CN102049040A - Artificial surface-active substance mixed liquid as well as preparation and application thereof - Google Patents
Artificial surface-active substance mixed liquid as well as preparation and application thereof Download PDFInfo
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- CN102049040A CN102049040A CN2009102103321A CN200910210332A CN102049040A CN 102049040 A CN102049040 A CN 102049040A CN 2009102103321 A CN2009102103321 A CN 2009102103321A CN 200910210332 A CN200910210332 A CN 200910210332A CN 102049040 A CN102049040 A CN 102049040A
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Abstract
The invention relates to an artificial surface-active substance mixed liquid as well as preparation and application thereof. The artificial surface-active substance mixed liquid disclosed by the invention is prepared from surfactant protein B (SP-B)/ surfactant protein C (SP-C) or natural polypeptide with surface activity, lipids, surface active agents and a buffer solution. The artificial surface-active substance mixed liquid is suitable for respiratory distress syndrome for new born children or adults and other diseases relevant to deficiency of surface substances or abnormal functions.
Description
Technical field:
The present invention relates to field of pharmaceutical preparations, relate to a kind of proportioning that contains the mixed liquor of pulmonary surfactant, and preparation method thereof with its application in medicine.
Background technology:
(Pulmonarysurfaetant mainly is synthetic and excretory a kind of protein-lipid complex by alveolar type II cells PS) to pulmonary surfactant, is the important substance of keeping normal respiratory function.PS is a kind of composite phospholipid, contains 85%～90% phospholipid, 8%～10% protein, 5% neutral fat and a spot of inorganic salt.In phospholipid, phosphatidylcholine (Phosphatidyleholine, PC) account for 60%～50%, phosphatidyl glycerol (Phosphatidylglycerol, PG) account for 5%～10%, also comprise phosphatidylinositols (phosphatidylinositol, PI), sphingomyelin (Sphingomyelin, SPH), Phosphatidylserine (Phosphatidylsersne, PSe) etc.PC is the main component in the phospholipid, and wherein again with disaturated phosphatidyl choline, promptly two palm fibres are put phosphatidyl choline (Dipalmitoylphosphatidyleholine is main DPPC), and it accounts for 50% of phospholipid total amount, is topmost surfactant.Because of hydrone has certain affinity to other polar molecules, and nonpolar molecule there is repulsive interaction, is repelled outside arrangement in the nonpolar part (satisfied fatty acid) of alveolar fluid surface DPPC molecule and form monolayer.This structure decrease former fluid molecule on the surface, thereby reduced surface tension.
Protein ingredient among the PS comprises non-specific and specific proteins.(surfactant-associated protein SP) is lung specificity protein to the pulmonary surfactant associated protein, and at present known have four kinds, i.e. SP-A, B, C, D.Though this specific proteins only accounts for 1～2% among the PS, has the important physical function.In periodic breathing motion, simple DPPC can not be adsorbed onto the top layer rapidly from the liquid bottom, the DPPC molecule that enters the top layer formation monolayer of can not scattering soon, and PS albumen can promote absorption and the distribution of phospholipid to liquid-covered.Hydrophobin SP-B and SP-C promote that the function of phospholipid absorption and diffusion profile is the strongest.They independently bring into play physiological effect, do not have synergism mutually.Compare with SP-C, SP-B's is more with better function.Hydrophilic Protein S P-A also has similar physiological function, but effect is than a little less than SP-B and the SP-C.
Adult respiratory distress syndrome (Acute respiratory distress syndrome, ARDS) be meant that damaging with the alveolar blood capillary of the inside and outside attack of lungs such as severe infections, wound, shock back appearance is the main clinical syndrome that shows, (Acute lung injury ALI) is serious stage or type to belong to acute lung injury.Its Clinical symptoms is breathed speed and poverty-stricken frequently, carrying out property hypoxemia, and the X line presents the diffusivity alveolar and soaks into.Hyaline membrane disease of newborn (Neonatal respiratory distress syndrome, NRDS) claim respiratory distress syndrome (Hyaline membrane disease again, HMD), M ﹠ M is all very high, be the major reason of premature infant's perinatal death, because due to premature infant's alveolar type II cells secretion pulmonary surfactant PS shortage.Carrying out property dyspnea and respiratory failure promptly appear after clinical manifestation is made a living soon; Pathology with on the alveolar wall with having a liking for Yihong hyaline membrane and pulmonary atelectasis is a feature.
PS in 1980 is first by after the clinical practice, and different according to the source, the PS medicine is divided into 4 classes: the first kind: natural type PS (Natural Pulmonary Surfaetant) extracts from animal lung or people's amniotic fluid.Mainly from Pulmonis Sus domestica and calf lung-douching fluid or lung homogenate, prepare; Second class: improved natural type PS replenishes some PS main component of proper proportion in natural type PS, make the natural type medicine more effective; The 3rd class: artificial type, formulated by a certain percentage by the main phospholipid composition of the PS of synthetic or other succedaneum, its main feature is not contain PS protein; The 4th class: synthetic " natural " type PS adds a certain proportion of PS egg of producing with genetic engineering by the main phospholipid composition of the PS of synthetic and forms from plasmogamy system.According to the clinical research result, natural type PS and modified model PS curative effect are sure, rapid-action, remarkable especially to the curative effect of NRDS.
The accompanying drawing summary:
Fig. 1. different formulations differential scanning heat diagram: differential scanning heat diagram comparative study behind SP-B, the KL4 of different formulations adding variable concentrations.
Fig. 2. the research of different formulations external surface tension detection
Summary of the invention:
The present invention relates to the proportioning that a kind of NRDS of being used for the treatment of and ARDS must contain the mixed liquor of pulmonary surfactant, and preparation method thereof with its application in medicine.
Described mixed liquor has surface-active polypeptide by native protein SP-B or SP-C or its, lipid, and surfactant, buffer is formed; It is characterized in that the solution formed by following prescription:
Native protein SP-B (SP-C) or surface activity polypeptide 0.01～10%w/v
Lipid 1～90%w/v
Surfactant 0.01～10%w/v
Buffer is formed surplus
Above-mentioned native protein SP-B (SP-C) is the natural pulmonary surfactant protein matter of people or mammal.
The polypeptide of above-mentioned native protein SP-B (SP-C) behave or mammal SP-B (SP-C) have a surface-active partial amino-acid series, can obtain by natural product cracking acquisition or synthetic.
The preferred people's surface activity of above-mentioned polypeptide polypeptide KL4.Sequential structure is: lysine-leucine-leucine-leucine-leucine-lysine-leucine-leucine-leucine-leucine-lysine-leucine-leucine-leucine-leucine-lysine-leucine-leucine-leucine-leucine-lysine (KLLLLKLLLLKLLLLKLLLLK).
Above-mentioned lipid is natural lipid or synthetic lipid.Be selected from distearyl acid PHOSPHATIDYL ETHANOLAMINE, two Palmic acid PHOSPHATIDYL ETHANOLAMINE, phosphatidyl glycerol, cholesterol, sphingosine, lipid sphyngomyelin, ceramide, cerebroside, sulfolipide, ganglioside, glucoside (fat) ceramide, two hydrogen (nerve) sphingols of 4-hydroxyl; L-a-phosphoric acid lecithin, platelet activating factor, phosphatidyl glycerol, PHOSPHATIDYL ETHANOLAMINE, phosphatidylinositols, phosphatidylinositol-4phosphate, phosphatidylinositols-4,5-diphosphate, cuorin, phosphatidic acid, lysophosphatide.PHOSPHATIDYL ETHANOLAMINE-NH2 end group, comprise caproamide group, laurylamide group, phosphatidyl mercaptamine, succinyl group, glutaryl group, dodecane carboxylic group, biotin group, phosphatidyl ethylene glycol, biotinylated phospholipid medicated cap.One or more mixture of the lipid of lysophosphatidylcholine, lysophosphatidyl ethanolamine, lysophosphatidyl glycerol, lysophosphoglyceride, lysophosphatidic acid, alkyl phosphate choline, oxidation, biotinylated lipid, plasmalogen, polymeric phospholipid, Halogenated Phospholipids, poly-PEGization phospholipid with any mixed.
The preferred dipalmitoyl phosphatidyl choline of above-mentioned lipid (DPPC), one or both mixture of palmityl oleoyl glycerol (POPG) with any mixed.
Above-mentioned surfactant is ionic surfactant and nonionic surfactant.
The preferred oleic acid of above-mentioned surfactant, stearic one or both mixture with any mixed.
Above-mentioned buffer is the acceptable ion-type buffer of any human body.Buffer is selected from phosphate, hydrochlorate, and carbonate, borate, citrate, acetic acid-sodium acetate, one or more kinds of Tris buffer are with the mixture of any mixed.
Above-mentioned mixed liquor is used for neonate and adult respiratory distress syndrome and lacks or other relevant disease of dysfunction with surface mass.
Embodiment
The mixed liquor and the preparation thereof of embodiment 1 pulmonary surfactant
Prescription: DPPC 23g
POPG 8g
Oleic acid 4g
SP-B 1g
Phosphate buffer adds to 100g
Preparation: with chloroform: methanol=2: 1 (v/v) ratio is made solvent; DPPC, POPG are added to mixing in the solvent according to the above ratio, and rapid evaporation is removed organic solvent, and frozen drying gets Powdered phospholipid; Phosphate buffer adds 1% SP-B and oleic acid, adds freeze-dried mixed DPPC, POPG composition, and 40 ℃ of temperature are bathed to be stirred to fully and dissolved promptly, make final concentration reach SP-B1-2%, DPPC 20-30%, POPG5-15%, and packing is standby.
The mixed liquor and the preparation thereof of embodiment 2 pulmonary surfactants
Prescription: DPPC 23g
POPG 8g
Oleic acid 4g
SP-B 0.5g
SP-C 0.5g
Phosphate buffer adds to 100g
Preparation: with chloroform: methanol=2: 1 (v/v) ratio is made solvent; DPPC, POPG, oleic acid are added to mixing in the solvent according to the above ratio, and rapid evaporation is removed organic solvent, and frozen drying gets Powdered phospholipid; The SP-B of phosphate buffer adding 0.5% and 0.5% SP-C, add freeze-dried mixed DPPC, POPG composition, 40 ℃ of temperature are bathed to be stirred to fully and are dissolved promptly, make final concentration reach SP-B0.5-1%, SP-C0.5-1%, DPPC 20-30%, POPG5-15%, and packing is standby.
The mixed liquor and the preparation thereof of embodiment 3 pulmonary surfactants
Prescription: DPPC 23g
POPG 8g
Oleic acid 5g
KL
4 1g
Tris buffer buffer adds to 100g
Preparation: with chloroform: methanol=2: 1 (v/v) ratio is made solvent; DPPC, POPG, oleic acid are added to mixing in the solvent according to the above ratio, and rapid evaporation is removed organic solvent, and frozen drying gets Powdered phospholipid; Phosphate buffer adds 1% KL
4, adding freeze-dried mixed DPPC, POPG composition, 40 ℃ of temperature are bathed to be stirred to fully and are dissolved promptly, make final concentration reach KL
41-2%, DPPC 20-30%, POPG5-15%, packing is standby.
The mixed liquor and the preparation thereof of embodiment 4 pulmonary surfactants
Prescription: DPPC 23g
POPG 8g
Palmic acid 5g
SP-B 1g
Phosphate buffer adds to 100g
Preparation: with chloroform: methanol=2: 1 (v/v) ratio is made solvent; DPPC, POPG are added to mixing in the solvent according to the above ratio, and rapid evaporation is removed organic solvent, and frozen drying gets Powdered phospholipid; Phosphate buffer adds 1% SP-B and Palmic acid, adds freeze-dried mixed DPPC, POPG composition, and 40 ℃ of temperature are bathed to be stirred to fully and dissolved promptly, make final concentration reach SP-B1-2%, DPPC 20-30%, POPG5-15%, and packing is standby.
The mixed liquor and the preparation thereof of embodiment 5 pulmonary surfactants
Prescription: DPPC 23g
POPG 8g
Palmic acid 5g
SP-B 0.5g
SP-C 0.5g
Phosphate buffer adds to 100g
Preparation: with chloroform: methanol=2: 1 (v/v) ratio is made solvent; DPPC, POPG, Palmic acid are added to mixing in the solvent according to the above ratio, and rapid evaporation is removed organic solvent, and frozen drying gets Powdered phospholipid; The SP-B of phosphate buffer adding 0.5% and 0.5% SP-C add freeze-dried mixed DPPC, POPG composition, and 40 ℃ of temperature are bathed to be stirred to fully and dissolved promptly, make final concentration reach SP-B 0.5-1%, SP-C
0.5-1%, DPPC 20-30%, POPG 5-15%, packing is standby.
The mixed liquor and the preparation thereof of embodiment 6 pulmonary surfactants
Prescription: DPPC 23g
POPG 8g
Palmic acid 5g
KL
4 1g
Tris buffer buffer adds to 100g
Preparation: with chloroform: methanol=2: 1 (v/v) ratio is made solvent; DPPC, POPG, Palmic acid are added to mixing in the solvent according to the above ratio, and rapid evaporation is removed organic solvent, and frozen drying gets Powdered phospholipid; Phosphate buffer adds 1% KL
4, adding freeze-dried mixed DPPC, POPG composition, 40 ℃ of temperature are bathed to be stirred to fully and are dissolved promptly, make final concentration reach KL
41-2%, DPPC 20-30%, POPG5-15%, packing is standby.
The mixed liquor and the preparation thereof of embodiment 7 pulmonary surfactants
Prescription: lecithin 28g
Palmic acid 5g
Tris buffer buffer adds to 100g
Preparation: with chloroform: methanol=2: 1 (v/v) ratio is made solvent; Lecithin, Palmic acid are added to mixing in the solvent according to the above ratio, and rapid evaporation is removed organic solvent, and frozen drying gets Powdered phospholipid; Phosphate buffer adds freeze-dried mixed DPPC, Palmic acid composition, and 40 ℃ of temperature are bathed and are stirred to dissolving fully promptly, and packing is standby.
The mixed liquor and the preparation thereof of embodiment 8 pulmonary surfactants
Prescription: DPPC 28g
Lecithin 9g
Palmic acid 5g
The Tris buffer adds to 100g
Preparation: with chloroform: methanol=2: 1 (v/v) ratio is made solvent; DPPC, lecithin, Palmic acid are added to mixing in the solvent according to the above ratio, and rapid evaporation is removed organic solvent, and frozen drying gets Powdered phospholipid; Phosphate buffer adds freeze-dried mixed DPPC, lecithin ingredient, and 40 ℃ of temperature are bathed to be stirred to fully and dissolved promptly, make final concentration reach DPPC 28%, lecithin 9%, and packing is standby.
The mixed liquor and the preparation thereof of embodiment 9 pulmonary surfactants
Prescription: DPPC 28g
Lecithin 9g
Palmic acid 5g
KL
4 1-2g
The Tris buffer adds to 100g
Preparation: with chloroform: methanol=2: 1 (v/v) ratio is made solvent; DPPC, lecithin, Palmic acid are added to mixing in the solvent according to the above ratio, and rapid evaporation is removed organic solvent, and frozen drying gets Powdered phospholipid; Phosphate buffer adds 1% KL
4, adding freeze-dried mixed DPPC, lecithin ingredient, 40 ℃ of temperature are bathed to be stirred to fully and are dissolved promptly, make final concentration reach KL
41-2%, DPPC 20-30%, lecithin 5-15%, packing is standby.
Embodiment 10.
The mixed liquor of the pulmonary surfactant that embodiment 1 to embodiment 9 is prepared is used for neonate and adult respiratory distress syndrome and lacks or other relevant disease of dysfunction with surface mass.
Claims (12)
1. an artificial surface active substance mixed liquor is characterized in that said preparation is to have surface-active polypeptide by native protein SP-B (SP-C) or its, lipid, and surfactant, buffer is formed.
2. the described mixed liquor of claim 1 is characterized in that the solution of being made up of following prescription:
Prescription:
Native protein SP-B (SP-C) or surface activity polypeptide 0.01～10%w/v
Lipid 1～90%w/v
Surfactant 0.01～10%w/v
Buffer is formed surplus
3. the described native protein SP-B of claim 2 (SP-C) is the natural pulmonary surfactant protein matter of people or mammal.
The polypeptide of the described native protein SP-B of claim 2 (SP-C) behave or mammal SP-B (SP-C) have a surface-active partial amino-acid series, can obtain by natural product cracking acquisition or synthetic.
5. the preferred people's surface activity of the described polypeptide of claim 4 polypeptide KL
4
6. the described lipid of claim 2 is natural lipid or synthetic lipid.
Described lipid is selected from distearyl acid PHOSPHATIDYL ETHANOLAMINE, two Palmic acid PHOSPHATIDYL ETHANOLAMINE, phosphatidyl glycerol, cholesterol, sphingosine, lipid sphyngomyelin, ceramide, cerebroside, sulfolipide, ganglioside, glucoside (fat) ceramide, two hydrogen (nerve) sphingols of 4-hydroxyl; L-a-phosphoric acid lecithin, platelet activating factor, phosphatidyl glycerol, PHOSPHATIDYL ETHANOLAMINE, phosphatidylinositols, phosphatidylinositol-4phosphate, phosphatidylinositols-4,5-diphosphate, cuorin, phosphatidic acid, lysophosphatide.PHOSPHATIDYL ETHANOLAMINE-NH2 end group, comprise caproamide group, laurylamide group, phosphatidyl mercaptamine, succinyl group, glutaryl group, dodecane carboxylic group, biotin group, phosphatidyl ethylene glycol, biotinylated phospholipid medicated cap.One or more mixture of the lipid of lysophosphatidylcholine, lysophosphatidyl ethanolamine, lysophosphatidyl glycerol, lysophosphoglyceride, lysophosphatidic acid, alkyl phosphate choline, oxidation, biotinylated lipid, plasmalogen, polymeric phospholipid, Halogenated Phospholipids, poly-PEGization phospholipid with any mixed.
7. the preferred dipalmitoyl phosphatidyl choline of the described lipid of claim 6 (DPPC), one or both mixture of palmityl oleoyl glycerol (POPG) with any mixed.
8. the described surfactant of claim 2 is ionic surfactant and nonionic surfactant.
9. the preferred oleic acid of the described surfactant of claim 8, stearic one or both mixture with any mixed.
10. the described buffer of claim 2 is the acceptable ion-type buffer of any human body.
11. the described buffer of claim 10 is a phosphate, hydrochlorate, and carbonate, borate, citrate, acetic acid-sodium acetate, one or more kinds of Tris buffer are with the mixture of any mixed.
12. the described mixed liquor of claim 1-11 is used for neonate and adult respiratory distress syndrome and lacks or other relevant disease of dysfunction with surface mass.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109562139A (en) * | 2016-08-24 | 2019-04-02 | 奇斯药制品公司 | Stabilised pharmaceutical preparation comprising reconstructing pulmonary surfactant composition |
| CN111973563A (en) * | 2020-09-02 | 2020-11-24 | 崔海港 | Rhamnolipid freeze-dried powder preparation and preparation method and application thereof |
| EP3727353A4 (en) * | 2017-12-21 | 2021-10-13 | Civitas Therapeutics, Inc. | Surfactant formulations for inhalation |
| CN114159546A (en) * | 2021-12-20 | 2022-03-11 | 双鹤药业(海南)有限责任公司 | New generation of synthetic lung surfactant preparation and clinical application thereof |
-
2009
- 2009-10-30 CN CN2009102103321A patent/CN102049040A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109562139A (en) * | 2016-08-24 | 2019-04-02 | 奇斯药制品公司 | Stabilised pharmaceutical preparation comprising reconstructing pulmonary surfactant composition |
| EP3727353A4 (en) * | 2017-12-21 | 2021-10-13 | Civitas Therapeutics, Inc. | Surfactant formulations for inhalation |
| CN111973563A (en) * | 2020-09-02 | 2020-11-24 | 崔海港 | Rhamnolipid freeze-dried powder preparation and preparation method and application thereof |
| CN111973563B (en) * | 2020-09-02 | 2022-06-28 | 崔海港 | Rhamnolipid freeze-dried powder preparation and preparation method and application thereof |
| CN114159546A (en) * | 2021-12-20 | 2022-03-11 | 双鹤药业(海南)有限责任公司 | New generation of synthetic lung surfactant preparation and clinical application thereof |
| WO2023115789A1 (en) * | 2021-12-20 | 2023-06-29 | 北京双鹤润创科技有限公司 | New generation synthetic pulmonary surfactant formulation and clinical use thereof |
| CN114159546B (en) * | 2021-12-20 | 2024-06-04 | 北京双鹤润创科技有限公司 | New generation synthetic lung surfactant preparation and clinical application thereof |
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