CN104083756A - Auxiliary agent for stabilizing pharmaceutical composition and pharmaceutical composition containing auxiliary agent - Google Patents
Auxiliary agent for stabilizing pharmaceutical composition and pharmaceutical composition containing auxiliary agent Download PDFInfo
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- CN104083756A CN104083756A CN201410348725.XA CN201410348725A CN104083756A CN 104083756 A CN104083756 A CN 104083756A CN 201410348725 A CN201410348725 A CN 201410348725A CN 104083756 A CN104083756 A CN 104083756A
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- enzyme activity
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- pharmaceutical composition
- defibrase
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Abstract
The invention provides an auxiliary agent for stabilizing a pharmaceutical composition and the pharmaceutical composition containing the auxiliary agent and in particular relates to a high-stability pharmaceutical composition with defibrase as a main drug. An enzyme activity protective agent is added into an original defibrase powder injection and an injection formula, the active ingredient of the drug is defibrase, other inactive ingredients in the prescription are a stabilizer, an excipient dextran and the enzyme activity protective agent, and the enzyme activity protective agent is a small molecule enzyme activity protective agent or macromolecule enzyme activity protective agent or a combination of the small molecule enzyme activity protective agent or macromolecule enzyme activity protective agent. Therefore, stabilization of titer of the defibrase in the production, storage and sales process is guaranteed, the production feeding ratio is reduced, stable titer of the finished product is guaranteed, and the safety and curative effect of clinical medication are improved.
Description
Technical field
The pharmaceutical composition that the present patent application relates to a kind of adjuvant and contains this adjuvant, particularly a kind of high stability be take the pharmaceutical composition that Defibrase is principal agent, belong to biological and biochemical pharmacy field.
Background technology
A kind of batroxobin sample enzyme extracting in the agkistrodon halys ussuriensis that Defibrase Shi Cong China is exclusive or Agkistrodon acutus snake venom, the medicine intravenous drip made from it, in human body, has the effect that reduces plasma fibrinogen concentration, reduces blood viscosity and anticoagulant.Clinically for treatment and the prevention of the diseases such as cerebral infarction, thromboangiitis obliterans, femoral artery thromboembolism, pulmonary infarction.Its street drug dosage form is freeze-dried powder (chief component composition is Defibrase, adds appropriate stabilizing agent and excipient dextran) and injection.The specification of every kind of dosage form has 5U/ to prop up with 10U/ to prop up.
The Defibrase of purification is the protease of high specific activity, and its Defibrase specific activity can reach 2500-3000U/mg, and in Defibrase freeze-dried powder and injection, in every medicine, the content of Defibrase is few, is generally below ten Gamma Magnitude.Cause thus the Defibrase of low concentration in medicine very easily oxidated, the impact of the multiple factors such as temperature, pH value, self-polymerization and degraded, the stability that its enzyme is lived reduces greatly.Cause from pharmaceutical production (dissolving, prepare, dilute the steps such as standardize solution, subpackage, lyophilizing) to each link of terminal sale, the very easily inactivation of tiring of Defibrase preparation, there is many related questions in the stability that enzyme is lived: in the production process of Defibrase preparation, in order to guarantee that finished product content meets drug standard, each manufacturer transfinites and feeds intake by the labelled amount 140%-180% of enzyme activity according to the preparation production technique of oneself, strengthened enterprise production cost, wasted valuable enzyme resource, strengthened uncertainty that finished product tires and the risk of clinical application; In the process of production, storage, transportation, sale, clinical use, due to the reduction of enzyme activity, had a strong impact on by the efficacy and saferry of prescribed dose rational use of drug.
One of existing technical scheme is in the production process of Defibrase preparation, in medicine prescription, to add the human albumin of 0.01-5% as enzyme protective agent alive.Yet, because the blood-borne pathogens that serum albumin is potential is polluted, scarcity and the higher cost of resource have limited it as protectant application.
Summary of the invention
The object of the present patent application is to solve the above-mentioned defect that current pharmaceutical composition (especially Defibrase preparation) exists in the process of producing, store, selling, the core of its technical problem be improve organized enzyme (especially Defibrase preparation) in pharmaceutical composition produce and the process of circulation in stability.
An object of the present patent application is to provide a kind of adjuvant of stabilizing pharmaceutical composition, and this adjuvant contains following compositions:
Dextran: 1%-5% (W/V%); The quality of this material that w/v% representation unit volume pharmaceutical composition contains;
Enzyme activity protective agent: micromolecule enzyme activity protective agent, macromole enzyme activity protective agent or micromolecule enzyme activity protective agent and the protectant combination of macromole enzyme activity.
Further, described micromolecule enzyme activity protective agent is mannitol or glycine, and its content is 0.1%-5% (W/V%).
Further, described macromole enzyme activity protective agent is partial hydrolysis gelatin or gelatin hydrolysate, and its content is 0.001%-0.5% (W/V%).
Further, described partial hydrolysis gelatin or gelatin hydrolysate by 18 seed amino acids form, its molecular weight is at the polypeptide of 3000-20000, wherein the highest with the content of glycine, by multiple protective mechanism, makes the enzyme activity of Defibrase preparation keep stable.
Another object of the present patent application is to provide the pharmaceutical composition that contains above-mentioned adjuvant, and described pharmaceutical composition contains following compositions:
Defibrase: principal agent;
Dextran: 1%-5% (W/V%);
Enzyme activity protective agent: micromolecule enzyme activity protective agent, macromole enzyme activity protective agent or micromolecule enzyme activity protective agent and the protectant combination of macromole enzyme activity.
Wherein to take the medicine liquid irrigation loading amount of every medicine be foundation in the cubage of (W/V%), refers to the quality (representing with g) of contained a certain component in every milliliter of medicinal liquid preparing, and unit is g/ml.
Further, described micromolecule enzyme activity protective agent is mannitol or glycine, and its content is 0.1%-5% (W/V%).
Further, described macromole enzyme activity protective agent is partial hydrolysis gelatin or gelatin hydrolysate, and its content is 0.001%-0.5% (W/V%).
Further, described partial hydrolysis gelatin or gelatin hydrolysate by 18 seed amino acids form, its molecular weight is at the polypeptide of 3000-20000, wherein the highest with the content of glycine, by multiple protective mechanism, makes the enzyme activity of Defibrase preparation keep stable.
In actual applications, also can as required, in the pharmaceutical composition described in the present patent application, add antibacterial.Conventional antibacterial has chlorobutanol, thimerosal etc.
Particularly, the enzyme activity protective agent of the present patent application can have following different combination:
1, mannitol: 0.1%-5% (W/V%)
2, glycine: 0.1%-5% (W/V%)
3, partial hydrolysis gelatin: 0.001%-0.5% (W/V%)
4, gelatin hydrolysate: 0.001%-0.5% (W/V%)
5, mannitol 0.1%-5% (W/V%) and partial hydrolysis gelatin 0.001%-0.5% (W/V%) combination;
6, mannitol 0.1%-5% (W/V%) and gelatin hydrolysate 0.001%-0.5% (W/V%) combination;
7, glycine 0.1%-5% (W/V%) and partial hydrolysis gelatin 0.001%-0.5% (W/V%) combination;
8, glycine 0.1%-5% (W/V%) and gelatin hydrolysate 0.001%-0.5% (W/V%) combination.
Above-mentioned adjuvant, makes pheron reduced by the impact of hydrone, and enzyme fluid viscosity increases, and makes enzyme liquid system homogeneous, stable more, improves the stability of liquid enzymes.Mannitol, as freeze drying protectant, stops the gathering of pharmaceutical grade protein by the formation of undefined structure, kept alive the stablizing of enzyme.Glycine stops Defibrase degeneration by suppressing the change of pH of cushioning fluid.Glycine in freeze-drying process also can stop the gathering of Defibrase molecule in freeze-drying process.Above-mentioned adjuvant; partial hydrolysis gelatin (or gelatin hydrolysate) is obtained by gelatin hydrolysis; the Pleiotropic Protections with polymer stabilizing protease, thus preferentially from protease surface, separate out, surface activity, protein enzyme solution viscosity is raise stop other micromolecule (as sugar and polyol) crystallization, suppress the acute variation of pH value freeze-drying process etc.Gelatin hydrolysate can commercially availablely obtain or prepare by the method described in document below: (close the Yunshan Mountain. the trial-production of Producing of Gelatin Hydrolysate [J]. Qinghai University's journal (natural science edition), 2001,19 (1): 32～34.).Partial hydrolysis gelatin can utilize gelatin to prepare by the method described in document below: (K.Stocker and G.H.Barlow The coagulant enzyme from Bothrops atrox venom (Batroxobin) Methods in Enzymology, 1976, V0l.45, p214-233, L.Lorand (Ed), Academic.New York).
Above-mentioned pharmaceutical composition, can various clinical applicable dosage forms be used, and includes but not limited to lyophilized injectable powder and injection.
The present patent application is the purposes of claimed described pharmaceutical composition in the medicine of preparation treatment or prevention of thromboembolic disorders also.
Pharmaceutical composition described in the present patent application; in original Defibrase freeze-dried powder and injection, add enzyme activity protective agent or its combination, the protective agent combination through screening; stable with what in assurance production, storage, sales process, Defibrase was tired, reduce production rate of charge, guaranteed that tiring of finished product is stable, improved safety and the curative effect of clinical application.
The specific embodiment
Below in conjunction with specific embodiment, described technology contents is carried out to nonrestrictive description, object is understood described technology for the public is better.
Embodiment 1
Defibrase injection (specification 10U/ props up)
With balance, weigh 4.0g Dextran-20, add appropriate water for injection and dissolve, add 5% needle-use activated carbon, jointly boil 30-60 minute, to be cooledly after room temperature, remove by filter active carbon, filtrate is stand-by.Accurately weigh glycine 4g, stand-by after dissolving with appropriate water for injection.Get the Defibrase raw material lyophilized powder of 2000U, with the standing dissolving of a small amount of physiological saline solution, adding afterwards the above-mentioned Dextran-20 solution of handling well and glycine solution to merge mixes, with water for injection, be settled to 200ml, filter membrane filter filtration sterilization with 0.22 μ m, the medicinal liquid of handling well props up subpackage in the 2R cillin bottle of handling well by 1.0ml/, tamponade, roll lid, labeling is standby.
Embodiment 2
Defibrase injection (specification 10U/ props up)
With balance, weigh 4.0g Dextran-20, add appropriate water for injection and dissolve, add 5% needle-use activated carbon, jointly boil 30-60 minute, to be cooledly after room temperature, remove by filter active carbon, filtrate is stand-by.Accurately weigh glycine 10g, stand-by after dissolving with appropriate water for injection.Subsequent step is with embodiment 1.
Embodiment 3
Defibrase injection (specification 10U/ props up)
With balance, weigh 4.0g Dextran-20, add appropriate water for injection and dissolve, add 5% needle-use activated carbon, jointly boil 30-60 minute, to be cooledly after room temperature, remove by filter active carbon, filtrate is stand-by.Accurately weigh glycine 0.4g, stand-by after dissolving with appropriate water for injection.Subsequent step is with embodiment 1.
Embodiment 4
Defibrase injection (specification 10U/ props up)
Specific operation process is with embodiment 1.
Embodiment 5
Defibrase injection (specification 10U/ props up)
Specific operation process is with embodiment 1.
Embodiment 6
Defibrase injection (specification 10U/ props up)
Specific operation process is with embodiment 1.
Embodiment 7
Defibrase freeze-dried powder (specification 5U/ props up)
With balance, weigh 30g Dextran-20, add appropriate water for injection and dissolve, add 5% needle-use activated carbon, jointly boil 30-60 minute, to be cooledly after room temperature, remove by filter active carbon, filtrate is stand-by.Accurately weigh glycine 20g, stand-by after dissolving with appropriate water for injection.Get the Defibrase raw material lyophilized powder of 5000U, with the standing dissolving of a small amount of physiological saline solution, adding afterwards the above-mentioned Dextran-20 solution of handling well and glycine solution to merge mixes, with water for injection, be settled to 1000ml, with the filter membrane filter filtration sterilization of 0.22 μ m, the medicinal liquid of handling well props up in the aseptic subpackaged 2R cillin bottle to handling well by 1.0ml/, add plug, enter freeze dryer lyophilizing, after lyophilizing finishes, tamponade, roll lid, labeling is standby.
Embodiment 8
Defibrase freeze-dried powder (specification 10U/ props up)
With balance, weigh 30g Dextran-20, add appropriate water for injection and dissolve, add 5% needle-use activated carbon, jointly boil 30-60 minute, to be cooledly after room temperature, remove by filter active carbon, filtrate is stand-by.Accurately weigh partial hydrolysis gelatin 200mg and glycine 20g, stand-by after dissolving with appropriate water for injection.Get the Defibrase raw material lyophilized powder of 5000U, with the standing dissolving of a small amount of physiological saline solution, add afterwards the above-mentioned Dextran-20 solution of handling well and partial hydrolysis gelatin solution to merge and mix, with water for injection, be settled to 1000ml.Subsequent step is with example 7.
The protective effect of the various different protective agent combinations of test example one to Defibrase injection enzyme activity
Table-1
The Defibrase injection liquid samples of different protective agent combinations is accelerated experiment under 37 ℃ of conditions, and timing sampling is measured Defibrase vigor.
From upper table data and the rate of descent of tiring, can find out, protective agent combination A does not add any protective agent, and enzyme activity (tiring) declines the fastest, and during not to experiment terminal, enzyme activity completely loses.Protective agent combination B: prop up+2% dextran of Defibrase 10U/ml/ (protective agent is blank), wherein dextran mainly plays thickening agent effect (having certain enzyme activity protective effect), and during experiment terminal, enzyme activity also has a small amount of reservation.Protective agent combination C-G has added different protective agent combinations, and during to experiment terminal, enzyme activity rate of descent is 48%-65%, illustrates that protective agent has played obvious enzyme activity protective effect.
The protective effect of the various different protective agent combinations of test example two to Defibrase freeze-dried powder enzyme activity
Table-2 (preserve in 10 ℃ of low temperature storehouses of sample)
The study on the stability data of the Defibrase freeze-dried powder combining from the different protective agents of upper table can be found out, do not add protectant sample and (form; The major part of tiring while prop up+2% dextran of Defibrase 5u/ (protective agent is blank)) investigating terminal is lost, and the rate of descent of tiring is 68.4%; And other add protectant sample rate of descent of tiring and are only: 0.4%-13.2%, sample is tired still in the qualified scope of medicine.
The different protective agent combinations of test example three are to Defibrase freeze-dried powder enzyme activity protection acceleration experiment
Table-3 (5U/ props up, labelled amount %) temperature: 37+2 ℃, humidity 60+10%
As can be seen from the above table; after blank protectant sample (prop up+3% dextran of Defibrase 5u/ (protective agent is blank)) lyophilizing completes, its potency labeling amount is only 33.4% of standard; be the just most of loss of tiring in production process, follow-up acceleration experiment exam has lost practical significance to itself.After the protectant sample lyophilizing alive of other interpolation enzymes completes, potency labeling amount is 89.6%-114.1%, illustrates that in production process, enzyme maintenance alive is stable, and after acceleration investigation in 1 month, self enzyme stable percentage ratio alive is: 86%-93.3%.The protective agent that each sample is described has reached protective enzyme stable effect alive.
It should be understood that; foregoing does not have any restriction to the present patent application technical scheme required for protection; in fact, all change or replacements of the various compositions of described pharmaceutical composition being carried out with identical or approximate principle, all within the desired technology contents of the present patent application.
Claims (10)
1. an adjuvant for stabilizing pharmaceutical composition, is characterized in that, described adjuvant contains following compositions:
Dextran content is 1%-5% (W/V%) and enzyme activity protective agent; W/v% is the quality of this material of containing of unit volume pharmaceutical composition;
Described enzyme activity protective agent is micromolecule enzyme activity protective agent, macromole enzyme activity protective agent or micromolecule enzyme activity protective agent and the protectant combination of macromole enzyme activity.
2. the adjuvant of stabilizing pharmaceutical composition according to claim 1, is characterized in that, described micromolecule enzyme activity protective agent is mannitol or glycine, and its content is 0.1%-5% (W/V%).
3. the adjuvant of stabilizing pharmaceutical composition according to claim 1, is characterized in that, described macromole enzyme activity protective agent is partial hydrolysis gelatin or gelatin hydrolysate, and its content is 0.001%-0.5% (W/V%).
4. the adjuvant of stabilizing pharmaceutical composition according to claim 3; it is characterized in that: described partial hydrolysis gelatin or gelatin hydrolysate by 18 seed amino acids form, its molecular weight is at the polypeptide of 3000-20000; wherein the highest with the content of glycine, by multiple protective mechanism, make the enzyme activity of Defibrase preparation keep stable.
5. the pharmaceutical composition that contains adjuvant described in claim 1-4, is characterized in that, described compositions contains enzyme activity protective agent composition or its combination described in claim 1-4;
Defibrase
Dextran: 1%-5% (W/V%);
Enzyme activity protective agent: micromolecule enzyme activity protective agent, macromole enzyme activity protective agent or micromolecule enzyme activity protective agent and the protectant combination of macromole enzyme activity.
6. pharmaceutical composition according to claim 5, is characterized in that: described micromolecule enzyme activity protective agent is mannitol or glycine, and its content is 0.1%-5% (W/V%).
7. according to the pharmaceutical composition described in claim 5 or 6, it is characterized in that: described macromole enzyme activity protective agent is partial hydrolysis gelatin or gelatin hydrolysate, its content is 0.001%-0.5% (W/V%).
8. pharmaceutical composition according to claim 7; it is characterized in that: described partial hydrolysis gelatin or gelatin hydrolysate by 18 seed amino acids form, its molecular weight is at the polypeptide of 3000-20000; wherein the highest with the content of glycine, by multiple protective mechanism, make the enzyme activity of Defibrase preparation keep stable.
9. the pharmaceutical composition described in any one in claim 5-8, said composition is freeze-dried powder or injection.
10. the purposes of the pharmaceutical composition described in claim 5-8 in the medicine of preparation treatment or prevention of thromboembolic disorders.
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Cited By (3)
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| CN108245669A (en) * | 2018-02-06 | 2018-07-06 | 昆明龙津药业股份有限公司 | The Defibrase injection and preparation method of a kind of stabilization |
| CN108273067A (en) * | 2018-02-06 | 2018-07-13 | 昆明龙津药业股份有限公司 | Glutamic acid stabilizer and preparation method for snake venom enzyme preparation |
| CN113908263A (en) * | 2021-12-15 | 2022-01-11 | 北京斯耐客科技发展有限责任公司 | Preparation method of gelatin enzyme activity protective agent and application of gelatin enzyme activity protective agent in defibrase preparation |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108245669A (en) * | 2018-02-06 | 2018-07-06 | 昆明龙津药业股份有限公司 | The Defibrase injection and preparation method of a kind of stabilization |
| CN108273067A (en) * | 2018-02-06 | 2018-07-13 | 昆明龙津药业股份有限公司 | Glutamic acid stabilizer and preparation method for snake venom enzyme preparation |
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| CN113908263A (en) * | 2021-12-15 | 2022-01-11 | 北京斯耐客科技发展有限责任公司 | Preparation method of gelatin enzyme activity protective agent and application of gelatin enzyme activity protective agent in defibrase preparation |
| CN114712491A (en) * | 2021-12-15 | 2022-07-08 | 北京斯耐客科技发展有限责任公司 | Preparation method of gelatin enzyme activity protective agent and application of gelatin enzyme activity protective agent in defibrase preparation |
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