CN101019836B - Nanometer cytochrome liposome medicine and its preparation - Google Patents
Nanometer cytochrome liposome medicine and its preparation Download PDFInfo
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- CN101019836B CN101019836B CN200710086421A CN200710086421A CN101019836B CN 101019836 B CN101019836 B CN 101019836B CN 200710086421 A CN200710086421 A CN 200710086421A CN 200710086421 A CN200710086421 A CN 200710086421A CN 101019836 B CN101019836 B CN 101019836B
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Abstract
The present invention relates to nanometer cytochrome C liposome medicine and its preparation process. The nanometer cytochrome liposome medicine consists of neutral phosphatide 40-80 weight portions,sitosterol 10-20 weight portions, cholesterol 20-40 weight portions, cytochrome C 10-30 weight portions, polyglycol 20-25 weight portions, reductive glutathione 5-10 weight portions, and vitamin C 40-50 weight portions. The nanometer cytochrome liposome medicine is used in the first aid and auxiliary treatment of anoxia clinically.
Description
Technical field
The present invention relates to nanometer cytochrome liposome medicine and preparation method thereof.
Background technology
Cytochrome C is called Cytochrome C again, and Cytochromum C, this medicine are the Cellular respiration activator that extracts from Cor Sus domestica or Cor Bovis seu Bubali, is one of internal respiration chain constituent.In the internal respiration chain, play the effect of transmitting electronics.Under normal circumstances, this medicine can not permeate through cell membranes, but when histanoxia, permeability of cell membrane strengthens, and exogenous preparation can enter in the cell by cell membrane, thereby brings into play the effect that it corrects Cellular respiration and substance metabolism.Thereby it can be used for clinical various anoxybiotic first aid or auxiliary treatment.The anoxia that dyspnea, mountain hypoxia, encephalopathy and the heart disease that causes as carbon monoxide poisoning, central depressant poisoning, asphyxia of newborn, serious shock anoxia, anesthesia and pulmonary disease causes etc.
But there are two big defectives in this medicine of prior art for preparing, and one is that curative effect is unstable sometimes, the 2nd, there is anaphylaxis.Because curative effect and security consideration have influenced the application clinically of this medicine greatly.
Summary of the invention
In order to solve the above-mentioned defective that existing cytochrome C class medicine exists, the invention provides a kind of nanometer cytochrome liposome medicine.
Technical scheme of the present invention is as follows:
The invention provides a kind of nanometer cytochrome liposome medicine, comprise the raw material of following parts by weight:
Neutral phospholipid 40-80;
Sitosterol 10-20;
Cholesterol 20-40;
Cytochrome C 10-30;
Polyethylene Glycol 20-25;
Reductive glutathione 5-10;
Vitamin C 40-50.
Specifically, described neutral phospholipid is meant egg lecithin or hydrogenated soy phosphatidyl choline and cephalin weight ratio 1-3: 1 mixture, and described sitosterol is meant cupreol, described Polyethylene Glycol is meant Macrogol 4000.
Hydrogenated soy phosphatidyl choline mixes with cephalin, sitosterol, cholesterol, formed the special liposome structure of medicine of the present invention, Polyethylene Glycol mixes in the liposome, form long circulating liposomes, glutathion is the antioxidant vivo activation agent of cytochrome C of holding concurrently in the body, and vitamin C is the excipient external antioxidant of holding concurrently.
The present invention also provides the preparation method of above-mentioned nanometer cytochrome liposome medicine, and step is as follows:
(1) dissolves cytochrome C, Polyethylene Glycol, reductive glutathione and the vitamin C of described amount with phosphate buffer, make solution;
(2) the solution ultra filtration molecular cut off 13000 daltonian filter membranes that step (1) made are got filtrate, remove molecular weight greater than 13000 daltonian impurity foreign preteins matter;
(3) dissolve neutral phospholipid, sitosterol, the cholesterol of described amount with the chloroform/methanol mixed liquor of 2: 1 volume mixture, make solution;
(4) solution that step (3) is made filters molecular cut off 5000 daltonian filter membranes, gets filtrate;
(5) filtrate evaporate to dryness in Rotary Evaporators that step (4) is made makes liposome membrane;
(6) under nitrogen protection, get the liposome membrane of filtrate hydration step (5) preparation of step (2) preparation, push repeatedly with homogenizer, until filtering, make the nano liposome medicament carrier particle dispersion liquid of particle diameter 50-120nm by 0.05 μ m nucleopore membranes;
(7) make acceptable dosage form on the pharmaceutics.
The acceptable dosage form is meant small-volume injection or lyophilized injection on the above-mentioned pharmaceutics.
The beneficial effect that nanometer cytochrome liposome medicine provided by the invention is realized is as follows:
1. medicine of the present invention is made nano liposome medicament to cytochrome C, make cytochrome C enter the interior targeting of body in hypoxic cell, and phospholipid is the main constituent of cell membrane, so the permeability of medicine cell membrane provided by the present invention improves greatly.
2. between the nanometer liposome particle diameter 50-120nm of medicine of the present invention, just in time be oxygen-starved tissue's blood capillary void size, enter the hypoxic cell position from circulating system easily, increased targeting, improved curative effect.
3. medicine of the present invention has mixed Polyethylene Glycol, has avoided being eliminated in liver, be called long circulating liposomes, but major part enters hypoxic cell.
4. owing to mixed reduced glutathion in the medicament nano liposome medicament of the present invention, eliminated because foreign cell pigment C oxidation in vivo and in vitro makes the active drawback that reduces of exogenous cytochrome C, simultaneously, reduced glutathion still is the activator of cytochrome C.
5. with foreign preteins molecule and other impurity among the molecular cut off 13000 daltonian filter membrane isolated cell pigment C, improve purity and removed thermal source, reduced anaphylaxis.
6. medicine bacterial endotoxin residual quantity of the present invention is little, greatly reduces its sensitization.
7. drug manufacture process using membrane separation technique of the present invention has substituted the activated carbon adsorption bacterial endotoxin technology in the existing technology, has eliminated active carbon and has polluted the sensitization that causes.
8. medicine of the present invention is made the nano liposome medicament carrier, and cytochrome C is encapsulated in the liposome, has reduced its sensitization.
9. medicine of the present invention has added antioxidant, has avoided cytochrome C oxidation in vivo and in vitro, has reduced side reaction, thereby has reduced toxicity and sensitization.
The specific embodiment
Embodiment 1:
In the prescription that present embodiment adopted, each raw material and parts by weight thereof are as follows:
Neutral phospholipid 40;
Sitosterol 20;
Cholesterol 20;
Cytochrome C 30;
Polyethylene Glycol 20;
Reductive glutathione 10;
Vitamin C 40.
Described neutral phospholipid is meant hydrogenated soy phosphatidyl choline and cephalin weight ratio 1-3: 1 mixture, and described sitosterol is meant cupreol, described Polyethylene Glycol is meant Macrogol 4000.
Hydrogenated soy phosphatidyl choline mixes with cephalin, sitosterol, cholesterol, formed the special liposome structure of medicine of the present invention, Polyethylene Glycol mixes in the liposome, form long circulating liposomes, glutathion is the antioxidant vivo activation agent of cytochrome C of holding concurrently in the body, and vitamin C is the excipient external antioxidant of holding concurrently.
Preparation process is as follows:
(1) dissolves cytochrome C, Polyethylene Glycol, reductive glutathione and the vitamin C of described amount with phosphate buffer, make solution;
(2) the solution ultra filtration molecular cut off 13000 daltonian filter membranes that step (1) made are got filtrate, remove molecular weight greater than 13000 daltonian impurity foreign preteins matter;
(3) dissolve neutral phospholipid, sitosterol, the cholesterol of described amount with the chloroform/methanol mixed liquor of 2: 1 volume mixture, make solution;
(4) solution that step (3) is made filters molecular cut off 5000 daltonian filter membranes, gets filtrate;
(5) filtrate evaporate to dryness in Rotary Evaporators that step (4) is made makes liposome membrane;
(6) under nitrogen protection, get the liposome membrane of filtrate hydration step (5) preparation of step (2) preparation, push repeatedly with homogenizer, until filtering, make the nano liposome medicament carrier particle dispersion liquid of particle diameter 50-120nm by 0.05 μ m nucleopore membranes;
(7) make acceptable dosage form on the pharmaceutics.
The drug effect demonstration test is as follows:
White mice is placed in the hermetic container, pass to the mist of 96.2% nitrogen and 3.8% oxygen, fall down to the ground, till the loss of consciousness, cause anoxia until white mice.Treatment group selection medicine of the present invention, dosage is: in cytochrome C, each one group of 1.0mg/kg consumption (treatment group 1), 0.5mg/kg consumption (treatment group 2), be administered once every day, intraperitoneal injection.Matched group uses existing cytochron-Sinjection15 medicine, each one group of 1.0mg/kg consumption (matched group 1), 0.5mg/kg consumption (matched group 2), and dosage and administration number of times are with the treatment group.Treatment group and matched group are established 30 of white mice for every group, administration time 3 days, and it serves as effective bringing back to life existence and reply the normal activity ability with white mice.
The white mice of more than testing all is mices of testing used drug sensitivity pass the test in advance.The irritated incidence rate of statistics in process of the test.
Result of the test is as follows:
Embodiment 2:
In the prescription that present embodiment adopted, each raw material and parts by weight thereof are as follows:
Neutral phospholipid 80;
Sitosterol 10;
Cholesterol 40;
Cytochrome C 10;
Polyethylene Glycol 25;
Reductive glutathione 5;
Vitamin C 50.
Described neutral phospholipid is meant hydrogenated soy phosphatidyl choline and cephalin weight ratio 1-3: 1 mixture, and described sitosterol is meant cupreol, described Polyethylene Glycol is meant Macrogol 4000.
Hydrogenated soy phosphatidyl choline mixes with cephalin, sitosterol, cholesterol, formed the special liposome structure of medicine of the present invention, Polyethylene Glycol mixes in the liposome, form long circulating liposomes, glutathion is the antioxidant vivo activation agent of cytochrome C of holding concurrently in the body, and vitamin C is the excipient external antioxidant of holding concurrently.
Preparation process is as follows:
(1) dissolves cytochrome C, Polyethylene Glycol, reductive glutathione and the vitamin C of described amount with phosphate buffer, make solution;
(2) solution that step (1) is made filters molecular cut off 13000 daltonian filter membranes, gets filtrate;
(3) dissolve neutral phospholipid, sitosterol, the cholesterol of described amount with the chloroform/methanol mixed liquor of 2: 1 volume mixture, make solution;
(4) solution that step (3) is made filters molecular cut off 5000 daltonian filter membranes, gets filtrate;
(5) filtrate evaporate to dryness in Rotary Evaporators that step (4) is made makes liposome membrane;
(6) under nitrogen protection, get the liposome membrane of filtrate hydration step (5) preparation of step (2) preparation, make the nano liposome medicament carrier particle dispersion liquid of particle diameter 50-120nm;
(7) make the dosage form that can receive on the pharmaceutics.
The drug effect demonstration test is as follows:
White mice is placed in the hermetic container, pass to the mist of 96.2% nitrogen and 3.8% oxygen, fall down to the ground, till the loss of consciousness, cause anoxia until white mice.Treatment group selection medicine of the present invention, dosage is: in cytochrome C, each one group of 1.0mg/kg consumption (treatment group 1), 0.5mg/kg consumption (treatment group 2), be administered once every day, intraperitoneal injection.Matched group uses existing cytochron-Sinjection15 medicine, each one group of 1.0mg/kg consumption (matched group 1), 0.5mg/kg consumption (matched group 2), and dosage and administration number of times are with the treatment group.Treatment group and matched group are established 30 of white mice for every group, administration time 3 days, and it serves as effective bringing back to life existence and reply the normal activity ability with white mice.
The white mice of more than testing all is mices of testing used drug sensitivity pass the test in advance.The irritated incidence rate of statistics in process of the test.
Result of the test is as follows:
Embodiment 3:
In the prescription that present embodiment adopted, each raw material and parts by weight thereof are as follows:
Neutral phospholipid 80;
Sitosterol 20;
Cholesterol 40;
Cytochrome C 30;
Polyethylene Glycol 25;
Reductive glutathione 10;
Vitamin C 50.
Described neutral phospholipid is meant hydrogenated soy phosphatidyl choline and cephalin weight ratio 1-3: 1 mixture, and described sitosterol is meant cupreol, described Polyethylene Glycol is meant Macrogol 4000.
Hydrogenated soy phosphatidyl choline mixes with cephalin, sitosterol, cholesterol, formed the special liposome structure of medicine of the present invention, Polyethylene Glycol mixes in the liposome, form long circulating liposomes, glutathion is the antioxidant vivo activation agent of cytochrome C of holding concurrently in the body, and vitamin C is the excipient external antioxidant of holding concurrently.
Preparation process is as follows:
(1) dissolves cytochrome C, Polyethylene Glycol, reductive glutathione and the vitamin C of described amount with phosphate buffer, make solution;
(2) solution that step (1) is made filters molecular cut off 13000 daltonian filter membranes, gets filtrate;
(3) dissolve neutral phospholipid, sitosterol, the cholesterol of described amount with the chloroform/methanol mixed liquor of 2: 1 volume mixture, make solution;
(4) solution that step (3) is made filters molecular cut off 5000 daltonian filter membranes, gets filtrate;
(5) filtrate evaporate to dryness in Rotary Evaporators that step (4) is made makes liposome membrane;
(6) under nitrogen protection, get the liposome membrane of filtrate hydration step (5) preparation of step (2) preparation, make the nano liposome medicament carrier particle dispersion liquid of particle diameter 50-120nm;
(7) make acceptable dosage form on the pharmaceutics.
The drug effect demonstration test is as follows:
White mice is placed in the hermetic container, pass to the mist of 96.2% nitrogen and 3.8% oxygen, fall down to the ground, till the loss of consciousness, cause anoxia until white mice.Treatment group selection medicine of the present invention, dosage is: in cytochrome C, each one group of 1.0mg/kg consumption (treatment group 1), 0.5mg/kg consumption (treatment group 2), be administered once every day, intraperitoneal injection.Matched group uses existing cytochron-Sinjection15 medicine, each one group of 1.0mg/kg consumption (matched group 1), 0.5mg/kg consumption (matched group 2), and dosage and administration number of times are with the treatment group.Treatment group and matched group are established 30 of white mice for every group, administration time 3 days, and it serves as effective bringing back to life existence and reply the normal activity ability with white mice.
The white mice of more than testing all is mices of testing used drug sensitivity pass the test in advance.The irritated incidence rate of statistics in process of the test.
Result of the test is as follows:
Embodiment 4:
In the prescription that present embodiment adopted, each raw material and parts by weight thereof are as follows:
Neutral phospholipid 80;
Sitosterol 20;
Cholesterol 40;
Cytochrome C 30;
Polyethylene Glycol 25;
Reductive glutathione 10;
Vitamin C 50.
Described neutral phospholipid is meant egg lecithin, and described sitosterol is meant cupreol, and described Polyethylene Glycol is meant Macrogol 4000.
Hydrogenated soy phosphatidyl choline mixes with cephalin, sitosterol, cholesterol, formed the special liposome structure of medicine of the present invention, Polyethylene Glycol mixes in the liposome, form long circulating liposomes, glutathion is the antioxidant vivo activation agent of cytochrome C of holding concurrently in the body, and vitamin C is the excipient external antioxidant of holding concurrently.
Preparation process is as follows:
(1) dissolves cytochrome C, Polyethylene Glycol, reductive glutathione and the vitamin C of described amount with phosphate buffer, make solution;
(2) solution that step (1) is made filters molecular cut off 13000 daltonian filter membranes, gets filtrate;
(3) dissolve neutral phospholipid, sitosterol, the cholesterol of described amount with the chloroform/methanol mixed liquor of 2: 1 volume mixture, make solution;
(4) solution that step (3) is made filters molecular cut off 5000 daltonian filter membranes, gets filtrate;
(5) filtrate evaporate to dryness in Rotary Evaporators that step (4) is made makes liposome membrane;
(6) under nitrogen protection, get the liposome membrane of filtrate hydration step (5) preparation of step (2) preparation, make the nano liposome medicament carrier particle dispersion liquid of particle diameter 50-120nm;
(7) make acceptable dosage form on the pharmaceutics.
The drug effect demonstration test is as follows:
White mice is placed in the hermetic container, pass to the mist of 96.2% nitrogen and 3.8% oxygen, fall down to the ground, till the loss of consciousness, cause anoxia until white mice.Treatment group selection medicine of the present invention, dosage is: in cytochrome C, each one group of 1.0mg/kg consumption (treatment group 1), 0.5mg/kg consumption (treatment group 2), be administered once every day, intraperitoneal injection.Matched group uses existing cytochron-Sinjection15 medicine, each one group of 1.0mg/kg consumption (matched group 1), 0.5mg/kg consumption (matched group 2), and dosage and administration number of times are with the treatment group.Treatment group and matched group are established 30 of white mice for every group, administration time 3 days, and it serves as effective bringing back to life existence and reply the normal activity ability with white mice.
The white mice of more than testing all is mices of testing used drug sensitivity pass the test in advance.The irritated incidence rate of statistics in process of the test.
Result of the test is as follows:
Medicine provided by the invention, curative effect improves greatly, and sensitization reduces greatly simultaneously.
Claims (2)
1. nanometer cytochrome liposome medicine, by the raw material of following parts by weight:
Neutral phospholipid 40-80,
Sitosterol 10-20,
Cholesterol 20-40,
Cytochrome C 10-30,
Polyethylene Glycol 20-25,
Reductive glutathione 5-10,
Vitamin C 40-50;
Be prepared from through the following step:
(1) dissolve cytochrome C, Polyethylene Glycol, reductive glutathione and the vitamin C of described amount with phosphate buffer, make solution,
(2) the solution ultra filtration molecular cut off 13000 daltonian filter membranes that step (1) made are got filtrate,
(3) dissolve neutral phospholipid, sitosterol, the cholesterol of described amount with the chloroform/methanol mixed liquor of 2: 1 volume mixture, make solution,
(4) solution that step (3) is made filters molecular cut off 5000 daltonian filter membranes, gets filtrate,
(5) filtrate evaporate to dryness in Rotary Evaporators that step (4) is made makes liposome membrane,
(6) under nitrogen protection, get the liposome membrane of filtrate hydration step (5) preparation of step (2) preparation, make the nano liposome medicament carrier particle dispersion liquid of particle diameter 50-120nm,
(7) make acceptable dosage form on the pharmaceutics;
Wherein, described neutral phospholipid is meant hydrogenated soy phosphatidyl choline and cephalin weight ratio 1-3: 1 mixture, and described sitosterol is meant cupreol, described Polyethylene Glycol is meant Macrogol 4000.
2. according to the described medicine of claim 1, it is characterized in that the acceptable dosage form is meant small-volume injection or lyophilized injection on the described pharmaceutics.
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| Application Number | Priority Date | Filing Date | Title |
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| CN200710086421A CN101019836B (en) | 2007-03-08 | 2007-03-08 | Nanometer cytochrome liposome medicine and its preparation |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710086421A CN101019836B (en) | 2007-03-08 | 2007-03-08 | Nanometer cytochrome liposome medicine and its preparation |
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| CN101019836A CN101019836A (en) | 2007-08-22 |
| CN101019836B true CN101019836B (en) | 2010-05-26 |
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Families Citing this family (3)
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| CN103055305B (en) * | 2012-12-27 | 2014-06-18 | 马鞍山丰原制药有限公司 | A lyophilized preparation of a cytochrome C-containing pharmaceutical composition for injection and a preparation method thereof |
| CN104799430A (en) * | 2015-03-26 | 2015-07-29 | 江南大学 | Long-circulating lipidosome as well as preparation method and application thereof |
| UA119921C2 (en) | 2017-10-31 | 2019-08-27 | Консорціум "Укріндустрія" | METHOD OF OBTAINING PHARMACOLOGICALLY ACTIVE COMPLEX OF LIPOSOMAL CYTOCHROME WITH NITROGEN OXIDE |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1087544A (en) * | 1992-12-03 | 1994-06-08 | 张国财 | A kind of preparation method for the treatment of hepatitis B medicament |
| RU2110990C1 (en) * | 1994-07-14 | 1998-05-20 | Российский научно-исследовательский институт гематологии и трансфузиологии | Liposomal vesicle with cytochrome c |
| WO2003059279A2 (en) * | 2002-01-09 | 2003-07-24 | Elan Pharmaceuticals, Inc. | Efficient liposomal encapsulation under mild conditions |
| CN1861193A (en) * | 2006-01-17 | 2006-11-15 | 四川大学 | Kidney target precursor medicine, said prepn., its preparing method and application |
-
2007
- 2007-03-08 CN CN200710086421A patent/CN101019836B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1087544A (en) * | 1992-12-03 | 1994-06-08 | 张国财 | A kind of preparation method for the treatment of hepatitis B medicament |
| RU2110990C1 (en) * | 1994-07-14 | 1998-05-20 | Российский научно-исследовательский институт гематологии и трансфузиологии | Liposomal vesicle with cytochrome c |
| WO2003059279A2 (en) * | 2002-01-09 | 2003-07-24 | Elan Pharmaceuticals, Inc. | Efficient liposomal encapsulation under mild conditions |
| CN1861193A (en) * | 2006-01-17 | 2006-11-15 | 四川大学 | Kidney target precursor medicine, said prepn., its preparing method and application |
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| CN101019836A (en) | 2007-08-22 |
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