CN101816782B - Composite enzyme apophlegmatisant - Google Patents
Composite enzyme apophlegmatisant Download PDFInfo
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- CN101816782B CN101816782B CN 201010145875 CN201010145875A CN101816782B CN 101816782 B CN101816782 B CN 101816782B CN 201010145875 CN201010145875 CN 201010145875 CN 201010145875 A CN201010145875 A CN 201010145875A CN 101816782 B CN101816782 B CN 101816782B
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- deoxyribonuclease
- apophlegmatisant
- protease
- enzyme
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Abstract
The invention relates to a composite enzyme apophlegmatisant and belongs to the technical field of medicament. The apophlegmatisant is a solid preparation or a liquid preparation which is prepared from combination of one or more deoxyribonuclease and one or more protease and a medicinal auxiliary material; in a solid preparation prescription, the mass proportion (W/W) of the deoxyribonuclease, the protease to the medicinal auxiliary material is 1 to (0.1-1) to (50-2,000); and in a liquid preparation prescription, the mass proportion (W/W, excluding water, a propellent and other cosolvents) of the deoxyribonuclease, the protease to the medicinal auxiliary material is 1 to (0.1-1) to (0.01-100). The composite enzyme apophlegmatisant can effectively remove sputum, especially thick sputum in oral cavity, laryngeal and trachea so as to overcome the block of the sputum to respiration.
Description
Technical field
The invention belongs to medical technical field, the particularly prescription of enzyme apophlegmatisant, preparation and clinical practice thereof, prescription, preparation and the preparation method of the compound enzyme apophlegmatisant that is especially formed by protease and deoxyribonuclease (DNase).
Background technology
Sputum under the normal physiological state is the main way of realization of respiratory tract self-cleaning, yet in pathological state, in the situations such as pneumonia, bronchitis, pulmonary carcinoma, sputum is because its toughness and zest can cause multiple physiological reaction, cough, breathe and to have some setbacks etc., thereby in the serious situation even can cause airway obstruction to threaten patient's life.Therefore an important component part in the treatment of respiratory diseases just is to reduce phlegm.
The toughness of sputum mainly comes from one of its composition-mucin, and the Apophlegmatisant that designs on this basis on the market at present has several, for example acetylcysteine aerosol, papain buccal tablet etc. (all including for Chinese Pharmacopoeia 2005 editions).But the toughness of sputum not merely comes from mucin, in the respiratory inflammation reaction, dead pathogenic bacteria, impaired respiratory tract cell, dead leukocyte all can discharge a large amount of DNA (deoxyribonucleic acid) (DNA) and enter sputum, thereby the high polymerization degree of dna molecular and Complicated Spatial Structure can further be strengthened the toughness of sputum and form thick sputum, and in the time of dna molecular and mucin molecule weave in, sterically hindered increasing has increased the degraded difficulty of protein in the sputum.Therefore, in apophlegmatisant prescription, introduce to the ingredient of DNA effect for example deoxyribonuclease (DNase) may greatly improve the ability of dissolving to thick sputum.To this, a large amount of laboratory research both at home and abroad shows, the streptodornase in the DNase of doses such as people's recombined human deoxyribonuclease I or Hemolytic streptococcus source can approximately finishing in 5-10 minute, be a kind of fast and efficiently Apophlegmatisant resource in external Degradation for the inflammatory purulent sputum.But up to the present, take deoxyribonuclease as the principal agent composition or the listing apophlegmatisant of one of principal agent composition not yet occur.
It is to be noted, with protease similar be, deoxyribonuclease also successfully is applied to the treatment of various diseases, for example the streptodornase injection is applied to thrombosis and eliminates (2005 editions injection types of including of Chinese Pharmacopoeia), and the recombined human deoxyribonuclease I is applied to the treatment (U.S.'s marketed drug) of pulmonary cystic fibrosis disease.In recent years, people find that also deoxyribonuclease I has significant pulmonary function improvement effect for bronchiectasis patient, and this shows that deoxyribonuclease can be applied to the treatment of respiratory tract disease more and more, and the safety of its respiratory tract medication is unquestionable.
Summary of the invention
The objective of the invention is to propose a kind of composite enzyme apophlegmatisant for overcoming the weak point of prior art, can effectively dissolve the sputum, particularly thick sputum of oral cavity, throat and trachea, to overcome the obstruction of sputum to breathing.
A kind of composite enzyme apophlegmatisant that the present invention proposes, solid preparation or liquid preparation that this apophlegmatisant is made by one or more deoxyribonuclease and one or more proteinase combinations and pharmaceutic adjuvant; The mass ratio range (W/W) of deoxyribonuclease, protease, adjuvant is 1 in the solid preparation prescription: (0.1-1): (50-2000); The mass ratio range (W/W does not comprise water, propellant and other cosolvent) of deoxyribonuclease, protease, adjuvant is 1 in the liquid preparation prescription: (0.1-1): (0.01-100).
Composite enzyme apophlegmatisant involved in the present invention, deoxyribonuclease wherein can comprise the recombined human deoxyribonuclease I, ox pancreas deoxyribonuclease I, pig spleen Deoxyribonuclease II, Lumbricus deoxyribonuclease EWD1, the Hemolytic streptococcus streptodornase; Protease in the prescription comprises trypsin, pepsin, Chymotrypsin, papain, bromelain, Serratieae protease, subtilisin, streptococcus cinereus protease, pupa albumen enzyme.
Because deoxyribonuclease is a kind of protein material; thereby easily lost using value by protease hydrolysis; therefore its dosage form of composite enzyme apophlegmatisant involved in the present invention is quite important; adopting suitable technique to be prepared into the needs that different dosage forms is not only clinical practice, also is protection and the bioactive needs of keeping composite enzyme apophlegmatisant.Specifically:
At first be can guarantee protease and deoxyribonuclease by the solid-state characteristics of the dosage forms such as lyophilized formulations, tablet, powder spray in well-mixed situation and Degradation can not occur, thus can long preservation.Wherein but the lyophilized formulations matching while using becomes aqueous solution or atomization preparation, is used for interim aerosol or the spray of loading, and the mode that also can adopt clinically organ to splash into is used for the treatment of reducing phlegm of critically ill patient; Tablet can be taken with the buccal tablet form, is used for dissolving the sputum of oral cavity and throat; Powder spray then can cooperate specific powder inhaler to use, and can make drug microparticles enter respiratory tract, effectively dissolves the sputum of trachea.
Secondly, as respiratory tract or the administration of rear portion, oral cavity, also can adopt two kinds of liquid preparation forms of aerosol or spray.Because the effect of the proteasome degradation deoxyribonuclease that liquid preparation may exist, therefore above-mentioned two kinds of liquid preparations can adopt two kinds of main components to prepare respectively, the again combination of row mixing before the use; Also can in liquid preparation, introduce enzyme stabilizers, regulate simultaneously water solution system pH=2-5, thereby effectively avoid the proteasome degradation effect.
The invention allows for a kind of adopt above-mentioned composite enzyme apophlegmatisant can be steady in a long-term the compound enzyme water solution preparation method:
A) deoxyribonuclease and enzyme stabilizers are dissolved in a certain amount of water to get solution I
B) with dilute hydrochloric acid solution I is adjusted to pH=3-5, gets solution II;
C) protease is dissolved in obtain in the solution II can the compound enzyme aqueous solution of preserving steady in a long-term.
This wherein selects metal ion (Mg
2+, Ca
2+), the combination of aminoacid (leucine, isoleucine, cysteine), polyol (glucose, mannitol, chitin, Sorbitol) is as enzyme stabilizers, can stablize on the one hand the conformation of two kinds of enzymes, on the other hand in conjunction with the conciliation of pH can establishment protease to the Degradation of deoxyribonuclease.
Except above-mentioned Formulation, modular design and corresponding technology of preparing; the concrete technology of preparing of preparation involved in the present invention is routine techniques; selected relevant auxiliary materials is that " the corresponding preparations adjuvant that Chinese pharmacopoeia is included is not within the protection domain of patent of the present invention, therefore do not give unnecessary details.
The present invention prepares deoxyribonuclease/protease apophlegmatisant by above design and step, has following advantage:
The combination deoxyribonuclease that the present invention proposes and the composite enzyme apophlegmatisant of protease can significantly improve the ability that medicine is dissolved sputum, the thick sputum of especially can validation unblock respiratory tract, severe jamming respiratory function;
The compound enzyme water solution preparation method that the present invention proposes has well been protected the biological activity of deoxyribonuclease in the presence of protease, so that the stability of this compound enzyme drug can realize;
The present invention can satisfy the needs that various clinical is used.
The specific embodiment
Embodiment 1
Lyophilized formulations: get 10mg Hemolytic streptococcus streptodornase powder, 5mg ox pancreas deoxyribonuclease I powder and 15mg subtilisin powder dissolution in the 10mL normal saline, add 5mg calcium lactate and 5g lactose, fully regulating pH value with dilute sodium hydroxide after the dissolving is 7.2, puts packing behind the lyophilization that spends the night in-16 ℃ of lyophilization machines.Be dose (trachea splashes into, suction or mouthspray) with this lyophilized formulations of 2-10mL physiological saline solution when using.
Embodiment 2
Tablet: 1g Pancreas Sus domestica gland deoxyribonuclease I powder, 1g Lumbricus deoxyribonuclease EWD1,500mg papain powder, 100mg pupa albumen enzyme, 200mg pepsin, 10g calcium carbonate and 35g leucine are added in the 150g Sionit, the tabletting preparation can be made up enzymology expectorant buccal tablet (every contains 10000 unit papains, 2000 unit pupa albumen enzymes, 4000 unit pepsin, 4000 unit ox pancreas deoxyribonuclease Is and the 4000 Lumbricus deoxyribonuclease EWD1 of unit, each buccal 1-2 sheet) behind the stirring and evenly mixing.
Embodiment 3
Powder spray: get the 1g citric acid and be dissolved in the 1000mL normal saline, add 200mg recombined human deoxyribonuclease I, 10mg Serratieae protease, 10mg streptococcus cinereus protease stirring and dissolving, add again 15 gram mannitol, 2 gram threonine, fully spray drying gets the compound enzymic preparation powder after the dissolving, be sub-packed in the hard capsule and be used for powder spray and suck, contain 2000 unit Serratieae protease, 1000 unit streptococcus cinereus protease and 2000 unit recombined human deoxyribonuclease Is in the suction volume of every capsule.
Embodiment 4
Powder spray: the 200mg trypsin is dissolved in the 1000mL normal saline, adds 10 gram lactose, fully spray drying must contain tryptic powders A after the dissolving; 500mg recombined human deoxyribonuclease I is dissolved in the 1000mL normal saline, adds 10 gram lactose, fully the rear spray drying of dissolving must contain the powder B of recombined human deoxyribonuclease I; Be sub-packed in after powders A and powder B fully mixed and be used for dust cloud in the hard capsule and suck, contain 2000 unit trypsin and 1000 unit recombined human deoxyribonuclease Is in the suction volume of every capsule.
Embodiment 5
Spray (interim fill): 5mg pig spleen Deoxyribonuclease II, 0.5mg Borneolum Syntheticum, 1mg chitin be dissolved in the 10mL normal saline be prepared into medicinal liquid, after during use 1mg bromelain powder being added in this medicinal liquid fully dissolving, in the oral cavity aerosol apparatus that medicinal liquid and ethanol are packed into behind the ratio mix homogeneously according to 9: 1 (W/W) for mouthspray.
Embodiment 6
Aerosol (interim fill): 10mg ox pancreas deoxyribonuclease I, 0.1mg xylitol, 0.1mg propolis be dissolved in be prepared into medicinal liquid A in the 5mL normal saline; 2mg Chymotrypsin, 0.1mg xylitol, 0.1mg propolis be dissolved in the 5mL normal saline be prepared into medical liquid B.Before using with medicinal liquid A, medical liquid B, isopropyl alcohol, HFA 134a according to 1: 1: 0.1: the ratio of 98 (W/W) is packed in the aerosol suction apparatus and uses.
Embodiment 7
Aerosol (long preservation):
The first step:
A) 100mg recombined human deoxyribonuclease I is dissolved in the 5mL normal saline, adds the 1mg calcium lactate, fully dissolve to get solution I;
B) with dilute hydrochloric acid regulator solution I to pH=3, get solution II;
C) in solution II, add again the 25mg Chymotrypsin and obtain compound enzyme aqueous solution steady in a long-term;
Second step: with this solution and ethanol, HFA 134a according to the ratio of 1: 0.1: 95 (W/W) be packed into then be prepared in the aerosol suction apparatus can long preservation the suction-type aerosol.
Embodiment 8
Spray (long preservation):
The first step:
A) the 100mg streptodornase is dissolved in the 5mL normal saline, adds 0.2mg magnesium chloride, 1mg isoleucine, 1mg chitin, fully dissolve to get solution I;
B) with dilute hydrochloric acid regulator solution I to pH=4.5, get solution II;
C) in solution II, add again the 5mg trypsin and obtain compound enzyme aqueous solution steady in a long-term;
Second step: with this solution and ethanol according to the ratio of 9: 1 (W/W) pack into then be prepared in the compression sprayer can long preservation oral spray.
Embodiment 9
Aerosol (long preservation):
The first step:
A) 50mg ox pancreas deoxyribonuclease I and 50mg pig spleen Deoxyribonuclease II are dissolved in the 5mL D/W (5%), add 2mg leucine, 1.5mg Sorbitol, fully dissolve to get solution I;
B) with dilute hydrochloric acid regulator solution I to pH=3, get solution II;
C) in solution II, add again the 15mg trypsin and obtain compound enzyme aqueous solution steady in a long-term;
Second step: with this solution and ethanol, normal butane, HFC-227ea according to 1: 0.1: 5: the ratio of 90 (W/W) be packed into then be prepared in the aerosol suction apparatus can long preservation the suction-type aerosol.
Embodiment 10
Spray (long preservation):
The first step:
A) 100mg recombined human deoxyribonuclease I is dissolved in the 5mL normal saline, adds 0.1mg magnesium chloride, 1mg cysteine, 2mg mannitol, fully dissolve to get solution I;
B) with dilute hydrochloric acid regulator solution I to pH=4, get solution II;
C) in solution II, add again the compound enzyme aqueous solution that 5mg papain and 5mg bromelain obtain long-term stability;
Second step: with this solution and ethanol according to the ratio of 9: 1 (W/W) pack into then be prepared in the compression sprayer can long preservation oral spray.
Protease proved by clinical to the effect of dissolving of sputum, and compound enzyme Apophlegmatisant involved in the present invention can be in the enterprising strong drug action of its pharmacological basis, and external resolve phlegm effect test is as shown in table 1:
Table 1
| The external test of reducing phlegm | Sputum sample 1 | Sputum sample 2 | Sputum sample 3 | Sputum sample 4 | Sputum sample 5 | Sputum sample 6 | Meansigma methods |
| The papain buccal tablet | 18min | ＞30min | 6min | ＞30min | 5min | 21min | 22±12min |
| Chymotrypsin solution | 16min | 24min | 9min | ＞30min | 5min | 22min | 20±11min |
| Embodiment 2 prescriptions | 9min | 11min | 7min | 13min | 4min | 7min | 9±4min |
| Aqueous solution among the embodiment 6 | 11min | 10min | 8min | 15min | 5min | 10min | 10±4min |
| Aqueous solution among the embodiment 7 | 9min | 7min | 8min | 11min | 5min | 7min | 8±3min |
In the table 1; The sputum sample is clinical respiratory disease patient expectoration purulent sputum liquid;
The interpolation total amount of various enzymes is 1% of sputum weight in each Experimental agents;
Add 37 ℃ of temperature of an amount of normal saline juxtaposition when reducing phlegm test and bathe slight vibration, be separated into the index of reducing phlegm fully with sputum.
Above-mentioned experiment shows, in the Apophlegmatisant prescription, add an amount of deoxyribonuclease really can greatly accelerate sputum especially purulent sputum dissolve speed.
For another the above, the compound enzyme water solution preparation method that the present invention proposes is intended to protect the biological activity of deoxyribonuclease in the presence of protease, and the result is as shown in table 2:
Table 2
Embodiment 5 in the table 2 is the compound enzyme aqueous solution behind the dissolving respective amount protease in solution.
Above-mentioned experiment shows that the compound enzyme water solution preparation method that the present invention proposes dissolves with respect to simple preparation, can greatly improve the stability of deoxyribonuclease under the protease existence condition; Certainly such preparation is still advised stored refrigerated, and carrying medicine should be finished within 1 week, and this is that characteristic by protein medicaments determines.
Claims (3)
1. composite enzyme apophlegmatisant is characterized in that:
1) this apophlegmatisant is the liquid preparation of being made by one or more deoxyribonuclease and one or more proteinase combinations and pharmaceutic adjuvant, namely is used for the compound enzyme aqueous solution of suction-type aerosol or oral spray;
2) mass ratio range (W/W) of deoxyribonuclease, protease, adjuvant is 1 in this apophlegmatisant preparation prescription: (0.1-1): (0.01-100); Described deoxyribonuclease is selected from the recombined human deoxyribonuclease I, ox pancreas deoxyribonuclease I, Pancreas Sus domestica gland deoxyribonuclease I, pig spleen Deoxyribonuclease II, Lumbricus deoxyribonuclease EWD1, Hemolytic streptococcus streptodornase; Described protease is selected from trypsin, pepsin, papain, bromelain, Serratieae protease, subtilisin, streptococcus cinereus protease, pupa albumen enzyme;
3) above-mentioned compound enzyme water solution preparation method may further comprise the steps:
A) the fully dissolving in water with corresponding proportion deoxyribonuclease and enzyme stabilizers gets solution I;
B) with dilute hydrochloric acid solution I is adjusted to pH=2-5, gets solution II;
C) protease of corresponding proportion is dissolved in obtain in the solution II can the compound enzyme aqueous solution of preserving steady in a long-term.
2. composite enzyme apophlegmatisant as claimed in claim 1 is characterized in that, described enzyme stabilizers adopts one or more combinations in metal ion, aminoacid, the polyol.
3. composite enzyme apophlegmatisant as claimed in claim 2 is characterized in that, described metal ion is Mg
2+Or Ca
2+Described aminoacid be in leucine, isoleucine or the cysteine any; Described polyol be in glucose, xylitol, mannitol, chitin or the Sorbitol any.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010145875 CN101816782B (en) | 2010-04-09 | 2010-04-09 | Composite enzyme apophlegmatisant |
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|---|---|---|---|
| CN 201010145875 CN101816782B (en) | 2010-04-09 | 2010-04-09 | Composite enzyme apophlegmatisant |
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| CN101816782A CN101816782A (en) | 2010-09-01 |
| CN101816782B true CN101816782B (en) | 2013-04-24 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105277402A (en) * | 2014-07-14 | 2016-01-27 | 汪振宏 | Rapid liquefaction agent of sputamentum beneficial to isolated culture of bacteria |
| CN206531717U (en) * | 2017-02-23 | 2017-09-29 | 郑州安图生物工程股份有限公司 | The sample adding system of automatic addition phlegm digestive juice |
| CN109260231B (en) * | 2017-07-18 | 2021-09-03 | 首都儿科研究所 | Preparation method of earthworm extract with cough stopping, phlegm eliminating, anti-inflammatory and antimicrobial functions |
| CN113749086A (en) * | 2021-08-27 | 2021-12-07 | 佛山科学技术学院 | Application of DNase I and pharmaceutically acceptable salts thereof in preparation of semen dilution medicine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1366042A (en) * | 2001-01-19 | 2002-08-28 | 北京华大基因研究中心 | Process for preparing recombinant deoxyribonuclease I |
| CN1376519A (en) * | 2002-04-19 | 2002-10-30 | 北京世诺医药科技有限公司 | Multi-enzyme complex capsule |
-
2010
- 2010-04-09 CN CN 201010145875 patent/CN101816782B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1366042A (en) * | 2001-01-19 | 2002-08-28 | 北京华大基因研究中心 | Process for preparing recombinant deoxyribonuclease I |
| CN1376519A (en) * | 2002-04-19 | 2002-10-30 | 北京世诺医药科技有限公司 | Multi-enzyme complex capsule |
Non-Patent Citations (2)
| Title |
|---|
| 王春等.祛痰药的临床应用评价.《中国医院用药评价与分析》.2006, * |
| 罗佳.地龙生物祛痰药物的研究.《中国优秀博硕士学位论文全文数据库(硕士) 医药卫生科技辑》.2006, * |
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