CN104474789B - China clay material, ceramic material and the glass material purposes in preparation cattle, pig or other mammal lung surface active extracts - Google Patents

China clay material, ceramic material and the glass material purposes in preparation cattle, pig or other mammal lung surface active extracts Download PDF

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CN104474789B
CN104474789B CN201410546624.3A CN201410546624A CN104474789B CN 104474789 B CN104474789 B CN 104474789B CN 201410546624 A CN201410546624 A CN 201410546624A CN 104474789 B CN104474789 B CN 104474789B
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lung
pig
surface active
mammal
cattle
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CN104474789A (en
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寇同欣
杨小杉
张宇
于顺廷
周宜遂
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Beijing Shuanghe Runchuang Technology Co ltd
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China Resources Double Crane Pharmaceutical Co Ltd
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Abstract

The present invention relates to china clay material, ceramic material and the glass material purposes in preparation cattle, pig or other mammal lung surface active extracts.

Description

China clay material, ceramic material and glass material are preparation cattle, pig or other mammals Purposes in lung surface active extract
The application be filing date JIUYUE in 2011 6 days, Application No. 201110261440.9, Invention entitled " china clay material, ceramic material and glass material preparation cattle, pig or other Purposes in mammal lung surface active extract " the divisional application of application for a patent for invention.
Technical field
The present invention relates to inorganic material, including china clay material, ceramic material and glass material in system Purposes in standby cattle, pig or other mammal lung surface active extracts.
Background technology
Cattle, pig or other mammals lung surface active extract (PS) refer to cattle, pig or other The lung-douching fluid of mammal or full lung homogenate extracting solution, separated, extract, product that purification obtains Thing, described product comprises multicomponent phospholipid and surfactant protein, is prevention and treatment premature labor The important first aid medicine of youngster's respiratory distress syndrome (NRDS), in whole world most countries and area Application, what application was more is the Curosurf injection of Italy's Chiesi pharmacy at presentThe full pulmonis Bovis seu Bubali that the subsidiary Ross of Abbott of the U.S. produces extracts preparation(Survanta is low because of effective ingredient lecithin content, with the addition of the phospholipid fraction of synthesis) And ONY company of the U.S.First two preparation is all from full lung homogenate extracting solution Isolated, latter is to extract to obtain from the irrigating solution of little pulmonis Bovis seu Bubali.
The lung surface active extract extracted from animal lung, no matter its raw material is full lung homogenate is extracted Liquid, or lung-douching fluid, be required to process substantial amounts of, containing multicomponent phospholipid and surface-active substance The suspension of matter albumen or emulsion.In the prior art, mainly by centrifugal as multistage centrifugal, Differential centrifugation or gradient centrifugation, carried by organic solvent extraction, chromatography purification or supercritical the most again The step such as pure prepares lung surface active extract.Wherein multistage centrifugal, differential centrifugation or gradient centrifugation Step duration, energy consumption is big, and yield is low, and production cost is high.Prior art also has do not use from Heart technology, and use organic membrane or compositing organic material as filtering raw material (lung-douching fluid Or full lung homogenate extracting solution) filtering material, but organic membrane or compositing organic material can with phospholipid, Protein ingredient mutually adsorbs, and the yield of activated product is relatively low.It is, thus, sought for one does not affects Yield, the method for the industrialization PS preparation simultaneously reduced energy consumption and production costs.
Summary of the invention
The present inventor finds under study for action, uses inorganic material to carry as separation and Extraction lung surface active Take the filtering material of thing, energy consumption and production can be reduced respectively while improving activated product yield Cycle.Use unlike the prior art for this present invention, can more effectively live on separation and Extraction lung surface Property extract inorganic material, solve that PS preparation production cycle length, energy consumption be high, low the asking of yield The industrialization that topic, more conducively pulmonary surfactant are extracted.
In the present invention, selection inorganic material is as filtering material, by the lung-douching fluid of mammal Or after lung homogenate extracting solution concentrates entirely, obtain trapped fluid only lung-douching fluid or full lung homogenate carries Take the 1/5~1/100 of liquid, the active component of trapped fluid and lung-douching fluid (or full lung homogenate extracting solution) Unanimously, total phospholipids yield is more than 90%, and lecithin yield is more than 90%, surfactant protein Yield is more than 85% (by weight).The purified step of trapped fluid prepares lung surface active extract, In the lung surface active extract of final preparation, total phospholipids content is more than 90%, and lecithin accounts for The 70-80% of total phospholipids, surfactant protein content is 1-2% (by weight).Use this The lung surface active extract of invention preparation, its active component, ratio and the former technique one of each component Causing, every quality index includes that the PS product that surface activity is also prepared with prior art is consistent.Wherein, Fill with the lung of the total phospholipids in the lung surface active extract of final preparation and the mammal before filtration Final total phospholipids yield is calculated based on washing liquid or full lung homogenate extracting solution.The final total phospholipids of gained is received Rate improves 10-15% than prior art.The lung-douching fluid of mammal used in the present invention or full lung Homogenate extracting solution can use techniques well known (such as, " Surfactant Replacement Therapy ", Donald L.Shapiro and Robert H.Notter et al, Alan R.Liss Inc.New York, 1989) prepare from the lung of mammal.Described mammal include cattle, Pig or other mammals.
In the present invention, described inorganic material is generally and phospholipid, protein component do not produce mutually absorption, So that to trapped fluid be only lung-douching fluid or the 1/5~1/100 of full lung homogenate extracting solution, total phosphorus Fat yield is more than 90%, and lecithin yield is more than 90%, and surfactant protein yield is more than 85% (by weight).The example of described inorganic material includes, but are not limited to china clay material, potter's clay Material processes, through various physics, chemical method, the inorganic material made, such as ceramic material, and Glass material etc..In the present invention, inorganic material aperture is: 10-1000nm, preferably 10-350nm. In the present invention, inorganic material preferred microporous ceramic material or micropore glass material, it can use Micropore ceramics chimney filter or the form of micropore glass chimney filter.
Therefore, the present invention relates to the inorganic material selected from china clay material, ceramic material or glass material Purposes in preparation cattle, pig or other mammal lung surface active extracts.
Following two kinds of methods are used to detect lung surface active extract prepared by this law, with former technique phase Ratio, its index of correlation reaches international similar PS standard preparation:
(1) external activity detection-lowest surface tension: use through state-promulgated pharmacopoeia meeting technical appraisement, specially Door for detect PS dosage surface activity controllable closed foam type surface tension instrument (CB-1 type, specifically See controllable closed foam type surface tension determination instrument patent specification, CN 94200787.5), detection is originally Surface tension (the development of controllable closed foam type surface tension determination instrument of the prepared sample of invention;China Medical apparatus and instruments magazine, the 2nd phase in 1994).Result shows, when the lung surface active of the present invention extracts When thing is in 1-5mg/ml concentration range, its surface tension can be rapidly decreased in 1 minute Below 1mN/m, illustrates that it can spread rapidly at gas-liquid interface, has excellent physiologically active;
(2) vivo test: Cavia porcellus is made pulmonary surfactant through normal saline lavation pulmonary Lack model, then give the lung surface active extract prepared by the present invention through tracheal intubation, see Examine guinea pig blood partial pressure of oxygen and lung compliance change before and after administration (referring specifically to Liu Chuanhe, Dong Shenghuan etc., The experiment of two kinds of Curosurf drug effects is compared.Chinese Journal of New Drugs, 1997 volume 6 the 2nd Phase), to evaluate the drug effect of PS preparation.Result of the test shows the lung surface active prepared by the present invention Extract, can improve rapidly the blood oxygen saturation of Cavia porcellus, in 5-10 minute in 30-60 minute The lung compliance of Cavia porcellus is returned to about the 70-80% of normal level, improves rapidly, evident in efficacy.
Compared with prior art, treating capacity is big for the inventive method, and total phospholipids yield is high, the production cycle Shortening about 40-50%, energy consumption declines about 60%, and industrialization degree is greatly improved.
Detailed description of the invention
Embodiment 1:
Document (" Surfactant with reference to Donald L.Shapiro and Robert H.Notter etc. Replacement Therapy ", Alan R.Liss Inc.New York, 1989) described in Method, uses self-control pulmonis Bovis seu Bubali irrigating solution 1000L to prepare pulmonis Bovis seu Bubali surface activity extract, difference Be to use micropore ceramics chimney filter (aperture 350nm) filtration step of Jiangsu for a long time my company replace from Heart step.After pulmonis Bovis seu Bubali irrigating solution is carried out thickening filtration, obtain trapped fluid 50L.Trapped fluid is through carrying Take purification process and prepare pulmonis Bovis seu Bubali surface activity extract 185g.
Total phospholipids measures and uses molybdenum orchid method, first by sample sulphuric acid or Perchloric Acid Digestion, then uses molybdic acid Ammonium develops the color;Lecithin measures and uses HPLC method (evaporative light scattering detector);Protein determination makes With BCA test kit (Sigma Co., USA), with front, reagent BCA reagent is pressed with Cu reagent Volume ratio 50:1 mixes, and detects wavelength about 560nm.
Trapped fluid testing result: after lung-douching fluid or the complete concentrated filtration of lung homogenate extracting solution, total phosphorus Fat yield 92%, lecithin yield 95%, surfactant protein yield is 90%.
Pulmonis Bovis seu Bubali surface activity extract testing result: total phospholipids content is 93%, and lecithin accounts for total phosphorus The ratio of fat is 80%, and surfactant protein content is 1.5%.
Surface activity testing result: pulmonis Bovis seu Bubali surface activity extract uses CB-1 type controllable closed foam type table Surface tension analyzer detects, sample under the conditions of least concentration (1mg/ml), surface tension 0.8mN/m can be dropped in 30 seconds.
Cavia porcellus result of the test shows, this law made pulmonis Bovis seu Bubali surface activity extract can be bright in 30 minutes The aobvious lung compliance improving Cavia porcellus, can make lung suitable according to dosage (40 to 70mg/kg body weight) difference Answering property returns to the 75-85% of normal level.
The total phospholipids yield of end product is 50%, and the full scale production cycle was 3 working days, total energy consumption About 400 kilowatt hours.
Embodiment 2:
Use method described in embodiment 1, use self-control pig full lung homogenate extracting solution 1000L to prepare pig Lung surface active extract, the difference is that only use Pall company micropore glass chimney filter (aperture 10nm) replace micropore ceramics chimney filter.After pig full lung homogenate extracting solution carries out thickening filtration, cut Stay liquid 40L.Prepare Pulmonis Sus domestica surface activity extract 184g.
Method described in embodiment 1 is used to detect, trapped fluid total phospholipids yield 90%, lecithin Yield 92%, surfactant protein yield 88%;Pulmonis Sus domestica surface activity extract total phospholipids contains Amount 90%, it is 75% that lecithin accounts for the ratio of total phospholipids, surfactant protein content 1.2%.
Surface activity testing result: Pulmonis Sus domestica surface activity extract uses CB-1 type controllable closed foam type table Surface tension analyzer detects, and sample is under 1.5mg/ml concentration conditions, and surface tension can be 60 0.95mN/m is dropped in Miao;
Cavia porcellus result of the test shows, (70 arrive the present embodiment method made Pulmonis Sus domestica surface activity extract 100mg/kg body weight) in 30 minutes, the lung compliance of Cavia porcellus can be returned to normal level 70%-80%.
The total phospholipids yield of end product is 46.2%, and the full scale production cycle was 2.7 working days, total energy Consumption about 370 kilowatt hours.
Embodiment 3:
Self-control pulmonis Bovis seu Bubali irrigating solution 1000L, uses existing gradient centrifugation procedure (Donald L.Shapiro With " the Surfactant Replacement Therapy " of Robert H.Notter etc., Alan R. Liss Inc.New York, 1989) carry out process and obtain crude product, the extracted purification of this crude product prepares Pulmonis Bovis seu Bubali surface activity extract 130g, end-product total phospholipids yield is 35%, and the full scale production cycle is 8 working days, total energy consumption about 1000 kilowatt hour.
Surface activity testing result: pulmonis Bovis seu Bubali surface activity extract uses CB-1 type controllable closed foam type table Surface tension analyzer detects, sample under least concentration condition (1mg/ml), surface tension 1.0mN/m can be dropped in 30 seconds.
Cavia porcellus result of the test shows, (70 arrive 100mg/kg to this law made pulmonis Bovis seu Bubali surface activity extract Body weight) lung compliance of Cavia porcellus can be significantly improved, in 30 minutes, lung compliance returns to normal water Flat about 70-80%.
Embodiment 4:
Self-control Pulmonis Sus domestica homogenate 1000L, uses the method for embodiment 3 to carry out process and obtains crude product, The extracted purification of this crude product prepares Pulmonis Sus domestica surface activity extract 107g, and end-product total phospholipids yield is 27%, the full scale production cycle was 7.2 working days, total energy consumption about 925 kilowatt hour.
Surface activity testing result: Pulmonis Sus domestica surface activity extract uses CB-1 type controllable closed foam type table Surface tension analyzer detects, sample under least concentration condition (1mg/ml), surface tension 1.19mN/m can be dropped in 30 seconds.
Cavia porcellus result of the test shows, (70 arrive 100mg/kg to this law made Pulmonis Sus domestica surface activity extract Body weight) lung compliance of Cavia porcellus can be significantly improved, in 30 minutes, lung compliance returns to normal water Flat about 65%-75%.
Comparative example 1,2,3 and 4, it is found that the side of the embodiment of the present invention 1 and 2 Method is compared with the centrifugal method of prior embodiment 3 and 4, and final total phospholipids yield improves 15-20%, the production cycle shortens about 40-60%, and energy consumption declines about 60%, and industrialization degree is big Big raising.

Claims (16)

1. the inorganic material selected from china clay material, glass material or ceramic material is preparing cattle, pig Or the purposes in other mammal lung surface active extracts, described inorganic material and phospholipid, egg Bai Zufen does not produce mutually absorption.
2. the purposes of claim 1, wherein said inorganic material aperture is 10-1000nm.
3. the purposes of claim 1, wherein said inorganic material aperture is 10-350nm.
4. the purposes of any one of claims 1 to 3, wherein said inorganic material is micropore ceramics Chimney filter or micropore glass chimney filter.
5. the purposes of any one of claims 1 to 3, wherein selects inorganic material as filter material Material.
6. the purposes of claim 5, wherein carries lung-douching fluid or the full lung homogenate of mammal Take after liquid concentrates, obtain trapped fluid and be only lung-douching fluid or full lung homogenate extracting solution 1/5~1/100, the active component of trapped fluid is consistent with lung-douching fluid or full lung homogenate extracting solution, retains The purified step of liquid prepares lung surface active extract, at the lung surface active extract of final preparation In, by weight, total phospholipids content is more than 90%, and lecithin accounts for the 70-80% of total phospholipids, table Face surfactant protein content is 1-2%.
7. the purposes of claim 4, wherein selects inorganic material as filtering material.
8. the purposes of claim 7, wherein carries lung-douching fluid or the full lung homogenate of mammal Take after liquid concentrates, obtain trapped fluid and be only lung-douching fluid or full lung homogenate extracting solution 1/5~1/100, the active component of trapped fluid is consistent with lung-douching fluid or full lung homogenate extracting solution, retains The purified step of liquid prepares lung surface active extract, at the lung surface active extract of final preparation In, by weight, total phospholipids content is more than 90%, and lecithin accounts for the 70-80% of total phospholipids, table Face surfactant protein content is 1-2%.
9. cattle, pig or other mammal lung surface active extracts, described cattle, pig or other food in one's mouths Breast animal lung surface activity extract is by following preparation:
Select selected from china clay material, glass material or do not produce mutually suction with phospholipid, protein component The inorganic material of attached ceramic material is as filtering material, by lung-douching fluid or the full lung of mammal Homogenate is after extracting solution concentrates, and obtains trapped fluid and is only lung-douching fluid or full lung homogenate extracting solution 1/5~1/100, the active component of trapped fluid is consistent with lung-douching fluid or full lung homogenate extracting solution.
10. the cattle of claim 9, pig or other mammal lung surface active extracts, wherein Described inorganic material aperture is 10-1000nm.
The cattle of 11. claim 9, pig or other mammal lung surface active extracts, wherein Described inorganic material aperture is 10-350nm.
The cattle of 12. any one of claim 9 to 11, pig or other mammal lung surface actives Extract, wherein said inorganic material is micropore ceramics chimney filter or micropore glass chimney filter.
The cattle of 13. any one of claim 9 to 11, pig or other mammal lung surface actives Extract, total phospholipids yield is more than 90%, and lecithin yield is big in described trapped fluid by weight In 90%, surfactant protein yield is more than 85%.
The cattle of 14. any one of claim 9 to 11, pig or other mammal lung surface actives Extract, in the lung surface active extract of final preparation, by weight, total phospholipids content is big In 90%, lecithin accounts for the 70-80% of total phospholipids, and surfactant protein content is 1-2%.
The cattle of 15. claim 12, pig or other mammal lung surface active extracts, institute Stating in trapped fluid by weight, total phospholipids yield is more than 90%, and lecithin yield is more than 90%, table Face surfactant protein yield is more than 85%.
The cattle of 16. claim 12, pig or other mammal lung surface active extracts, Eventually in the lung surface active extract of preparation, by weight, total phospholipids content is more than 90%, ovum phosphorus Fat accounts for the 70-80% of total phospholipids, and surfactant protein content is 1-2%.
CN201410546624.3A 2011-09-06 2011-09-06 China clay material, ceramic material and the glass material purposes in preparation cattle, pig or other mammal lung surface active extracts Active CN104474789B (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002143655A (en) * 2000-11-14 2002-05-21 Nok Corp Ceramic filter and producing method of ceramic filter
EP1508356A1 (en) * 1999-09-29 2005-02-23 Ibiden Co., Ltd. Honeycomb filter and ceramic filter assembly
CN1727032A (en) * 2005-07-26 2006-02-01 清华大学 Microbe filter made from micropore ceramics
CN101264401A (en) * 2007-03-14 2008-09-17 济南圣泉倍进陶瓷过滤器有限公司 Ceramic filter containing carbonaceous material and bonded with silica adhesive and manufacturing method thereof
CN101607158A (en) * 2008-06-21 2009-12-23 淄博鑫拓耐火材料有限公司 Silicon carbide porous ceramic filter and manufacture method thereof

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3997825B2 (en) * 2001-06-28 2007-10-24 株式会社デンソー Ceramic filter and ceramic filter with catalyst
CN102553355B (en) * 2011-09-06 2014-11-19 华润双鹤药业股份有限公司 Application of clay material, ceramic material and glass material in preparation of pulmonary surfactant extract of calf, pig or other mammals

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1508356A1 (en) * 1999-09-29 2005-02-23 Ibiden Co., Ltd. Honeycomb filter and ceramic filter assembly
JP2002143655A (en) * 2000-11-14 2002-05-21 Nok Corp Ceramic filter and producing method of ceramic filter
CN1727032A (en) * 2005-07-26 2006-02-01 清华大学 Microbe filter made from micropore ceramics
CN101264401A (en) * 2007-03-14 2008-09-17 济南圣泉倍进陶瓷过滤器有限公司 Ceramic filter containing carbonaceous material and bonded with silica adhesive and manufacturing method thereof
CN101607158A (en) * 2008-06-21 2009-12-23 淄博鑫拓耐火材料有限公司 Silicon carbide porous ceramic filter and manufacture method thereof

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