CN101439180A - Medicament composition for improving stability of Ulinastatin - Google Patents
Medicament composition for improving stability of Ulinastatin Download PDFInfo
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- CN101439180A CN101439180A CNA200810187702XA CN200810187702A CN101439180A CN 101439180 A CN101439180 A CN 101439180A CN A200810187702X A CNA200810187702X A CN A200810187702XA CN 200810187702 A CN200810187702 A CN 200810187702A CN 101439180 A CN101439180 A CN 101439180A
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- ulinastatin
- mannitol
- sodium chloride
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Abstract
The invention discloses a stable ulinastatin sterile injection powder pharmaceutical composition which contains an effective dose of ulinastatin and a pharmaceutical excipient, and the excipient is one or the combination of a plurality of kinds of mannitol, hydrolyzed gelatin, dextran and sodium chloride. The composition is generally used in the form of the freeze-dried sterile injection powder, when in clinical application, the composition is dissolved in glucose or physiological saline and other large infusions, and the composition can significantly reduce the decrease of the activity of the ulinastatin in water solution.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition, be specifically related to the compositions of ulinastatin and pharmaceutic adjuvant.
Background technology
Ulinastatin (Ulinastatin, urinary trypsin inhibitor Urlinary Trypsin Inhibitor, UT I) is a kind of glycoprotein that from NAM's urine, extracts, form by 143 aminoacid, the N end is alanine, the C end has sugar chain for leucine at the 10th serine and 45 aspartic acids.O-glycosides chain on the serine comprises a plurality of chondroitin sulfate unit.The molecular weight of ulinastatin is determined as 60-70KD through the HPLC method, is determined as 40-50KD through SDS-PAGE, and isoelectric point, IP is 2.6, is a kind of heat stable acidic protein.
Ulinastatin is inhibited to plurality of enzymes such as trypsin, hyaluronidase, fibrinolysins, is usually used in treating acute pancreatitis clinically.As a kind of biological activity protein; the problem that present ulinastatin in use exists is; the less stable of pure ulinastatin between the storage life; particularly surpass room temperature standing time 8h; reduction of medicine biological activity even inefficacy take place easily; therefore normally low-temp storage is protected the biological activity of ulinastatin, but the low-temperature protection cost is higher, and uses also inconvenient.During present clinical use ulinastatin lyophilized injectable powder, the method of taking be promptly join promptly with, promptly join fast usefulness, but because whether medicine also keeps original biological activity when being difficult to judge each use, when the case that occurs failing to respond to any medical treatment, can't determine it is because the incompatibility of the property of medicine still is because used the medicine of active reduction or inefficacy.Therefore treatment be may influence, and the inefficacy and the waste of medicine caused patient.
Summary of the invention
The objective of the invention is to overcome the problem of the existing easy inactivation of the clinical use of ulinastatin lyophilized powder, a kind of stable ulinastatin lyophilized injectable powder pharmaceutical composition is provided, its at room temperature bioactive stability obviously improves.
For achieving the above object; the technical solution used in the present invention is; choose and to shield to the ulinastatin activity; and do not produce antagonism, can do intravenous adjuvant with the ulinastatin pharmacological action; be prepared into lyophilized injectable powder according to a certain percentage with ulinastatin, when clinical use, dissolve in big liquid medium-sized vein infusion.Adjuvant is selected from stabilizing agent and wherein any one or a few combination of excipient mannitol, gelatin hydrolysate, dextran and sodium chloride.
Mannitol, gelatin hydrolysate, dextran and sodium chloride can prevent that medicine from volatilizing with steam, the active component of protection medicine as stabilizing agent and excipient in freeze-dry process.Especially mannitol, does not have hygroscopicity at its stable in properties, and has the active effect of protected protein, is preferably the adjuvant of ulinastatin freeze-dried powder.
The pharmaceutical composition that contains ulinastatin of the present invention, the proportioning that it is characterized in that ulinastatin and adjuvant are 2.5 ten thousand-100,000 unit: 0.01-0.2g; Preferred proportioning is 50,000-100,000 unit: 0.015-0.02g.The concrete consumption of ulinastatin and adjuvant can be prepared according to aforementioned proportion as required.As prepare ulinastatin 100,000 units, supplementary product consumption can be 0.01-0.2g, preferred supplementary product consumption 0.015-0.02g.
The adjuvant of comparative optimization of the present invention is formed and is comprised: mannitol, sodium chloride; Perhaps mannitol, gelatin hydrolysate, sodium chloride; Perhaps mannitol, dextran, sodium chloride.
The composition of pharmaceutical composition comparative optimization of the present invention and proportioning: whenever contain the ulinastatin of 50,000-100,000 units in the compositions, adjuvant can be mannitol 0.015g, sodium chloride 0.0001g; Or mannitol 0.015g, gelatin hydrolysate 0.01g, sodium chloride 0.0001g; Or mannitol 0.015g, dextran 0.01g, sodium chloride 0.0001g.The concrete consumption of ulinastatin and adjuvant can be prepared according to aforementioned proportion as required, and as containing ulinastatin 100,000 units in the compositions, then adjuvant can be mannitol 0.015g, sodium chloride 0.0001g; Or mannitol 0.015g, gelatin hydrolysate 0.01g, sodium chloride 0.0001g; Or mannitol 0.015g, dextran 0.01g, sodium chloride 0.0001g.
In this article, ulinastatin unit be defined as 2 μ g tryptic activities 50% when being suppressed the amount of ulinastatin be 1 unit.
The above-described preferred formulation that contains the pharmaceutical composition of ulinastatin is a lyophilized injectable powder.According to the ulinastatin lyophilized injection of above-mentioned formulation, when clinical practice, add and do the vein input in glucose or the big liquid of sodium chloride, the each application dose of ulinastatin is 100,000 units.
A kind of compound method of stable ulinastatin lyophilized injectable powder pharmaceutical composition is characterized in that:
(1) phosphate buffer preparation: be mixed with the phosphate buffer of 0.2mol/L, pH7.0, aseptic filtration with sodium dihydrogen phosphate, sodium hydrogen phosphate, water for injection; Face with preceding and be diluted to 5mmol/L with water for injection, pH7.0;
(2) medicinal liquid preparation: take by weighing needed raw material except that mannitol and sodium chloride according to prescription, add in the dosing bucket, add the pH7.0 phosphate buffer after diluting, stir evenly; Required mannitol and the sodium chloride of preparation is joined in the dosing bucket, stir evenly; Regulate pH value to 6.0～7.0 with the sodium hydroxide solution of 1mol/L or the hydrochloric acid solution of 1mol/L;
(3) aseptic filtration: the medicinal liquid filter membrane with 0.22 μ m under hundred grades of laminar flows for preparing is carried out aseptic filtration;
(4) fill, false add plug: under hundred grades of laminar flows, carry out fill, false add plug;
(5) lyophilizing and tamponade: in freeze dryer, carry out lyophilization and tamponade;
(6) roll lid, packing.
The solution pH value may change in the above-mentioned operational process of craft, influence the activity (ulinastatin solution is stable at pH5.8-7.5) of ulinastatin, phosphate buffer by pH value regulator sodium dihydrogen phosphate, sodium hydrogen phosphate preparation can be kept pH value of solution in the 5.8-7.5 scope, guarantees the stability of ulinastatin.
The ulinastatin lyophilized injectable powder that the inventor uses formulation of the present invention has carried out stability study, the result shows: the ulinastatin lyophilized injectable powder of using formulation of the present invention, placed one day after adding big liquid, tiring of ulinastatin still remains on more than 97%; Particularly, be ulinastatin 100,000 units according to optimization formula, mannitol 0.015g, sodium chloride 0.0001g and the ulinastatin lyophilized injectable powder for preparing were placed one day after adding big liquid, and tiring of ulinastatin still remains on more than 99%; And after the ulinastatin lyophilized injectable powder that does not use adjuvant dissolved in big liquid, it was tired and just reduces to below 93% through 12h; Through one day, to tire and reduce to below 84%, medical value reduces.
The ulinastatin lyophilized injectable powder that contains that the inventor adopts this method to prepare gained has carried out pharmacodynamics test, and the result shows: lyophilized injectable powder of the present invention has effects such as treating acute pancreatitis, acute organ nonfunction preferably.
The specific embodiment
The inventor further elaborates the present invention by following embodiment, but is not limited to this practical range.
Embodiment 1: the preparation of ulinastatin lyophilized injectable powder
1-9 is as follows for prescription:
| Ulinastatin (ten thousand units) | Mannitol (g) | Gelatin hydrolysate (g) | Dextran (g) | Sodium chloride (g) | Ulinastatin: adjuvant (ten thousand units: g) | |
| Prescription 1 | 10000 | 5 | —— | —— | 0.05 | 10：0.005 |
| Prescription 2 | 10000 | 5 | 5 | —— | 0.05 | 10：0.01 |
| Prescription 3 | 10000 | 5 | 5 | 5 | 0.05 | 10：0.015 |
| Prescription 4 | 10000 | 15 | —— | —— | 0.1 | 10：0.015 |
| Prescription 5 | 10000 | 15 | 10 | —— | 0.1 | 10：0.025 |
| Prescription 6 | 10000 | 15 | —— | 10 | 0.1 | 10：0.025 |
| Prescription 7 | 10000 | 15 | 10 | 5 | 0.09 | 10：0.03 |
| Prescription 8 | 10000 | 15 | 10 | 10 | 0.08 | 10：0.035 |
| Prescription 9 | 10000 | 0 | 0 | 0 | 0 | 10：0 |
Preparation method:
(1) pH7.0 phosphate buffer preparation:
0.2mol/L phosphate buffer, pH7.0, compound method is as follows:
Benchmark preparation inventory
Correctly take by weighing required sodium hydrogen phosphate and the sodium dihydrogen phosphate powder of preparation, pour in the dosing bucket, add about 80% water for injection and be stirred to whole dissolvings.Add medicinal charcoal 30g, stir, then heated and boiled, sucking filtration while hot.Measure the filtrate volume number, add water for injection to cumulative volume 10000ml, mixing carries out aseptic filtration with 0.22 μ m filter membrane under hundred grades of laminar flows, and packing is airtight then, freezing preservation; Face with preceding and be diluted to 5mmol/L with water for injection, pH7.0;
(2) medicinal liquid preparation (mannitol use in process of production be 20% formula mannitol injection liquid or mannitol):
Take by weighing needed raw material except that mannitol and sodium chloride according to prescription, add in the dosing bucket, the pH7.0 phosphate buffer after will diluting then adds in the dosing bucket, stirs evenly; Required formula mannitol injection liquid (or mannitol) and the sodium chloride of preparation is joined in the dosing bucket, stir evenly; Regulate pH value to 6.0～7.0 with the sodium hydroxide solution of 1mol/L or the hydrochloric acid solution of 1mol/L;
(3) aseptic filtration: the medicinal liquid filter membrane with 0.22 μ m under hundred grades of laminar flows for preparing is carried out aseptic filtration;
(4) fill, false add plug: under hundred grades of laminar flows, carry out fill (being distributed into 1000), false add plug;
(5) lyophilizing and tamponade: in freeze dryer, carry out lyophilization and tamponade;
(6) roll lid, packing.
Ulinastatin lyophilized injectable powder specification according to above step preparation is: ulinastatin 100,000 units/.
Embodiment 2: the stability test of ulinastatin in the glucose infusion solutions
Get respectively according to one of 100,000 unit ulinastatin lyophilized injectable powder of prescription 1-9 method preparation among the embodiment 1, injecting 100 milliliter of 5% glucose isosmotic solution shakes up, 25 ℃ of placements, 2,4,8,12,16,24 hours (h) sampling and measuring activity residual rates, the result was as follows respectively:
The activity residual rate (%) of ulinastatin in the glucose infusion solutions of table 1 prescription 1-10 preparation
| | sample time (h) | 0 | 2 | 4 | 8 | 12 | 16 | 24 |
| Prescription 1 | 100 | 100 | 99.3 | 98.9 | 96.8 | 94.2 | 93.5 |
| Prescription 2 | 100 | 100 | 99.1 | 97.5 | 93.5 | 92.8 | 90.0 |
| Prescription 3 | 100 | 100 | 99.2 | 98.6 | 95.7 | 93.6 | 92.3 |
| Prescription 4 | 100 | 100 | 100 | 100 | 99.9 | 99.8 | 99.4 |
| Prescription 5 | 100 | 100 | 99.9 | 98.7 | 97.2 | 96.4 | 95.2 |
| Prescription 6 | 100 | 100 | 99.9 | 98.6 | 96.9 | 95.7 | 94.2 |
| Prescription 7 | 100 | 100 | 99.4 | 99.0 | 96.9 | 94.5 | 93.8 |
| Prescription 8 | 100 | 100 | 99.9 | 98.8 | 97.5 | 96.9 | 95.6 |
| Prescription 9 | 100 | 99.8 | 96.9 | 94.6 | 91.2 | 88.1 | 82.3 |
The stability test of embodiment 3 ulinastatins in the sodium chloride infusion solutions
Get respectively according to one of 100,000 unit ulinastatin lyophilized injectable powder of prescription 1-9 method preparation among the embodiment 1, injecting 100 milliliter of 0.9% sodium chloride solution shakes up, 25 ℃ of placements, 2,4,8,12,16,24 hours (h) sampling and measuring activity residual rates, the result was as follows respectively:
The activity residual rate (%) of ulinastatin in the sodium chloride infusion solutions of table 2 embodiment 1-4 preparation
| Sample time (h) | 0 | 2 | 4 | 8 | 12 | 16 | 24 |
| Prescription 1 | 100 | 99.8 | 98.6 | 96.8 | 94.6 | 92.7 | 91.8 |
| Prescription 2 | 100 | 99.8 | 98.9 | 97.0 | 95.2 | 93.6 | 92.5 |
| Prescription 3 | 100 | 99.8 | 98.9 | 97.5 | 95.6 | 94.7 | 93.6 |
| Prescription 4 | 100 | 100 | 100 | 100 | 99.8 | 99.8 | 99.5 |
| Prescription 5 | 100 | 100 | 99.9 | 98.9 | 97.6 | 95.9 | 94.2 |
| Prescription 6 | 100 | 100 | 99.8 | 98.7 | 97.9 | 96.1 | 95.0 |
| Prescription 7 | 100 | 99.8 | 99.0 | 97.3 | 95.8 | 94.1 | 93.0 |
| Prescription 8 | 100 | 99.7 | 98.7 | 96.9 | 95.0 | 93.3 | 92.1 |
| Prescription 9 | 100 | 99.6 | 97.4 | 95.0 | 92.5 | 89.2 | 83.6 |
Above experimental result explanation contains the adjuvant among the above-mentioned prescription 1-8 in the ulinastatin lyophilized injectable powder, can effectively keep the activity of ulinastatin, and stability is better, and the activity residual rate of ulinastatin is greater than 99.9% in the more excellent prescription 4; And do not add in the ulinastatin lyophilized injectable powder (prescription 9) of adjuvant, ulinastatin is easily degraded, and room temperature is placed after 24 hours its activity residual rate and is reduced to about 80%, can not be applied to clinical.
Claims (7)
1, a kind of pharmaceutical composition that improves ulinastatin stability is characterized in that comprising the ulinastatin of effective dose and any one or a few adjuvant of being selected from mannitol, gelatin hydrolysate, dextran, the sodium chloride is formed.
2, pharmaceutical composition according to claim 1 is characterized in that the proportioning between ulinastatin and the adjuvant is 2.5-10 ten thousand units: 0.01～0.2g.
3, pharmaceutical composition according to claim 2 is characterized in that the proportioning between ulinastatin and the adjuvant is 5-10 ten thousand units: 0.015～0.02g.
4, pharmaceutical composition according to claim 1 is characterized in that the proportioning between adjuvant mannitol, gelatin hydrolysate, dextran, the sodium chloride is 1:0～1:0～1:0～0.01.
5,, it is characterized in that said composition exists with the lyophilized injectable powder form according to the described pharmaceutical composition of the arbitrary claim of claim 1-4.
6, pharmaceutical composition according to claim 5 is characterized in that whenever containing in the compositions ulinastatin of 5 ten thousand-10 ten thousand units, and adjuvant can be mannitol 0.015g, sodium chloride 0.0001g; Or mannitol 0.015g, gelatin hydrolysate 0.01g, sodium chloride 0.0001g; Or mannitol 0.015g, dextran 0.01g, sodium chloride 0.0001g.
7, a kind of compound method that improves the pharmaceutical composition of ulinastatin stability is characterized in that:
(1) phosphate buffer preparation: be mixed with the phosphate buffer of 0.2mol/L, pH7.0, aseptic filtration with sodium dihydrogen phosphate, sodium hydrogen phosphate, water for injection; Face with preceding and be diluted to 5mmol/L with water for injection, pH7.0;
(2) medicinal liquid preparation: take by weighing needed raw material except that mannitol and sodium chloride according to prescription, add in the dosing bucket, add the pH7.0 phosphate buffer after diluting, stir evenly; Required mannitol and the sodium chloride of preparation is joined in the dosing bucket, stir evenly; Regulate pH value to 6.0～7.0 with the sodium hydroxide solution of 1mol/L or the hydrochloric acid solution of 1mol/L;
(3) aseptic filtration: the medicinal liquid filter membrane with 0.22 μ m under hundred grades of laminar flows for preparing is carried out aseptic filtration;
(4) fill, false add plug: under hundred grades of laminar flows, carry out fill, false add plug;
(5) lyophilizing and tamponade: in freeze dryer, carry out lyophilization and tamponade;
(6) roll lid, packing.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA200810187702XA CN101439180A (en) | 2008-12-31 | 2008-12-31 | Medicament composition for improving stability of Ulinastatin |
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|---|---|---|---|
| CNA200810187702XA CN101439180A (en) | 2008-12-31 | 2008-12-31 | Medicament composition for improving stability of Ulinastatin |
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Cited By (10)
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| CN101954072A (en) * | 2010-10-08 | 2011-01-26 | 广东天普生化医药股份有限公司 | Use of ulinastatin in preparation of drugs for treating rheumatoid arthritis and pharmaceutical composition thereof |
| CN101954071A (en) * | 2010-10-08 | 2011-01-26 | 广东天普生化医药股份有限公司 | Use of ulinastatin in preparation of medicament for treating systemic lupus erythematosus and medicinal composition of ulinastatin |
| CN101972471A (en) * | 2010-10-08 | 2011-02-16 | 广东天普生化医药股份有限公司 | Application of Ulinastatin in preparing drug for curing autoimmune encephalomyelitis and pharmaceutical composition thereof |
| CN102038649B (en) * | 2009-10-20 | 2015-10-14 | 丽珠医药集团股份有限公司 | Urine-promoted follicle stimulating hormone freeze and preparation method thereof |
| CN105384812A (en) * | 2015-11-24 | 2016-03-09 | 青岛康原药业有限公司 | Method for purifying ulinastatin through increasing column efficiency by resin regeneration and pharmaceutical composition for improving resolubility of ulinastatin |
| CN105399819A (en) * | 2015-11-21 | 2016-03-16 | 青岛康原药业有限公司 | Method for purifying ulinastatin through affinity chromatography and pharmaceutical composition for improving stability of ulinastatin |
| CN105535951A (en) * | 2016-02-02 | 2016-05-04 | 广东天普生化医药股份有限公司 | Ulinastatin injection and preparation method for same |
| CN105596302A (en) * | 2016-02-02 | 2016-05-25 | 广东天普生化医药股份有限公司 | Ulinastatin freeze-dried powder preparation and preparation method thereof |
| CN109010290A (en) * | 2018-08-29 | 2018-12-18 | 江苏艾迪药业有限公司 | A kind of preparation method of ulinastatin freeze-dried powder preparation |
| CN111529696A (en) * | 2020-06-19 | 2020-08-14 | 广东天普生化医药股份有限公司 | Application of ulinastatin in preparing medicine for preventing nasopharyngeal cancer metastasis |
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2008
- 2008-12-31 CN CNA200810187702XA patent/CN101439180A/en active Pending
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102038649B (en) * | 2009-10-20 | 2015-10-14 | 丽珠医药集团股份有限公司 | Urine-promoted follicle stimulating hormone freeze and preparation method thereof |
| CN101954071A (en) * | 2010-10-08 | 2011-01-26 | 广东天普生化医药股份有限公司 | Use of ulinastatin in preparation of medicament for treating systemic lupus erythematosus and medicinal composition of ulinastatin |
| CN101972471A (en) * | 2010-10-08 | 2011-02-16 | 广东天普生化医药股份有限公司 | Application of Ulinastatin in preparing drug for curing autoimmune encephalomyelitis and pharmaceutical composition thereof |
| CN101972471B (en) * | 2010-10-08 | 2013-09-25 | 广东天普生化医药股份有限公司 | Application of Ulinastatin in preparing drug for curing autoimmune encephalomyelitis and pharmaceutical composition thereof |
| CN101954071B (en) * | 2010-10-08 | 2013-09-25 | 广东天普生化医药股份有限公司 | Use of ulinastatin in preparation of medicament for treating systemic lupus erythematosus and medicinal composition of ulinastatin |
| CN101954072A (en) * | 2010-10-08 | 2011-01-26 | 广东天普生化医药股份有限公司 | Use of ulinastatin in preparation of drugs for treating rheumatoid arthritis and pharmaceutical composition thereof |
| CN105399819A (en) * | 2015-11-21 | 2016-03-16 | 青岛康原药业有限公司 | Method for purifying ulinastatin through affinity chromatography and pharmaceutical composition for improving stability of ulinastatin |
| CN105384812A (en) * | 2015-11-24 | 2016-03-09 | 青岛康原药业有限公司 | Method for purifying ulinastatin through increasing column efficiency by resin regeneration and pharmaceutical composition for improving resolubility of ulinastatin |
| CN105535951A (en) * | 2016-02-02 | 2016-05-04 | 广东天普生化医药股份有限公司 | Ulinastatin injection and preparation method for same |
| CN105596302A (en) * | 2016-02-02 | 2016-05-25 | 广东天普生化医药股份有限公司 | Ulinastatin freeze-dried powder preparation and preparation method thereof |
| CN105596302B (en) * | 2016-02-02 | 2017-04-12 | 广东天普生化医药股份有限公司 | Ulinastatin freeze-dried powder preparation and preparation method thereof |
| CN109010290A (en) * | 2018-08-29 | 2018-12-18 | 江苏艾迪药业有限公司 | A kind of preparation method of ulinastatin freeze-dried powder preparation |
| CN111529696A (en) * | 2020-06-19 | 2020-08-14 | 广东天普生化医药股份有限公司 | Application of ulinastatin in preparing medicine for preventing nasopharyngeal cancer metastasis |
| CN111529696B (en) * | 2020-06-19 | 2021-02-19 | 广东天普生化医药股份有限公司 | Application of ulinastatin in preparing medicine for preventing nasopharyngeal cancer metastasis |
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Open date: 20090527 |