CN103599077A - Freeze-dried powder of pravastatin sodium composition for injection - Google Patents
Freeze-dried powder of pravastatin sodium composition for injection Download PDFInfo
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- CN103599077A CN103599077A CN201310481509.8A CN201310481509A CN103599077A CN 103599077 A CN103599077 A CN 103599077A CN 201310481509 A CN201310481509 A CN 201310481509A CN 103599077 A CN103599077 A CN 103599077A
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- pravastatin sodium
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Abstract
The invention provides a freeze-dried powder of a pravastatin sodium composition for injection, and relates to the technical field of medicines and medicine production. The freeze-dried powder comprises the following raw materials by weight: 1 part of pravastatin sodium, 0.2-1.4 parts of chitosan nanoparticles and 100-200 parts of water for injection. The freeze-dried powder has the advantages that (1) chitosan, as a cosolvent, can increase solubility of pravastatin sodium in water and shorten dissolution time, and is helpful for clinical application; (2) the composition can significantly enhance a lipid-decreasing of pravastatin sodium, reduce usage amount of pravastatin sodium clinically and alleviate adverse effects of pravastatin sodium; in-vitro experiments demonstrate that the lipid-decreasing capacity of 10 mg of the freeze-dried powder of pravastatin sodium composition comprising the chitosan nanoparticles is equivalent to that of 20 mg of pravastatin sodium with no chitosan nanoparticles; and (3) chitosan nanoparticles can replace mannitol to be used as a freeze-drying skeleton agent, so that active effects of mannitol to a human body can be eliminated.
Description
Technical field:
The present invention relates to medicine and medicine manufacture technology field, relate in particular to a kind of injection pravastatin sodium composition freeze-dried powder.
Background technology:
Pravastatin sodium is the competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), HMG-CoA reductase is the rate-limiting enzyme of Biosynthesis of cholesterol initial stage, this product reversibly suppresses HMG-CoA reductase, thereby the biosynthesis that suppresses cholesterol, its chemical structural formula as shown in the formula.
Pravastatin sodium is to study in the world at present the most extensively, and clinical practice obtains the maximum hypolipidemic of experience.In a series of clinical trials, to there being the patients with coronary artery disease of hypercholesterolemia can lower cardiovascular event danger, slow down atherosclerotic progress.Western Scotland chd prevention research (WOS test) confirmation, pravastatin sodium can reduce hypercholesterolemia patient myocardial infarction and the dead danger for the first time without coronary heart disease, and its outstanding clinical effectiveness is the just demonstrations in 6 months that start in treatment.To cholesterol and time, the research of recurrence shows, pravastatin is unique confirmation after deliberation to reducing the normal patients with coronary heart disease cardiovascular diseases of cholesterol levels, can reduce the HMG-CoA reductase inhibitor that apoplexy is caused danger.
But, stability test by pravastatin in conditions simulated in vivo is pointed out, the ordinary preparation pravastatin of oral pravastatin may quite a few be converted into the different pravastatin of 3 ' A-under the effect of gastric acid (pH value scope is between 0～4), its biological activity only has 1/40～1/10 of parent, thereby reduces the bioavailability of pravastatin.
Chitosan is a kind of aminopolysaccharide polymer, is that the chitin by natural non-activity obtains after deacetylation.Structure and the cellulose of chitosan are quite similar, and just the acetylamino on sugar ring C2 has replaced hydroxyl, and this acetylamino gives chitosan special characteristic, make it can be for pharmaceutical preparation aspect, and its chemical constitution is as above formula.
The ill reason of hyperlipidemia is the acidic materials accumulations in vivo such as fatty acid, cholesterol.Bile acid in chitosan energy and in body, reduces generation and the absorption of body to cholesterol of cholesterol; Can strong adsorption harmful fat, makes liparitosis by body, do not digested and not assimilated and to be excreted, and reduces serum triglycerides content, effectively prevents and improves cardiovascular and cerebrovascular disease; It also has stronger selection absorption and dual regulation to lipoprotein, can reduce ldl concn, improves high-density lipoprotein concentration.And the transcribing of relevant enzyme and albumen in the chitosan energy regulating lipid metabolism process of part vivo degradation; Strengthen activities of antioxidant enzymes, thereby effectively reduce body fat level, research finds that the chitosan lipid-lowering effect of deacetylation 90%, relative molecular mass 4.99 * 105 is best.
Chitosan nano is the microgranule that a kind of particle diameter is less than 100nm, can not only overcome the water-insoluble characteristic of chitosan itself, and has slow release and targeting as a kind of pharmaceutical carrier, also there is no clinically the pharmaceutical dosage form of chitosan-containing nanoparticle at present.
Summary of the invention:
The invention provides a kind of injection pravastatin sodium composition freeze-dried powder, said composition principal agent is: pravastatin sodium, chitosan nano, and described injection pravastatin sodium composition freeze-dried powder effect for reducing fat strengthens, and dissolubility strengthens, and solubility is good.
Technical problem to be solved by this invention realizes by the following technical solutions.
The invention provides pravastatin sodium composition, the prescription of said composition consists of pravastatin sodium, chitosan nano, water for injection (need in prescription remove solvent), it is characterized in that: chitosan nano can be used as synergist, cosolvent, the skeleton agent (chitosan nano itself has certain blood fat reducing ability, plays collaborative effect for reducing fat after combining with pravastatin sodium) of pravastatin sodium.
An injection pravastatin sodium composition freeze-dried powder, is characterized in that, the material composition that comprises following weight portion:
1 part of pravastatin sodium
0.2～1.4 part of chitosan nano
100 parts～200 parts of waters for injection
Preferred weight part of described material composition is:
1 part of pravastatin sodium
0.7～0.9 part of chitosan nano
100 parts～200 parts of waters for injection
In addition, the present invention also provides a kind of preparation method of injection pravastatin sodium composition freeze-dried powder, it is characterized in that, comprises the steps:
(1) preparation of chitosan nano:
1, will after the chitosan powder pulverizing of deacetylation 90%, relative molecular mass 4.99 * 105, through 100 eye mesh screens, sieve;
2, the chitosan powder that takes 100g at room temperature (20 ℃) adds 0.1mol/l acetic acid solution 40L, and magnetic agitation, dissolves chitosan completely, obtains chitosan acetic acid solution (C=2.5g/L);
3, with 1%NaOH, regulate pH=5.0;
4, add 1% sodium tripolyphosphate 1667g to chitosan acetic acid solution under stirring, making chitosan/sodium tripolyphosphate mass ratio is 6:1, and the electrostatic interaction by zwitterion is cross-linked into nanoparticle;
5,, by 4 ℃ of high speed centrifugations of above-mentioned colloid solution (18000r/min) 30min, collect lower sediment, with after pure water washing 3 times, cooling final vacuum dry (30 ℃ following) obtains chitosan nano, moisture is lower than 2%, particle diameter≤100nm, and zeta current potential is about 15mv.
(2) preparation of injection pravastatin sodium composition freeze-dried powder:
1, the chitosan nano of recipe quantity is slowly joined in the water for injection of recipe quantity (theoretical loading amount 2ml/ props up), stir while adding to dissolving.
2, continue to add pravastatin sodium the extremely clarification of stirring and dissolving of recipe quantity.
3, with sodium hydroxide, adjust pH to 5.5～6.0, add the active carbon of water for injection volume 0.1% to stir 30 minutes; By titanium rod, carry out decarburization circulating filtration again, 30 minutes time; And then carry out degerming circulating filtration, 30 minutes time by 0.45 μ m, 0.22 μ m; Detect intermediate content, by pravastatin sodium, every bottle of 10mg calculates loading amount.
4, according to testing requirement fill, after half tamponade, send in freezer dryer, be cooled to-40 ℃, be incubated 2 as a child, be slowly warming up to-5 ℃～0 ℃ sublimation drying, then be warming up to after 35 ℃, be incubated 3 hours, lyophilization finishes, outlet.
Beneficial effect of the present invention is:
Inventor finds through test of many times, and pravastatin sodium and chitosan nano have collaborative effect for reducing fat, the compositions of mixing in specific proportions, and make injection freeze-dried powder and have the following advantages for tool as fat-reducing medicament:
(1) pravastatin sodium is slightly molten in water, chitosan makes pravastatin sodium composition can improve the dissolubility of pravastatin sodium in water and can shorten its dissolution time as cosolvent, and said composition pH is between 5.1～6.0, by drug administration by injection, can effectively avoid pravastatin sodium to be converted into the different pravastatin of 3 ' A-, be conducive to clinical practice;
(2) this compositions can significantly strengthen the lipid-lowering effect of pravastatin sodium, can reduce pravastatin sodium consumption clinically, alleviate pravastatin sodium untoward reaction, by experiment in vitro, prove that the 10mg pravastatin sodium composition lyophilized powder of chitosan-containing nanoparticle is suitable with the 20mg pravastatin sodium blood fat reducing ability of chitosan-containing nanoparticle not.
(3) the alternative mannitol of chitosan nano, as the lyophilizing skeleton agent of freeze-dried powder, has been eliminated the active function of mannitol to human body.
The specific embodiment:
Following examples are used for illustrating the present invention, yet these embodiment do not limit the scope of the invention.
The preparation of embodiment mono-, injection pravastatin sodium composition freeze-dried powder (specification: 10mg, in pravastatin sodium), in 1000.
1, prescription:
Pravastatin sodium 10g
Chitosan nano 8g
Water for injection 2000ml
2, preparation technology:
1) chitosan nano of 8g is slowly joined in the water for injection of recipe quantity (theoretical loading amount 2ml/ props up), stir while adding to dissolving.
2) continue to add pravastatin sodium the extremely clarification of stirring and dissolving of 10g.
3) with sodium hydroxide, adjust PH to 5.5～6.0, add the active carbon of water for injection volume 0.1% to stir 30 minutes; By titanium rod, carry out decarburization circulating filtration again, 30 minutes time; And then carry out degerming circulating filtration, 30 minutes time by 0.45 μ m, 0.22 μ m; Detect intermediate content, by pravastatin sodium, every bottle of 10mg calculates loading amount.
4) according to testing requirement fill, after half tamponade, send in freezer dryer, be cooled to-40 ℃, be incubated 2 as a child, be slowly warming up to-5 ℃～0 ℃ sublimation drying, then be warming up to after 35 ℃, be incubated 3 hours, lyophilization finishes, outlet.
The preparation of embodiment bis-, injection pravastatin sodium composition freeze-dried powder (specification: 10mg, in pravastatin sodium), in 1000.
1, prescription:
Pravastatin sodium 10g
Chitosan nano 9g
Water for injection 2000ml
2, preparation technology:
1) chitosan nano of 9g is slowly joined in the water for injection of recipe quantity (theoretical loading amount 2ml/ props up), stir while adding to dissolving.
2) continue to add pravastatin sodium the extremely clarification of stirring and dissolving of 10g.
3) with sodium hydroxide, adjust PH to 5.5～6.0, add the active carbon of water for injection volume 0.1% to stir 30 minutes; By titanium rod, carry out decarburization circulating filtration again, 30 minutes time; And then carry out degerming circulating filtration, 30 minutes time by 0.45 μ m, 0.22 μ m; Detect intermediate content, by pravastatin sodium, every bottle of 10mg calculates loading amount.
4) according to testing requirement fill, after half tamponade, send in freezer dryer, be cooled to-40 ℃, be incubated 2 as a child, be slowly warming up to-5 ℃～0 ℃ sublimation drying, then be warming up to after 35 ℃, be incubated 3 hours, lyophilization finishes, outlet.
The preparation of embodiment tri-, injection pravastatin sodium composition freeze-dried powder (specification: 10mg, in pravastatin sodium), in 1000.
1. write out a prescription:
Pravastatin sodium 10g
Chitosan nano 7g
Water for injection 2000ml
2. preparation technology:
1) chitosan nano of 7g is slowly joined in the water for injection of recipe quantity (theoretical loading amount 2ml/ props up), stir while adding to dissolving.
2) continue to add pravastatin sodium the extremely clarification of stirring and dissolving of 10g.
3) with sodium hydroxide, adjust PH to 5.5～6.0, add the active carbon of water for injection volume 0.1% to stir 30 minutes; By titanium rod, carry out decarburization circulating filtration again, 30 minutes time; And then carry out degerming circulating filtration, 30 minutes time by 0.45 μ m, 0.22 μ m; Detect intermediate content, by pravastatin sodium, every bottle of 10mg calculates loading amount.
4) according to testing requirement fill, after half tamponade, send in freezer dryer, be cooled to-40 ℃, be incubated 2 as a child, be slowly warming up to-5 ℃～0 ℃ sublimation drying, then be warming up to after 35 ℃, be incubated 3 hours, lyophilization finishes, outlet.
Embodiment tetra-: blood fat reducing animal model test
Comparison between the pravastatin sodium composition freeze-dried powder blood fat reducing ability that blood fat reducing animal model test is prepared for the embodiment of the present invention and pravastatin sodium, blank assay.
1 test method
Alloxan (alloxan) brings out Balb/c mice hyperlipidemia, set up the animal model of screening blood lipid-lowering medicine, then by test group medicine and blank group, respectively mice is carried out to administration 6 days, after the 4th day overnight fasting, IV alloxan 100mg/kg once, after 48h, broken end is got blood, measure serum triglycerides (TG), cholesterol (CHOL) and free fatty (FFA), then according to result, respectively organize the lipid-lowering effect between medicine.
2 test procedures
The foundation of animal test model: choose 40 of healthy Balb/c mice hyperlipidemia, be divided at random 4 groups (mono-group of embodiment, bis-groups of embodiment, pravastatin sodium group, blank groups), under 22～25 ℃ of conditions of room temperature, cultivate, after overnight fasting, give every mouse mainline alloxan, dosage is 110mg/kg, continuous four days, set up animal model.
Administration: carry out administration to respectively every group of 10 mices, mono-group of vein of embodiment gives embodiment mono-composite freeze-dried powder, and dosage is 2mg/ time, once a day; Bis-groups of veins of embodiment give embodiment bis-composite freeze-dried powders, and dosage is 2mg/ time, once a day; Pravastatin sodium group is oral gives pravastatin sodium sheet 4mg/ time (in pravastatin), once a day; Blank group vein gives water for injection 2ml/ time, once a day.Every group is administration in continuous 6 days, and in the 4th day every group of mice overnight fasting posterior vein injection alloxan 100mg/kg once, after 48h, broken end is got blood, measures serum triglycerides (TG), cholesterol (CHOL) and free fatty (FFA) level.
3 interpretations of result
Measurement result sees the following form.
Table 1 is serum triglycerides (TG), cholesterol (CHOL) and free fatty (FFA) level of fat-reducing medicament (IVorPO6d) in Balb/c mouse model relatively
As can be seen from the above table, the serum triglycerides of pravastatin sodium group (TG), cholesterol (CHOL) and free fatty (FFA) are compared bis-groups of the decline level of matched group and mono-group of embodiment and embodiment and are equal to, and result can point out the 2mg pravastatin sodium composition lyophilized powder of chitosan-containing nanoparticle suitable with the 4mg pravastatin sodium blood fat reducing ability of chitosan-containing nanoparticle not.
More than show and described ultimate principle of the present invention, principal character and advantage of the present invention.The technical staff of the industry should understand; the present invention is not restricted to the described embodiments; what in above-described embodiment and description, describe is only preference of the present invention; be not used for limiting the present invention; without departing from the spirit and scope of the present invention; the present invention also has various changes and modifications, and these changes and improvements all fall in the claimed scope of the invention.The claimed scope of the present invention is defined by appending claims and equivalent thereof.
Claims (2)
1. an injection pravastatin sodium composition freeze-dried powder, is characterized in that, the material composition that comprises following weight portion:
2. a preparation method for injection pravastatin sodium composition freeze-dried powder described in claim 1, is characterized in that, comprises the steps:
(1) preparation of chitosan nano:
(1) will after the chitosan powder pulverizing of deacetylation 90%, relative molecular mass 4.99 * 105, through 100 eye mesh screens, sieve;
(2) the chitosan powder that takes 100g at room temperature adds 0.1mol/l acetic acid solution 40L, and magnetic agitation, dissolves chitosan completely, obtains chitosan acetic acid solution;
(3) with 1%NaOH, regulate pH=5.0;
(4) add 1% sodium tripolyphosphate 1667g to chitosan acetic acid solution under stirring, making chitosan/sodium tripolyphosphate mass ratio is 6:1, and the electrostatic interaction by zwitterion is cross-linked into nanoparticle;
(5) by 4 ℃ of high speed centrifugation 30min of above-mentioned colloid solution, collect lower sediment, with after pure water washing 3 times, the dry chitosan nano that obtains of cooling final vacuum, moisture is lower than 2%, particle diameter≤100nm, zeta current potential is about 15mv;
(2) preparation of injection pravastatin sodium composition freeze-dried powder:
(1) chitosan nano of recipe quantity is slowly joined in the water for injection of recipe quantity, stir while adding to dissolving;
(2) continue to add pravastatin sodium the extremely clarification of stirring and dissolving of recipe quantity;
(3) with sodium hydroxide, adjust pH to 5.5～6.0, add the active carbon of water for injection volume 0.1% to stir 30 minutes; By titanium rod, carry out decarburization circulating filtration again, 30 minutes time; And then carry out degerming circulating filtration, 30 minutes time by 0.45 μ m, 0.22 μ m; Detect intermediate content, by pravastatin sodium, every bottle of 10mg calculates loading amount;
(4) according to testing requirement fill, after half tamponade, send in freezer dryer, be cooled to-40 ℃, be incubated 2 as a child, be slowly warming up to-5 ℃～0 ℃ sublimation drying, then be warming up to after 35 ℃, be incubated 3 hours, lyophilization finishes, outlet.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113133990A (en) * | 2021-03-29 | 2021-07-20 | 江苏宇锐医药科技有限公司 | Ezetimibe-containing compound preparation and preparation method thereof |
| WO2022259220A1 (en) * | 2021-06-10 | 2022-12-15 | S.I.I.T. s.r.l. - SERVIZIO INTERNAZIONALE IMBALLAGGI TERMOSALDANTI | Preparation in solid form comprising activated carbon and chitosan, method for preparing said preparation, composition comprising said preparation and uses of said composition |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US20070237827A1 (en) * | 2005-01-04 | 2007-10-11 | Hsing-Wen Sung | Nanoparticles for drug delivery |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070237827A1 (en) * | 2005-01-04 | 2007-10-11 | Hsing-Wen Sung | Nanoparticles for drug delivery |
Non-Patent Citations (1)
| Title |
|---|
| 刘慧: "壳聚糖微球/纳米粒的制备及其性能研究", 《中国优秀硕士学位论文全文数据库 工程科技I辑》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113133990A (en) * | 2021-03-29 | 2021-07-20 | 江苏宇锐医药科技有限公司 | Ezetimibe-containing compound preparation and preparation method thereof |
| WO2022259220A1 (en) * | 2021-06-10 | 2022-12-15 | S.I.I.T. s.r.l. - SERVIZIO INTERNAZIONALE IMBALLAGGI TERMOSALDANTI | Preparation in solid form comprising activated carbon and chitosan, method for preparing said preparation, composition comprising said preparation and uses of said composition |
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Application publication date: 20140226 |