filtering with microporous membrane at last; Filtrating detect qualified after, fill in 2ml sterilization cillin bottle (1ml/ bottle), lyophilisation; The vacuum tamponade, outlet rolls lid.Make every bottle to be equivalent to 15.0 μ g desmopressin acetates.
Make 1000 bottles of desmopressin acetate lyophilized injectable powders (containing desmopressin acetate 15.0 μ g) by present embodiment; Through stable accelerated test and animal blood vessels zest, muscle irritation, haemolysis and anaphylaxis experiment, its stability and clinical drug safety property are investigated.
The stability accelerated test:
The a collection of test sample that will go on the market respectively and to put into temperature by a collection of sample of commercially available back be that 40 ± 2 ℃, relative humidity are that 75% ± 5% climatic chamber is investigated, 0,1,2,3 and sampling and measuring 6 months the time, the result sees table 3-1 and table 3-2 respectively.
Table 3-1 listing reference substance accelerated test result
Table 3-2 self-control sample accelerated test result
Can find out through table 3-1 and table 3-2; Investigate 6 months through accelerated test; The desmopressin acetate lyophilized injectable powder of the present invention's preparation compares with the acetic acid desmopressin injection that has gone on the market, and appearance luster, acidity, clarity of solution do not have significant change, and the impurity of the test sample of listing increases, content descends obviously; Show that the desmopressin acetate lyophilized injectable powder that the present invention prepares can preserve under room temperature, stability increases.
Blood vessel irritation, muscle irritation, haemolysis and anaphylaxis experiment:
Blood vessel irritation:
Choose 6 of the undamaged healthy rabbits of ears, left side auricular vein injection embodiment 3 solution 1ml, capacity 5% glucose solutions such as auris dextra injection, were injected 7 days continuously at every day 1 time.
During the injection, regularly observe the irritative response of auricular vein every day.Put to death rabbit on the 8th day, and got bilateral auricular vein and surrounding tissue, use formaldehyde fixed, do the conventional organization section at the proximal part of injection site, light microscopic is observed down and is had or not pathological change.Observation index and criterion are seen table 3-3.
Table 3-3 blood vessel irritation scoring and criterion
The result shows that the zest of rabbit auricular vein injection embodiment 3 solution compares no significant difference with 5% glucose solution.Inflammatory reactions such as the congestion of blood vessel, surrounding tissue edema are not seen in perusal.Tissue slice inspection does not see that blood vessel structure is unusual, endothelial injury, thrombosis and other pathological change.The blood vessel of its naked eyes and om observation, the cumulative score of surrounding tissue show nonirritant all less than 0.5.
Swashing property of muscle package:
Get 6 of healthy rabbits, injection embodiment 3 solution 1ml in every rabbit left side quadriceps femoris, inject with the volume normal saline on the right side.The injection back is observed injection site muscle and is had or not reactions such as hyperemia, edema, and (the 3rd day) sacrificed by exsanguination behind the Half animals 48h is vertically cut skin, and injection site, perusal both sides has or not reactions such as hyperemia, edema, and gets its tissue and do pathologic finding.Then by the IR of showing this medicine of standard evaluation among the 3-4.Remaining animal continues to observe 14d, repeats aforesaid operations in the 18th day after the sacrificed by exsanguination, and evaluation criterion is seen table 3-4.
Table 3-4 muscular irritation reaction evaluating standard
The result shows; After injecting embodiment 3 solution in the quadriceps femoris of rabbit left side; Perusal injection site muscle does not have reactions such as hyperemia, edema, and explicitly IRs such as tissue degeneratiaon or necrosis are not also seen in the pathological tissue inspection, compare no significant difference with the normal saline side.
Sensitization to Cavia porcellus:
Choose 6 of healthy guinea pigs, every lumbar injection embodiment 3 solution 0.5ml, the next day, inject 1 time, injects altogether 3 times.Be divided into 2 groups then at random, after the 1st administration 14 or 21 days respectively, quiet notes embodiment 3 solution 1ml.Observe Cavia porcellus and have or not allergic symptoms such as excited uneasiness, dyspnea.
Two groups of Cavia porcelluss of result are all movable normal, do not see adnormal respiration etc.
External hemolytic test:
Prepare 2% rabbit red cell suspension.Get 7 in test tube, 3-5 adds various liquid by table.Each test tube is shaken up gently, put in 37 ℃ of waters bath with thermostatic control and hatch, observe 0.5,1,2,3,6 hour result.Erythrocyte agglutination in vitro and hemolytic criterion are seen table 3-6.
The outer hemolytic test application of sample table of table 3-5 desmopressin acetate solution body
Outer haemolysis of table 3-6 red cell body and agglutination test criterion
As a result, the distilled water control tube was complete hemolysis in 0.5 hour.Normal saline did not all have haemolysis with each desmopressin acetate solution in 6 hours.Jolting gently, the erythrocyte of normal saline and each concentration desmopressin acetate solution pipe bottom sediments all can disperse fully, shows that desmopressin acetate solution does not have red cell agglutination.
Blood vessel irritation, muscle irritation, external hemolytic and anaphylaxis experiment show that embodiment 3 solution do not have tangible zest, anaphylaxis, can not cause hemolytic reaction yet.Show that the desmopressin acetate lyophilized injectable powder safety that the present invention prepares is good, can supply clinical vein injection and intramuscular injection to use.
Embodiment 4:
15.0 μ g/ml desmopressin acetate, 9.0mg/ml sodium chloride, the 0.1%w/v sodium sulfite, the 0.4%w/v chlorobutanol, using hydrochloric acid to transfer pH is 4.0, its preparation technology is following:
Under aseptic condition, take by weighing desmopressin acetate 0.015g, sodium chloride 9.0g, sodium sulfite 1g and 4g chlorobutanol; Place sterilization container, add recipe quantity 80% water for injection, stir and make dissolving; Transfer pH to 4.0 with hydrochloric acid, add the injection water, stir to 1000ml.Add 25g injection active carbon and stir 30min, the sterilization filter coarse filtration is taken off charcoal, with 0.45 μ m filtering with microporous membrane, uses 0.22 μ m filtering with microporous membrane at last; Filtrating detect qualified after, fill in 2ml sterilization cillin bottle (1ml/ bottle), lyophilisation; The vacuum tamponade, outlet rolls lid.Make every bottle to be equivalent to 15.0 μ g desmopressin acetates.
Make 1000 bottles of desmopressin acetate lyophilized injectable powders (containing desmopressin acetate 15.0 μ g) by present embodiment; Through stable accelerated test and animal blood vessels zest, muscle irritation, haemolysis and anaphylaxis experiment, its stability and clinical drug safety property are investigated.
The stability accelerated test:
The a collection of test sample that will go on the market respectively and to put into temperature by a collection of sample of commercially available back be that 40 ± 2 ℃, relative humidity are that 75% ± 5% climatic chamber is investigated, 0,1,2,3 and sampling and measuring 6 months the time, the result sees table 4-1 and table 4-2 respectively.
Table 4-1 listing reference substance accelerated test result
Table 4-2 self-control sample accelerated test result
Can find out through table 4-1 and table 4-2; Investigate 6 months through accelerated test; The desmopressin acetate lyophilized injectable powder of the present invention's preparation compares with the acetic acid desmopressin injection that has gone on the market, and appearance luster, acidity, clarity of solution do not have significant change, and the impurity of the test sample of listing increases, content descends obviously; Show that the desmopressin acetate lyophilized injectable powder that the present invention prepares can preserve under room temperature, stability increases.
Blood vessel irritation, muscle irritation, haemolysis and anaphylaxis experiment:
Blood vessel irritation:
Choose 6 of the undamaged healthy rabbits of ears, left side auricular vein injection embodiment 4 solution 1ml, capacity 5% glucose solutions such as auris dextra injection, were injected 7 days continuously at every day 1 time.
During the injection, regularly observe the irritative response of auricular vein every day.Put to death rabbit on the 8th day, and got bilateral auricular vein and surrounding tissue, use formaldehyde fixed, do the conventional organization section at the proximal part of injection site, light microscopic is observed down and is had or not pathological change.Observation index and criterion are seen table 4-3.
Table 4-3 blood vessel irritation scoring and criterion
The result shows that the zest of rabbit auricular vein injection embodiment 4 solution compares no significant difference with 5% glucose solution.Inflammatory reactions such as the congestion of blood vessel, surrounding tissue edema are not seen in perusal.Tissue slice inspection does not see that blood vessel structure is unusual, endothelial injury, thrombosis and other pathological change.The blood vessel of its naked eyes and om observation, the cumulative score of surrounding tissue show nonirritant all less than 0.5.
Muscle irritation:
Get 6 of healthy rabbits, injection embodiment 4 solution 1ml in every rabbit left side quadriceps femoris, inject with the volume normal saline on the right side.The injection back is observed injection site muscle and is had or not reactions such as hyperemia, edema, and (the 3rd day) sacrificed by exsanguination behind the Half animals 48h is vertically cut skin, and injection site, perusal both sides has or not reactions such as hyperemia, edema, and gets its tissue and do pathologic finding.Then by the IR of showing this medicine of standard evaluation among the 4-4.Remaining animal continues to observe 14d, repeats aforesaid operations in the 18th day after the sacrificed by exsanguination, and evaluation criterion is seen table 4-4.
Table 4-4 muscular irritation reaction evaluating standard
The result shows; After injecting embodiment 4 solution in the quadriceps femoris of rabbit left side; Perusal injection site muscle does not have reactions such as hyperemia, edema, and explicitly IRs such as tissue degeneratiaon or necrosis are not also seen in the pathological tissue inspection, compare no significant difference with the normal saline side.
Sensitization to Cavia porcellus:
Choose 6 of healthy guinea pigs, every lumbar injection embodiment 4 solution 0.5ml, the next day, inject 1 time, injects altogether 3 times.Be divided into 2 groups then at random, after the 1st administration 14 or 21 days respectively, quiet notes embodiment 4 solution 1ml.Observe Cavia porcellus and have or not allergic symptoms such as excited uneasiness, dyspnea.
Two groups of Cavia porcelluss of result are all movable normal, do not see adnormal respiration etc.
External hemolytic test:
Prepare 2% rabbit red cell suspension.Get 7 in test tube, 4-5 adds various liquid by table.Each test tube is shaken up gently, put in 37 ℃ of waters bath with thermostatic control and hatch, observe 0.5,1,2,3,6 hour result.Erythrocyte agglutination in vitro and hemolytic criterion are seen table 4-6.
The outer hemolytic test application of sample table of table 4-5 desmopressin acetate solution body
Outer haemolysis of table 4-6 red cell body and agglutination test criterion
As a result, the distilled water control tube was complete hemolysis in 0.5 hour.Normal saline did not all have haemolysis with each desmopressin acetate solution in 6 hours.Jolting gently, the erythrocyte of normal saline and each concentration desmopressin acetate solution pipe bottom sediments all can disperse fully, shows that desmopressin acetate solution does not have red cell agglutination.
Blood vessel irritation, muscle irritation, external hemolytic and anaphylaxis experiment show that embodiment 4 solution do not have tangible zest, anaphylaxis, can not cause hemolytic reaction yet.Show that the desmopressin acetate lyophilized injectable powder safety that the present invention prepares is good, can supply clinical vein injection and intramuscular injection to use.
Claims (10)
1. more stable DDAVP polypeptide drugs lyophilized injectable powder; Adopt intravenous injection, subcutaneous injection or administered intramuscular; Its main component is a desmopressin acetate, it is characterized in that said preparation is made up of principal agent desmopressin acetate and osmotic pressure regulator, pH value regulator, antioxidant, local analgesia agent.
2. the said preparation of claim 1, its osmotic pressure regulator is selected from sodium chloride, glucose, glycerol, mannitol, sorbitol, boric acid, Borax etc.
3. the said preparation of claim 1, its pH value regulator is selected from hydrochloric acid, acetic acid, sodium acetate, sulphuric acid, lactic acid, malic acid, citric acid, phosphoric acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydrogen phosphate etc., and regulating pH is between 3.0 to 6.0.
4. the said preparation of claim 1, its antioxidant is selected from sodium sulfite, sodium pyrosulfite, ascorbic acid, sodium thiosulfate, sodium sulfite, glutathion, thiourea, TGA, vitamin E etc.
5. the said preparation of claim 1, its local analgesia agent is selected from benzyl alcohol, chlorobutanol and procaine hydrochloride etc.
6. the said preparation of claim 2-5; The preferred 0.1-50 μ of the concentration of its principal agent desmopressin acetate g/ml; The preferred 0.1-100mg/ml sodium chloride of its osmotic pressure regulator; Its pH value regulator preferably uses hydrochloric acid to transfer pH to be 3.5-5.5, preferred 0.01-2%w/v sodium sulfite of its antioxidant and 0.01-2%w/v sodium pyrosulfite, preferred 0.1-5%w/v benzyl alcohol of its local analgesia agent and 0.03-2%w/v chlorobutanol.
7. the said preparation of claim 6, its prescription consists of: 0.1-50 μ g/ml desmopressin acetate, 0.1-100mg/ml sodium chloride, the 0.01-2%w/v sodium sulfite, the 0.1-5%w/v benzyl alcohol uses hydrochloric acid to transfer pH to be 3.5-5.5.
8. the said preparation of claim 6, its prescription consists of: 0.1-50 μ g/ml desmopressin acetate, 0.1-100mg/ml sodium chloride, the 0.01-2%w/v sodium pyrosulfite, the 0.03-2%w/v chlorobutanol uses hydrochloric acid to transfer pH to be 3.5-5.5.
9. the said preparation of claim 6, its prescription consists of: 0.1-50 μ g/ml desmopressin acetate, 0.1-100mg/ml sodium chloride, the 0.01-2%w/v sodium pyrosulfite, the 0.1-5%w/v benzyl alcohol uses hydrochloric acid to transfer pH to be 3.5-5.5.
10. the said preparation of claim 6, its prescription consists of: 0.1-50 μ g/ml desmopressin acetate, 0.1-100mg/ml sodium chloride, the 0.01-2%w/v sodium sulfite, the 0.03-2%w/v chlorobutanol uses hydrochloric acid to transfer pH to be 3.5-5.5.
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| CN2011104276591A CN102440968A (en) | 2011-12-16 | 2011-12-16 | More stable desmopressin (DDAVP) polypeptide drug freeze-dried powder injection |
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| CN2011104276591A CN102440968A (en) | 2011-12-16 | 2011-12-16 | More stable desmopressin (DDAVP) polypeptide drug freeze-dried powder injection |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102863513A (en) * | 2012-09-12 | 2013-01-09 | 无锡市凯利药业有限公司 | Preparation method of desmopressin acetate |
| CN105310978A (en) * | 2014-08-04 | 2016-02-10 | 李峰 | Drug combination containing conivaptan hydrochloride as active ingredient and preparation of drug combination |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101322684A (en) * | 2007-06-11 | 2008-12-17 | 海南中和药业股份有限公司 | Acetic acid desmopressin injection prescription and preparation technique thereof |
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- 2011-12-16 CN CN2011104276591A patent/CN102440968A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101322684A (en) * | 2007-06-11 | 2008-12-17 | 海南中和药业股份有限公司 | Acetic acid desmopressin injection prescription and preparation technique thereof |
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| 崔福德: "《药剂学》", 28 February 2004, article "灭酶制剂与无菌制剂", pages: 61 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102863513A (en) * | 2012-09-12 | 2013-01-09 | 无锡市凯利药业有限公司 | Preparation method of desmopressin acetate |
| CN105310978A (en) * | 2014-08-04 | 2016-02-10 | 李峰 | Drug combination containing conivaptan hydrochloride as active ingredient and preparation of drug combination |
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Address after: 518057, room 2, building ten, Shenzhen biological incubation center, No. 412, Nanshan District hi tech, Shenzhen, Guangdong Applicant after: Shenzhen City Jianyuan Pharmaceutical Technology Co., Ltd. Address before: 518000, overseas student Pioneer Building, 29 South Ring Road, Nanshan hi tech Zone, Guangdong, Shenzhen 1702 Applicant before: Shenzhen City Jianyuan Pharmaceutical Technology Co., Ltd. |
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Application publication date: 20120509 |