CN110214019A - The pharmaceutical composition and preparation method thereof of trainingization Xihai sea horse peptide - Google Patents
The pharmaceutical composition and preparation method thereof of trainingization Xihai sea horse peptide Download PDFInfo
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Abstract
The present invention relates to the pharmaceutical compositions and preparation method thereof of trainingization Xihai sea horse peptide.The invention discloses a kind of using trainingization Xihai sea horse peptide as the pharmaceutical composition of active constituent.The physiology that described pharmaceutical composition contains trainingization Xihai sea horse peptide, pH value is 3.0-7.0 is subjected to buffer and pharmaceutically acceptable auxiliary material.Pharmaceutical composition of the present invention has good medicine stability and safety, and preparation method is easy, is suitble to industrialized production.
Description
The present invention relates to polypeptide drug formulation arts.Specifically, the present invention relates to the pharmaceutical preparations and preparation method thereof comprising trainingization Xihai sea horse peptide.
Trainingization Xihai sea horse peptide is polyethyleneglycol modified Erythropoietin mimetic peptide derivative, wherein EPO acts on myeloid element, the differentiation of mitosis and erythrocyte precursor cell is stimulated, erythron stem cell proliferation, differentiation are promoted, final maturation is endocrine hormone.Since EPO is required in erythrocyte forming process, it can promote red blood cell proliferation, improve hemoglobin (Hb) total amount of body, improve body oxygen carrying capacity, so the hormone has a wide range of applications in the hematologic disease that diagnosing and treating anerythropoiesis or red blood cell generate defect.Furthermore, it can also be used to anaemia, spinal cord injury, renal anemia, alpastic anemia caused by preoperative autotransfusion and the recovery of hand postoperative anemia, myelodysplastic syndrome anaemia, the dresbach's syndrome of hemoglobinopathy and β-thalassemia, anemia of prematurity, chronic inflammation or infection etc..
Trainingization Xihai sea horse peptide is product of the EPO simulating peptide after pegylation, belongs to chemically synthesized polypeptide drug, is clinically envisaged for anaemia caused by treatment kidney failure.The water solubility of trainingization Xihai sea horse peptide is good, and thermal stability is poor, and is easily digested in gastrointestinal tract.Therefore clinically, the form of administration of trainingization Xihai sea horse peptide uses injection or freeze-dried powder, preferably injection.
Summary of the invention
The purpose of the present invention is to provide a kind of stable training Xihai sea horse peptide medicine composites, can control polymeric impurities significantly, while preparation prescription is simple, safely and effectively, substantially increase the horse peptibody intracellular metabolite behavior of the trainingization Xihai sea, extend action time.
Specifically, the present invention is mainly implemented by following scheme:
Trainingization Xihai sea horse peptide medicine composite includes active constituent trainingization Xihai sea horse peptide, buffer and isotonic regulator, the structure of trainingization Xihai sea horse peptide are as follows:
N be selected from 400-600, preferably 455.
Trainingization Xihai sea horse peptide medicine composite of the present invention can be administered by oral or injection system, and injection system includes subcutaneous injection, intramuscular injection or intravenous drip.
Preferably, the concentration of the trainingization Xihai sea horse peptide is selected from 0.1mg/ml~100mg/ml, preferably 0.1mg/ml~20mg/ml, more preferable 2mg/ml, 4mg/ml or 6mg/ml.
Preferably, the trainingization Xihai sea horse peptide combinations are trainingization Xihai sea horse peptide injection, it includes the training Xihai sea horse peptide of 0.05%~5.0% (W/V), the buffer salt of 0.1%~5.0% (W/V), the isotonic regulators of 0.05%~5.0% (W/V).Wherein the unit of W/V is g/mL.
Preferably, the trainingization Xihai sea horse peptide injection includes the training Xihai sea horse peptide of 0.1%~2% (W/V), the buffer salt of 0.3%~3.0% (W/V), the isotonic regulator of 0.1%~2.0% (W/V).
Preferably, the trainingization Xihai sea horse peptide injection includes the training Xihai sea horse peptide of 0.1%~1.0% (W/V), the buffer salt of 0.5%~1.5% (W/V), the isotonic regulator of 0.1%~1.0% (W/V).
Preferably, the buffer is selected from phosphate buffer, acetate buffer, citrate buffer, carbonate buffer solution, tartrate buffer, Tris buffer, histidine salt, preferably acetate buffer or phosphate buffer.Wherein phosphate buffer includes dihydric phosphate and phosphoric acid hydrogen disalt.
Preferably, the isotonic regulator is selected from one or more, the preferably mannitol or sodium chloride of sodium chloride, mannitol, sorbierite, glycerol, glucose, xylitol.
Preferably, the trainingization Xihai sea horse peptide injection includes the training Xihai sea horse peptide of 0.1%~2% (W/V), the dihydric phosphate of 0.1%~2.0% (W/V), the phosphoric acid hydrogen disalt of 0.1%~2.0% (W/V), the sodium chloride of 0.1%~2.0% (W/V)；Preferably, the trainingization Xihai sea horse peptide injection includes the training Xihai sea horse peptide of 0.1%~1% (W/V), the dihydric phosphate of 0.2%~1% (W/V), the phosphoric acid hydrogen disalt of 0.1%~0.6% (W/V), the sodium chloride of 0.1%~1.0% (W/V), wherein the unit of W/V is g/mL.
Preferably, the weight ratio of the trainingization Xihai sea horse peptide and buffer salt is 1:1~10, preferably 1:2~4.
Preferably, the weight ratio of its alkali and acid is 1:1~10, preferably 1:1~5 in the buffer salt.It is further preferred that the buffer salt is selected from sodium dihydrogen phosphate and disodium hydrogen phosphate, weight ratio is 1~10:1, preferably 1~3:1, more preferable 1.2~2:1.
Preferably, the weight ratio of the trainingization Xihai sea horse peptide and isotonic regulator is 1:0.5~10, preferably 1:1~2.
Preferably, the weight ratio of the trainingization Xihai sea horse peptide, buffer salt and isotonic regulator is 1:1~10:0.5~10, preferably 1:2~4:1~2, and more preferable 1:2.8:1, wherein the weight ratio of sodium dihydrogen phosphate and disodium hydrogen phosphate is 1.6:1 in buffer salt.
Preferably, the pH range of described pharmaceutical composition is 4.0 to 7.0, preferably 5.0 to 6.0.
Another object of the present invention is to provide the method for preparation described pharmaceutical composition, buffer salt and isotonic regulator are dissolved in water for injection, active carbon is added, filtering decarbonization obtains intermediate medical fluid；Trainingization Xihai sea horse peptide is dissolved to above-mentioned medical fluid, stirring and dissolving, filtering, packing.
Preferably, the cryogenic conditions are between 2 DEG C~25 DEG C.
Preferably, preparation pharmaceutical composition is encapsulated through aseptic filtration, packing, inflated with nitrogen.
Preferably, intermediate drug solution preparing uses nitrogen charging gas shielded.
Preferably, intermediate medical fluid uses nitrogen filters pressing.
Preferably, pouring process is completed under nitrogen protection.
Preferably, the pharmaceutical composition, is dispensed using cillin bottle.
Preferably, the pharmaceutical composition, is dispensed using clamped bottle.
Preferably, the pharmaceutical composition, is dispensed using pre-encapsulated injector.
Another object of the present invention is to provide a kind for the treatment of to lack erythropoietin(EPO) or red cell population lacks or the method for deficiency disorders, give the original measurement of patient 0.02-0.10mg/kg, hereafter the maintenance dose of 0.015-0.15mg/kg is given within every 26-30 days, to maintain hemoglobin in the range of 10.0-12.0g/dL.
Preferably, the original measurement of patient 0.02-0.10mg/kg is given, the maintenance dose of 0.015-0.15mg/kg is hereafter given within every 26-30 days, to maintain hemoglobin in the range of 10.0-12.0g/dL.
Preferably, a kind of method for treating anaemia is provided, the original measurement of patient 0.02-0.10mg/kg is given, hereafter every maintenance dose for giving 0.015-0.15mg/kg for 28 days, to maintain hemoglobin in the range of 10.0-12.0g/dL.
Preferably, anemia caused by chronic renal failure is treated.
Dosage adjustment mode is as follows:
Erythrocyte raising≤1.0g/dL in 4 weeks after administration, and hemoglobin < 9.0g/dL need to raise 40%-60%.
Erythrocyte raising≤1.0g/dL in 4 weeks after administration, and 9.0g/dL≤hemoglobin≤10.0g/dL, need to raise 20%-30%.
Raising >=2.0g/dL in erythrocyte raising >=1.0g/dL, or 4 weeks in 2 weeks, need to lower 20%-30% after administration.
12.0g/dL < hemoglobin < 13.0g/dL, need to lower 20%-30%.
Hemoglobin >=13.0g/dL need to suspend administration, until hemoglobin≤12.0g/dL.
In addition to above situation, dosage remains unchanged.
Polymeric impurities are the polymers of trainingization Xihai sea horse peptide, and the presence of the impurity makes product degrade, and reduce the content of product.The present invention can be obtained the good training Xihai sea horse peptide medicine composite of stability, can efficiently control the polymeric impurities of trainingization Xihai sea horse peptide by the control to each component ratio by the screening of component in prescription without adding other auxiliary materials.
Another object of the present invention is to provide the detection method of polymer impurity, steps are as follows:
Instrument and reagent high performance liquid chromatograph, electronic balance, pH meter, electronic analytical balance, sodium hydroxide (AR), sodium dihydrogen phosphate (AR), disodium hydrogen phosphate (AR), acetonitrile.
Chromatographic condition chromatographic column filler: gel chromatographic columns (300 × 7.8mm of Shodex KW-803)；Flow velocity: 0.8ml/min；Detection wavelength: 220nm；Column temperature: 40 DEG C；Sample volume: 50 μ l.
The phosphate buffer for the 0.1mol/L that mobile phase pH is 6.8: acetonitrile=60:40.
Dilution: water test solution takes this product about 25mg, sets in 5ml measuring bottle, is dissolved in water and is diluted to scale, shakes up.
Contrast solution precision measures test solution 1ml, sets in 100ml measuring bottle, is diluted with water to scale, shakes up.
System suitability precision measures 40 μ l of blank solution, injects liquid chromatograph, records chromatogram；Precision measures 40 μ l of test solution, injects liquid chromatograph, records chromatography, and number of theoretical plate answers >=1000 based on the horse peptide of the trainingization Xihai sea.
The accurate 40 μ l of contrast solution that measures of polymer measurement injects liquid chromatograph, adjusts detection sensitivity, makes the 20%~30% of the peak height full scale of principal component chromatographic peak；It is accurate again to measure test solution and each 40 μ l of contrast solution, it is injected separately into liquid chromatograph, records chromatogram, such as aobvious polymer peak in test solution chromatogram is calculated as follows:
In formula: A
i--- --- calculate polymer when in test solution chromatogram the peak area of polymer and (peak that peak of the appearance earlier than EPO-018B is polymer)；
A
sThe peak area of main peak in --- -- contrast solution chromatogram.
Retention time is 8.2min.
1, Fig. 1 is that 100 μ g.kg are subcutaneously injected in macaque
-1Dosage, hemoglobin (Hgb) and granulophilocyte (Ret) time change
2. Fig. 2 is that 500 μ g.kg are subcutaneously injected in macaque
-1Dosage, hemoglobin (Hgb) and granulophilocyte (Ret) time change
3. Fig. 3 is that 1500 μ g.kg are subcutaneously injected in macaque
-1Dosage, hemoglobin (Hgb) and granulophilocyte (Ret) time change
4. Fig. 4 is that macaque is injected intravenously 100 μ g.kg
-1Dosage, hemoglobin (Hgb) and granulophilocyte (Ret) time change
The present invention is further illustrated by following examples, and the embodiment is not understood to further limit.Those skilled in the art should be readily appreciated that the ad hoc approach and result are merely illustrative.
Embodiment 1
The sodium dihydrogen phosphate 6.0g and disodium hydrogen phosphate 4.5g for weighing recipe quantity are dissolved in 800ml water for injection, and sodium chloride 4.0g, stirring and dissolving is added；Then the active carbon for being added 0.1% keeps the temperature 15min and while hot filtering decarbonization into the 60 DEG C of water-baths of above-mentioned solution juxtaposition, and subsequent filtrate is taken to be cooled to 20 DEG C；The training Xihai sea horse peptide 4.0g for weighing recipe quantity, is slowly stirred and is allowed to dissolve, and distinguishes regulating liquid medicine pH to 3.0,4.0,5.0,6.0,7.0 with sodium dihydrogen phosphate or sodium hydroxide；Above-mentioned medical fluid is settled to by 1000ml using water for injection respectively, finally by 0.22 μm of filtering with microporous membrane of medical fluid, is dispensed into cillin bottle, lid is rolled in tamponade after inflated with nitrogen.Its stability is investigated under the conditions of sample to be set to 25 DEG C and 40 DEG C respectively, inspection target is appearance, in relation to substance and content, the results are shown in Table 1.
Table 1
Embodiment 2
The sodium dihydrogen phosphate 6.0g and disodium hydrogen phosphate 4.5g for weighing recipe quantity are dissolved in 800ml water for injection, and sodium chloride, stirring and dissolving is added；Then the active carbon for being added 0.1% keeps the temperature 15min and while hot filtering decarbonization into the 60 DEG C of water-baths of above-mentioned solution juxtaposition, pH (5.0~6.0) are surveyed after blank auxiliary is cooling, if the pH to 5.0~6.0 of appropriate hydrochloric acid or sodium hydroxide solution regulating liquid medicine is added not in range, subsequent filtrate is taken to be cooled to 20 DEG C；The training Xihai sea horse peptide 4.0g for weighing recipe quantity, is slowly stirred and is allowed to dissolve, and above-mentioned medical fluid is settled to 1000ml respectively using water for injection, finally by 0.22 μm of filtering with microporous membrane of medical fluid, dispenses the tamponade after inflated with nitrogen into pre-encapsulated injector.Its stability is investigated under the conditions of sample to be set to 25 DEG C and 40 DEG C respectively, inspection target is appearance, in relation to substance and content, the results are shown in Table 3.
Table 2
Embodiment 3
The sodium dihydrogen phosphate and disodium hydrogen phosphate for weighing recipe quantity are dissolved in 800ml water for injection, and sodium chloride 4.0g, stirring and dissolving is added；Then the active carbon for being added 0.1% keeps the temperature 15min and while hot filtering decarbonization into the 60 DEG C of water-baths of above-mentioned solution juxtaposition, and subsequent filtrate is taken to be cooled to 20 DEG C；PH (5.0~6.0) are surveyed after blank auxiliary is cooling, if the pH to 5.0~6.0 of appropriate hydrochloric acid or sodium hydroxide solution regulating liquid medicine is added not in range, the training Xihai sea horse peptide for weighing recipe quantity is appropriate, it is slowly stirred and is allowed to dissolve, above-mentioned medical fluid is settled to by 1000ml using water for injection respectively, finally by 0.22 μm of filtering with microporous membrane of medical fluid, the tamponade after inflated with nitrogen into pre-encapsulated injector is dispensed.Its stability is investigated under the conditions of sample to be set to 25 DEG C and 40 DEG C respectively, inspection target is appearance, in relation to substance and content, the results are shown in Table 3.
Table 3
| Time (moon) | Temperature (DEG C) | Character | Polymeric impurities (%) | Total miscellaneous (%) | Content (%) |
| 0 | 25 | Colourless clear liquid | 0.24 | 1.02 | 99.6% |
| 3 | 25 | Colourless clear liquid | 0.24 | 1.03 | 99.6% |
| 6 | 25 | Colourless clear liquid | 0.25 | 1.08 | 99.5% |
| 3 | 40 | Colourless clear liquid | 0.23 | 1.07 | 99.5% |
| 6 | 40 | Colourless clear liquid | 0.28 | 1.13 | 99.5% |
Embodiment 4
The sodium dihydrogen phosphate and disodium hydrogen phosphate for weighing recipe quantity are dissolved in 800ml water for injection, and sodium chloride 4.0g, stirring and dissolving is added；Then the active carbon for being added 0.1% keeps the temperature 15min and while hot filtering decarbonization into the 60 DEG C of water-baths of above-mentioned solution juxtaposition, and subsequent filtrate is taken to be cooled to 20 DEG C；PH (5.0~6.0) are surveyed after blank auxiliary is cooling, if the pH to 5.0~6.0 of appropriate hydrochloric acid or sodium hydroxide solution regulating liquid medicine is added not in range, the training Xihai sea horse peptide for weighing recipe quantity is appropriate, it is slowly stirred and is allowed to dissolve, above-mentioned medical fluid is settled to by 1000ml using water for injection respectively, finally by 0.22 μm of filtering with microporous membrane of medical fluid, the tamponade after inflated with nitrogen into pre-encapsulated injector is dispensed.Its stability is investigated under the conditions of sample to be set to 25 DEG C and 40 DEG C respectively, inspection target is appearance, in relation to substance and content, the results are shown in Table 4.
Table 4
| Time (moon) | Temperature (DEG C) | Character | Polymeric impurities (%) | Total miscellaneous (%) | Content (%) |
| 0 | 25 | Colourless clear liquid | 0.22 | 1.03 | 99.5% |
| 3 | 25 | Colourless clear liquid | 0.23 | 1.05 | 99.5% |
| 6 | 25 | Colourless clear liquid | 0.23 | 1.09 | 99.4% |
| 3 | 40 | Colourless clear liquid | 0.24 | 1.11 | 99.4% |
| 6 | 40 | Colourless clear liquid | 0.26 | 1.14 | 99.4% |
Embodiment 5
The sodium dihydrogen phosphate and disodium hydrogen phosphate for weighing recipe quantity are dissolved in 800ml water for injection, and sodium chloride 4.0g, stirring and dissolving is added；Then the active carbon for being added 0.1% keeps the temperature 15min and while hot filtering decarbonization into the 60 DEG C of water-baths of above-mentioned solution juxtaposition, and subsequent filtrate is taken to be cooled to 20 DEG C；PH (5.0~6.0) are surveyed after blank auxiliary is cooling, if the pH to 5.0~6.0 of appropriate hydrochloric acid or sodium hydroxide solution regulating liquid medicine is added not in range, the training Xihai sea horse peptide for weighing recipe quantity is appropriate, it is slowly stirred and is allowed to dissolve, above-mentioned medical fluid is settled to by 1000ml using water for injection respectively, finally by 0.22 μm of filtering with microporous membrane of medical fluid, the tamponade after inflated with nitrogen into pre-encapsulated injector is dispensed.Its stability is investigated under the conditions of sample to be set to 25 DEG C and 40 DEG C respectively, inspection target is appearance, in relation to substance and content, the results are shown in Table 5.
Table 5
| Time (moon) | Temperature (DEG C) | Character | Polymeric impurities (%) | Total miscellaneous (%) | Content (%) |
| 0 | 25 | Colourless clear liquid | 0.16 | 0.93 | 99.6% |
| 3 | 25 | Colourless clear liquid | 0.17 | 0.94 | 99.6% |
| 6 | 25 | Colourless clear liquid | 0.19 | 0.96 | 99.5% |
| 3 | 40 | Colourless clear liquid | 0.19 | 0.97 | 99.5% |
| 6 | 40 | Colourless clear liquid | 0.21 | 1.01 | 99.6% |
One hemolytic test of test example
1, tested material:
1.1 test samples: the training Xihai sea horse peptide injection of embodiment 3-5 preparation；
1.2 solvents: sodium chloride injection.
2, experimental method:
The preparation of 2.1 blood cell supernatant liquids: taking dog blood 5ml, stirs blood with glass bar, removes fibrinogen, make defibrinated blood.About 10 times of 0.9% sodium chloride solution amounts are added, shake up, 1500 revs/min are centrifuged 15 minutes, remove supernatant, and the red blood cell of precipitating is washed 3 times with 0.9% sodium chloride solution according to the above method again, until the not aobvious red of supernatant.Blood cell 1.0ml is measured, adds normal saline dilution to 50ml, 2% suspension is made into and is for experiment.
2.2 drug solution preparings: 3 embodiment of embodiment, 4 injection normal saline dilution to 1.00mg/ml mixes spare.
2.3 sample-adding
Test one and test two take 8, test tube respectively, and various solution are added in the following order
1st to the 5th pipe is tested property management, and the 6th pipe is negative control pipe, and the 7th pipe is positive control pipe, and the 8th pipe is Vehicle controls pipe.Each pipe solution is gently shaken up, sets in 37 DEG C of water baths, observes and records the result of 15min, 30min, 45min, 1h, 2h, 3h.Per observing time point is taken pictures.If solution becomes clear and red colouration, that is, indicate haemolysis.Whether can be ruptured with micro- sem observation red blood cell when necessary.
6 trainingization Xihai sea horse peptide injection hemolytic experiment of table observes table (test one)
7 trainingization Xihai sea horse peptide injection hemolytic experiment of table observes table (test two)
8 trainingization Xihai sea horse peptide injection hemolytic experiment of table observes table (test three)
Trainingization Xihai sea horse peptide injection carry out hemolytic test, in addition to positive control pipe it is all it is test tube significant haemolysis and blood coagulation phenomenon does not occur, show that trainingization Xihai sea horse peptide injection does not cause haemolysis and blood coagulation phenomenon.
Test example two, general pharmacology, local stimulation Journal of Sex Research
The training Xihai sea horse peptide injection pharmacological research of 9 embodiment 3-5 of table preparation is summarized
Test two shows trainingization Xihai sea horse peptide injection safety prepared by the present invention, does not generate allergic reaction to nerve, cardiovascular, respiratory system and subcutaneous tissue.
Medicine generation and pharmacodynamic studies after test example three, macaque single SC or intravenous injection trainingization Xihai sea horse peptide
Training Xihai sea horse peptide (100,500 and 1500g.kg prepared by macaque single subcutaneous injection embodiment 3
-1, basic, normal, high dosage), between each dosage group, end phase half-life period t
1/2Increase with dosage and extend, systemic clearance CL increases with dosage and slowed down gradually, and prompts in 100~1500g.kg
-1In range, drug is in nonlinear pharmacokinetics feature in macaque body.
Macaque is injected intravenously 100g.kg
-12 minutes serum antigen concentration reaches 10081.5 ± 999.5ng.mL of highest after training Xihai sea horse peptide prepared by embodiment 3
-1, then gradually eliminate, 72 hours after administration, serum antigen concentration is down to background level.AUC (0-t) is 19835 ± 758.6 (ngh) mL
-1, (100 μ g.kg of P < 0.001vs sc
-1), AUC (0- ∞) is 207020 ± 758.6 (ngh) mL
-1(P<0.001vs sc 100μg.kg
-1), there is conspicuousness statistical significance difference compared with equal dosage sc group.End phase half-life period t
1/2βFor 17.4 ± 0.6h, with sc100 μ g.kg
-1Statistically significant difference (P < 0.01) is compared in administration, and systemic clearance CL is 5.0 ± 0.2mL.h
-1.kg
-1。
10 macaque of table is subcutaneous and pharmacokinetic data is administered in single intravenous
Pharmacodynamic studies show that trainingization Xihai sea horse peptide dose-dependently increases macaque hemoglobin level, and 100 and 500g.kg is subcutaneously injected
-1Dosage group is respectively 1.9 and 2.3g/dL, 1500 μ g.kg in the 14th day hemoglobin increasing value
-1The maximum value of group hemoglobin appears in the 24th day, increasing degree 3.4g/dL, until 45 days whens do not drop to also horizontal before administration, apparent long-acting effect is presented；It is injected intravenously 100g.kg
-1Dosage group is 3.2g/dL in the 14th day hemoglobin (Hgb) increasing value.Compared with before administration, trainingization Xihai sea horse peptide dose-dependently stimulates the synthesis of granulophilocyte (Ret), and 100 and 500g.kg is subcutaneously injected
-1It is respectively 527% and 796% that dosage group increases before the 6th day granulophilocyte is relatively administered, 1500 μ g.kg
-1Group granulophilocyte maximum value appears in the 9th day, increases by 1240% before being relatively administered, and does not drop to horizontal before administration when 3 dosage groups were to 45 days, and apparent long-acting effect is presented；It is injected intravenously 100 μ g.kg
-1Dosage group increases by 716% before the 6th day granulophilocyte is relatively administered, and sees attached drawing 1~4.
The training Xihai sea horse peptide of macaque continuous 4 weeks subcutaneous injection embodiments 5, peak time is respectively 20 ± 6.9h and 12.0 ± 0.0h after administration in the 1st week and the 4th week；It is respectively 2408.8 ± 262.3ngmL-1 and 2346.1 ± 247.6ngmL-1, end phase half-life period T up to Cmax Cmax
1/2βRespectively 31.2 ± 5.6h and 30.1 ± 3.8h.The AUC of (injection interval τ=1W) after being injected for the first time with the 4th
(0-t)Respectively 100751 ± 25759 and 126418 ± 26571ng.h.mL-1, AUC
(0-∞)Respectively 104974 ± 26184 and 134961 ± 29627ng.h.mL-1, the accumulation factor (the 4th week/AUC of AUC the 1st week) are 1.27 ± 0.09, are not obviously accumulated in vivo after prompting continuous subcutaneous injection that 500 μ gkg-1 trainingization Xihai sea horse peptides are administered.
Claims (17)
- Trainingization Xihai sea horse peptide medicine composite, which is characterized in that including active constituent trainingization Xihai sea horse peptide, buffer and isotonic regulator, the structure of the trainingization Xihai sea horse peptide are as follows:N be selected from 400-600, preferably 455.
- Trainingization Xihai sea horse peptide medicine composite according to claim 1, it is characterized in that, the dosage form of described pharmaceutical composition is injection, wherein the concentration of trainingization Xihai sea horse peptide is 0.1mg/ml~100mg/ml in unit dose, it is preferred that 1mg/ml~20mg/ml, more preferable 2mg/ml, 4mg/ml or 6mg/ml.
- Trainingization Xihai sea horse peptide medicine composite according to claim 2, which is characterized in that include the training Xihai sea horse peptide of 0.05%~5.0% (W/V), preferably 0.1%~1.0% (W/V) in the injection.
- Trainingization Xihai sea horse peptide medicine composite according to claim 2, which is characterized in that in the composition include 0.1%~5.0% (W/V) buffer salt, preferably 0.3%~3.0% (W/V), more preferable 0.5%~1.5%.
- Trainingization Xihai sea horse peptide medicine composite according to claim 2, which is characterized in that include the isotonic regulator of 0.05%~5.0% (W/V), preferably 0.1%~1.0% (W/V) in the composition.
- Trainingization Xihai sea horse peptide medicine composite according to claim 4, it is characterized in that, the buffer is selected from phosphate buffer, acetate buffer, citrate buffer, carbonate buffer solution, tartrate buffer, Tris buffer or histidine salt buffer, it is preferred that acetate buffer or phosphate buffer, more preferable dihydric phosphate and phosphoric acid hydrogen disalt.
- Trainingization Xihai sea horse peptide medicine composite according to claim 5, which is characterized in that the isotonic regulator is selected from the one or more of sodium chloride, mannitol, sorbierite, glycerol, glucose or xylitol, preferably mannitol or sodium chloride.
- Described in any item trainingization Xihai sea horse peptide medicine composites according to claim 1~7, which is characterized in that the pH range of described pharmaceutical composition is 4.0 to 7.0, preferably 5.0 to 6.0.
- Trainingization Xihai sea horse peptide medicine composite according to claim 8, which is characterized in that the buffer salt is selected from sodium dihydrogen phosphate and disodium hydrogen phosphate, and weight ratio is 1~10:1, preferably 1~3:1, more preferable 1.2~2:1.
- Trainingization Xihai sea horse peptide medicine composite according to claim 9, it is characterized in that, the trainingization Xihai sea horse peptide injection includes the training Xihai sea horse peptide of 0.1%~2% (W/V), the sodium dihydrogen phosphate of 0.1%~2.0% (W/V), the disodium hydrogen phosphate of 0.1%~2.0% (W/V), the sodium chloride of 0.1%~2.0% (W/V)；Preferably, the trainingization Xihai sea horse peptide injection includes the training Xihai sea horse peptide of 0.1%~1% (W/V), the sodium dihydrogen phosphate of 0.2%~1% (W/V), the disodium hydrogen phosphate of 0.1%~0.6% (W/V), the sodium chloride of 0.1%~1.0% (W/V).
- According to claim 1 or training Xihai sea horse peptide medicine composite described in 10, which is characterized in that the weight ratio of the trainingization Xihai sea horse peptide and buffer salt is 1:1~10, preferably 1:2~4.
- According to claim 1 or training Xihai sea horse peptide medicine composite described in 10, which is characterized in that the weight ratio of the trainingization Xihai sea horse peptide and isotonic regulator is 1:0.5~10, preferably 1:1~2.
- According to claim 1 or training Xihai sea horse peptide medicine composite described in 10, which is characterized in that the weight ratio of the trainingization Xihai sea horse peptide, buffer salt and isotonic regulator is 1:1~10:0.5~10, preferably 1:2~4:1~2, more preferable 1:2.8:1.
- The method for preparing trainingization Xihai sea horse peptide medicine composite, comprising the following steps:1) buffer salt and isotonic regulator are dissolved in water for injection；2) active carbon is added, filtering decarbonization obtains intermediate medical fluid；3) trainingization Xihai sea horse peptide is dissolved to the medical fluid of step 2), stirring and dissolving, filtering, packing.
- According to claim 1, trainingization Xihai sea horse peptide medicine composite described in -13 lacks erythropoietin(EPO) for treating in preparation or red cell population lacks or the application of deficiency disorders, preferably anaemia.
- A method for the treatment of is to lack erythropoietin(EPO) or red cell population lacks or deficiency disorders, give the original measurement of patient 0.02-0.10mg/kg, hereafter the maintenance dose of 0.015-0.15mg/kg is given within every 26-30 days, to maintain hemoglobin in the range of 10.0-12.0g/dL, preferably, give the original measurement of patient 0.025mg/kg, 0.05mg/kg or 0.08mg/kg, hereafter every maintenance dose for giving 0.015-0.16mg/kg for 28 days, to maintain hemoglobin in the range of 10.0-12.0g/dL.
- According to the method for claim 16, the shortage erythropoietin(EPO) or red cell population lack or deficiency disorders are anaemia, preferably anemia caused by chronic renal failure.
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| CN2017114773117 | 2017-12-29 | ||
| CN201711477311.7A CN109985232A (en) | 2017-12-29 | 2017-12-29 | The pharmaceutical composition and preparation method thereof of trainingization Xihai sea horse peptide |
| PCT/CN2018/125599 WO2019129278A1 (en) | 2017-12-29 | 2018-12-29 | Pharmaceutical composition of pegol-sihematide and preparation method therefor |
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| CN201880007454.8A Active CN110214019B (en) | 2017-12-29 | 2018-12-29 | Pharmaceutical composition for cultivating hippocampus japonicus peptide and preparation method thereof |
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| CN114601916A (en) * | 2022-04-12 | 2022-06-10 | 江苏豪森药业集团有限公司 | Pedized hippocampus japonicus peptide injection preparation and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103536900A (en) * | 2012-07-16 | 2014-01-29 | 江苏豪森药业股份有限公司 | Erythrogenin mimetic peptide-containing pharmaceutical composition |
| CN103570834A (en) * | 2012-07-19 | 2014-02-12 | 江苏豪森药业股份有限公司 | Methoxy polyethylene glycol-modified erythropoietin mimic peptide derivative |
| CN108606955A (en) * | 2016-12-09 | 2018-10-02 | 江苏豪森药业集团有限公司 | The Pharmaceutical composition and preparation method thereof of trainingization Xihai sea horse peptide |
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| CN104231039A (en) * | 2013-06-08 | 2014-12-24 | 江苏豪森药业股份有限公司 | Functional micromolecules for synthesizing erythropoietin mimetic peptide derivatives, and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103536900A (en) * | 2012-07-16 | 2014-01-29 | 江苏豪森药业股份有限公司 | Erythrogenin mimetic peptide-containing pharmaceutical composition |
| CN103570834A (en) * | 2012-07-19 | 2014-02-12 | 江苏豪森药业股份有限公司 | Methoxy polyethylene glycol-modified erythropoietin mimic peptide derivative |
| CN108606955A (en) * | 2016-12-09 | 2018-10-02 | 江苏豪森药业集团有限公司 | The Pharmaceutical composition and preparation method thereof of trainingization Xihai sea horse peptide |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114601916A (en) * | 2022-04-12 | 2022-06-10 | 江苏豪森药业集团有限公司 | Pedized hippocampus japonicus peptide injection preparation and preparation method thereof |
| CN114601916B (en) * | 2022-04-12 | 2024-04-16 | 江苏豪森药业集团有限公司 | Pegylated hippocampus peptide injection and preparation method thereof |
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| WO2019129278A1 (en) | 2019-07-04 |
| CN109985232A (en) | 2019-07-09 |
| CN110214019B (en) | 2021-07-30 |
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