CN102188395B - Stable meropenem injection and preparation method thereof - Google Patents
Stable meropenem injection and preparation method thereof Download PDFInfo
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- CN102188395B CN102188395B CN 201110109505 CN201110109505A CN102188395B CN 102188395 B CN102188395 B CN 102188395B CN 201110109505 CN201110109505 CN 201110109505 CN 201110109505 A CN201110109505 A CN 201110109505A CN 102188395 B CN102188395 B CN 102188395B
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Abstract
The invention provides a stable meropenem injection and a preparation method thereof. The injection is liposome freeze-dried preparation, which comprises the following components by weight: 5 to 15 parts of meropenem, 80 to 160 parts of phosphatide, 50 to 110 parts of cholesterol, 0.15 to 0.50 parts of vitamin E, 300 to 550 parts of sodium deoxycholate, and 30 to 100 parts of sugar. The liposome freeze-dried preparation provided in the invention has advantages of small particle size, high entrapment rate, low percolation rate, and good stability. Therefore, a problem of instability of ordinary powder injection under a room temperature during long time infusion can be solved, and thus the stable meropenem injection is suitable for clinical practice.
Description
Technical field
The present invention relates to antibiotic field of pharmaceutical preparations, be specifically related to a kind of more stable meropenem injection and method for making thereof.
Background technology
Meropenem (Meropenem), shown in I, chemical name is: 3-[[5-[(dimethylamino) carbonyl]-3-pyrrolidinyl] sulfo-]-6-(1-ethoxy)-4-methyl-7-oxo-1-azabicyclo [3,2,0] hept-2-ene"-2-carboxylic acid.Molecular formula: C
17H
25N
3O
5S, molecular weight: 383.46.
Formula I
Meropenem is a carbapenem antibiotic, and Italy is with trade name Merrem at first listing in 1994.Construction features is on 1 of carbapenem ring, to introduce methyl, thereby dehydropeptidase of kidney-1 (DHP-1) is had very high stability, becomes first carbapenem antibiotic that does not need adapted kidney protective agent just can use separately.Antimicrobial spectrum, antibacterial activity are all similar with imipenum, and post antibiotic effect is arranged.Meropenem is to G
-Bacterium and the high 2-16 of anaerobe specific activity imipenum times, imipenum is to G
+The bacterium activity is 2-4 a times of meropenem.Meropenem is applicable to that adult and child by the single or multiple bacterial infection responsive to meropenem, comprise pulmonary infection (comprising nosocomial pneumonia), urinary tract infection, gynecological infection (like endometritis and pelvic inflammatory disease), abdominal cavity infection, skin soft-tissue infection, meningitis, septicemia.
And imipenum need be united use with cilastatin, can cause central nervous system's untoward reaction when dosage is higher, like convulsions, tic, headache etc., particularly is prone among the patient of central nervous system disease take place with having at those impaired renal functions; But meropenem is less to central nervous system's toxicity, thereby can be used for central nervous system infection patients such as meningitis.
The 30min intravenous drip is adopted in the medication of meropenem tradition more, but along with the deepening continuously of pharmacokinetics and pharmacodynamics (PK/PD) theoretical research in recent years, finds to prolong administration time and can more effectively bring into play its curative effect.Belong to the time dependence antibacterials mainly due to meropenem; It (is %T＞MIC) that this type of medicine bactericidal effect depends primarily on the time that blood drug level surpasses the minimal inhibitory concentration (MIC) of institute directed toward bacteria; Little with blood peak concentration of drug (Cmax) relation; And the prolongation administration time can increase antibacterials concentration to maintain the time on the MIC, strengthens antibacterial effect.
Can or prolong administration time even the lasting infusion of antibacterials, the optimum curative effect of performance antibacterials through the repeated multiple times administration clinically.For the Pseudomonas aeruginosa that higher MIC is arranged, than the lasting 4h intravenous drip of low dosage meropenem, obtained the good clinical curative effect in clinical use, bacteria clearance, clinical improvement rate and relapse rate are higher than the more heavy dose of scheme of tradition.
In addition, meropenem to GPC and gram negative bacilli all have in various degree post antibiotic effect (PAEs) (2.2-3.5h), the administration interval of proper extension meropenem, when guaranteeing curative effect, also can reduce untoward reaction and expense.Aspect the treatment meningitis, lasting intravenously administrable can make meropenem in cerebrospinal fluid, reach bacteriocidal concentration especially.
The injectable powder that the meropenem injection that goes on the market at present is made up of meropenem and natrium carbonicum calcinatum; Need before the injection with 0.9% sodium chloride injection or glucose injection elder generation wiring solution-forming; But this solution is (10-25 ℃) less stable at room temperature; Only can stablize 3-4h, SM need carry out at low temperatures, has limited the application of this medicine aspect clinical continuous transfusion widely.
Therefore, a kind of technical scheme that can solve the problem of meropenem injection poor stability need be provided.
Discover, liposome technology is applied in the meropenem injection, can significantly improve the instability problem that exists in the clinical practice.
Liposomal formulation is a focus of domestic and international novel form research, has many-sided advantages such as targeting, reduction adverse effect.But its preparation difficulty is also very big, and low, the easy seepage equistability of ubiquity envelop rate problem.
Chinese patent CN101642431A discloses a kind of Ozagrel liposomes injection formula, by phospholipid, cholesterol, three kinds of combinations of materials of NaTDC, has obtained the Ozagrel liposomes more stable than conventional method.
Up to now, do not see the relevant report of meropenem lipidosome injection.
Summary of the invention
The object of the present invention is to provide a kind of meropenem injection of good stability.
Another object of the present invention provides a kind of method for preparing above-mentioned meropenem injection.
A kind of more stable meropenem injection provided by the invention; Said injection is a lipidosome freeze-dried preparation, is grouped into by the one-tenth of following weight portion: meropenem 5-15 part, phospholipid 80-160 part, cholesterol 50-110 part, vitamin E 0.15-0.50 part, NaTDC 300-550 part and sugared 30-100 part.
Preferably, the present invention is grouped into by the one-tenth of following weight portion: 30 parts of 8 parts of meropenems, 90 parts in phospholipid, 60 parts in cholesterol, 0.15 part of vitamin E, 300 parts of NaTDCs and sugar.
In the above-mentioned meropenem injection:
Said weight portion can be the known unit of weights of field of medicaments such as μ g, mg, g, kg;
Said phospholipid is selected from Ovum Gallus domesticus Flavus lecithin; Hydrogenated yolk lecithin; Two stearic acid lecithin; EPG; Egg yolk lecithin acyl serine; Egg yolk lecithin acyl inositol; Soybean lecithin; Hydrogenated soy phosphatidyl choline; Two palmitic acid lecithin; Two myristic acid lecithin; Two myristic acid phosphatidyl glycerols; The dilaurate phosphatidyl glycerol; Two stearic acid phosphatidyl glycerols; Two Semen Myristicaes are calculated phosphatidic acid; Two stearic acid phosphatidic acid; The dilaurate phosphatidic acid; Two palmitic acid phosphatidic acid; In two oleic acid Phosphatidylserine or the dilinoleic acid phosphatidylinositols one or more.
Phospholipid is preferably Ovum Gallus domesticus Flavus lecithin and two stearic acid phosphatidyl glycerols.
Add a certain amount of NaTDC in the liposome prescription of the present invention; Become the part of liposome membrane when cholate; The existence meeting of cholate is the stabilized liposome vesicle to a certain extent, and the medicine that wraps up in the liposome is played stronger protective effect, and stability significantly improves; Envelop rate improves, permeability reduction.
Also adding a certain amount of antioxidant in the liposome of the present invention prescription is vitamin E, purpose be for suppress or the liposome that slows down in the oxidation reaction of phospholipid etc., reduce permeability.
Said sugar is selected from glucose, lactose or trehalose, is preferably glucose, and as freeze drying protectant, the liposome encapsulation that makes is high by these sugar, and particle diameter is evenly distributed for a short time, and outward appearance is good.
The present invention also provides the method for preparing above-mentioned meropenem injection, may further comprise the steps:
1) preparation of blank liposome: take by weighing phospholipid, cholesterol, vitamin E and the NaTDC of said amount, add an amount of chloroform-dehydrated alcohol mixed solvent dissolving, remove solvent under reduced pressure; Process even exsiccant lipid membrane; Add 0.1mol/L citric acid-sodium citrate buffer then, make the complete aquation of lipid membrane, then through after the high pressure homogenize emulsifying; Through the filtering with microporous membrane of 0.8 and 0.45 μ m, promptly get blank liposome turbid liquor successively;
2) preparation contains the liposome of meropenem: meropenem is dissolved in the water for injection; Then the blank liposome suspension slowly is added drop-wise in the meropenem medicinal liquid; And, be incubated 20 minutes down at 40-50 ℃ with 0.2mol/L phosphate buffer adjusting pH to 7.0, promptly get the pastille liposome;
3) preparation meropenem liposome turbid liquor: by weight compound concentration is that the sugar aqueous solution of 5-10% and the glycine solution that adds 2.5mol/L are regulated pH value to 6.0-6.5; Get Liposomal dispersion; Use this dispersion liquid washing step 2 then) preparation the pastille liposome, make the meropenem liposome solutions be replaced into the meropenem liposome turbid liquor of pH value 6.0-6.5;
4) standardize solution, degerming, packing, lyophilizing: add injection water standardize solution, the meropenem liposome suspension is used the filtering with microporous membrane degerming, packing, lyophilization gets finished product.
In order further to understand the present invention, down in the face of the partial content of the present invention explanation that makes an explanation, but should not be construed as limiting the invention, in above-mentioned described method for preparing:
Said chloroform-dehydrated alcohol mixed solvent is to be 1.1-15 with dehydrated alcohol according to volume ratio with chloroform: 1 mixes;
Said step 1) adds 0.1mol/L citric acid-sodium citrate buffer, makes pH value be controlled at 3.0-4.0;
Said high pressure homogenize emulsifying be adopt high pressure homogenizer with above-mentioned blank liposome suspension under 110-120MPa pressure; Homogenizing 5 times; The mean diameter of gained liposome is 100-120nm; Narrow diameter distribution, between 60-250nm, the liposome particle diameter and the uniformity can detect with multi-angle nanoparticle analyzer.
Meropenem injection provided by the invention has the following advantages with respect to prior art:
1) compares with the common flour injection (occurring unstable in 4 hours) of listing; The meropenem lipidosome freeze-dried preparation that contains NaTDC and vitamin E is after being configured to transfusion; The stability of at room temperature placing is greatly enhanced; Can stablize more than 12 hours, and its stability also is superior to not containing the meropenem lipidosome freeze-dried preparation (8 hours occur unstable) of NaTDC and vitamin E and does not contain the transfusion (occurring unstable in 12 hours) that the meropenem lipidosome freeze-dried preparation of vitamin E is configured to;
2) it is little to contain the mean diameter of meropenem lipidosome freeze-dried preparation of NaTDC and vitamin E; Envelop rate is high; Percolation ratio is low; Quality obviously is superior to not containing the meropenem lipidosome freeze-dried preparation of NaTDC and vitamin E, and stability is better, also is superior to not containing simultaneously the meropenem lipidosome freeze-dried preparation of vitamin E;
3) the meropenem lipidosome freeze-dried preparation that contains NaTDC and vitamin E provided by the invention; The problem of unstable that has been occurred when having solved the at room temperature long-time infusion of this medicine; Have conspicuous effect, this provides better choice for meropenem in the application aspect the clinical continuous transfusion;
4) adopt general liposome membrane material phospholipid and cholesterol commonly used, bad according to the meropenem lipidosome freeze-dried preparation stability that conventional proportioning obtains, envelop rate is low, occurs seepage easily.The inventor is surprised to find that the meropenem liposome freeze-drying powder injection that adopts phospholipid, cholesterol, vitamin E and these four kinds of materials of NaTDC to be mixed with according to special ratios through long-term big quantity research, and stability significantly improves; Possibly mainly be because these four kinds of synergistic results of material; Adding percentage by weight is the NaTDC of 10-16%, and the stabilized liposome vesicle plays stronger protective effect to the medicine that wraps up in the liposome to a certain extent; The cholesterol that in the liposome bilayer, adds percentage by weight and be 2-4% fully solidifies film; Reduce the generation of free radical, reduce the oxidation level of phospholipid molecule, improved stability.Add cholesterol and vitamin E simultaneously and can bring into play collaborative antioxidation, reach better stablizing effect, thereby avoided a series of denaturalization phenomenons of causing owing to drug leakage.Selection for phospholipid; Because Ovum Gallus domesticus Flavus lecithin belongs to neutral phospholipid; Two stearic acid phosphatidyl glycerols belong to negative charge phospholipid, after the two stearic acid phosphatidyl glycerols of adding make film electronegative in bilayer, also can reduce phospholipid oxidation; And because of causing after charged that the liposome ball repels each other, and then improved the envelop rate of liposome.Based on above composition and proportioning thereof, finally obtained stable good meropenem lipidosome freeze-dried preparation;
5) in method for preparing:
Because meropenem has good stability under acid condition, alkali condition under degradation reaction can take place, thereby in the preparation process, the pH that pays special attention to environment controls, guaranteeing the stability of product, such as:
In step 2) when preparation contains the liposome of meropenem; Selecting for use the 0.2mol/L phosphate buffer to regulate pH, mainly is because in the liposome hatching process, pH can have influence on the stability of meropenem; PH value is adjusted to 7.0; The stability of solution that contains meropenem that obtains is best, but also has guaranteed to have enough pH gradients to guarantee hatching effect, so the present invention finally selects to regulate pH to 7.0 with the 0.2mol/L phosphate buffer;
The glycine solution that in step 3), adds 2.5mol/L in the sugar aqueous solution is regulated pH value to 6.0-6.5; Have good stability under acid condition mainly due to meropenem; Under the alkali condition degradation reaction can take place, thereby in sugar aqueous solution, add buffer agent glycine solution adjusting pH value to slant acidity environment;
The final meropenem lipidosome freeze-dried preparation that obtains excellent in stability.
The specific embodiment
Following examples are used to explain the present invention, but are not used for limiting scope of the present invention.
Embodiment 1: the meropenem liposome freeze-drying powder injection
1, prescription:
| Component | Weight | Percentage by weight (%) |
| Meropenem | 8g | 0.27 |
| Ovum Gallus domesticus Flavus lecithin | 60g | 2.01 |
| Two stearic acid phosphatidyl glycerols | 30g | 1.00 |
| Cholesterol | 60g | 2.01 |
| Vitamin E | 150mg | 0.01 |
| NaTDC | 300g | 10.04 |
| Glucose | 30g | 1.00 |
| Water for injection | 2500g | 83.66％ |
2, preparation technology
1) preparation of blank liposome: take by weighing the Ovum Gallus domesticus Flavus lecithin of said amount, two stearic acid phosphatidyl glycerol, cholesterol, vitamin E and NaTDC; Add an amount of chloroform-dehydrated alcohol mixed solvent (volume ratio 7: 1) dissolving; Remove solvent under reduced pressure, process even exsiccant lipid membrane, the citric acid-sodium citrate buffer that adds 0.1mol/L is then regulated pH to 3.2; Make the complete aquation of lipid membrane; Through after the high pressure homogenize emulsifying, through the filtering with microporous membrane of 0.8 and 0.45 μ m, promptly get blank liposome turbid liquor successively then;
2) preparation contains the liposome of meropenem: meropenem is dissolved in the water for injection; Then the blank liposome suspension slowly is added drop-wise in the meropenem medicinal liquid; And, be incubated 20 minutes down at 46 ℃ with 0.2mol/L phosphate buffer adjusting pH to 7.0, promptly get the pastille liposome;
3) preparation meropenem liposome turbid liquor: regulate pH value to 6.0 by weight the D/W of preparation 8% and the glycine solution that adds 2.5mol/L; Get Liposomal dispersion; With this dispersion liquid washing pastille liposome, make the meropenem liposome solutions be replaced into the meropenem liposome turbid liquor of pH value 6.0 then.
4) standardize solution, degerming, packing, lyophilizing: add the injection water and be settled to 2500ml, the meropenem liposome suspension is used the filtering with microporous membrane degerming, packing, lyophilization gets finished product.
Comparative Examples 1A: the meropenem lipidosome freeze-dried preparation that does not contain NaTDC and vitamin E
1, prescription:
| Component | Weight | Percentage by weight (%) |
| Meropenem | 8g | 0.30％ |
| Ovum Gallus domesticus Flavus lecithin | 60g | 2.27％ |
| Two stearic acid phosphatidyl glycerols | 30g | 1.13％ |
| Cholesterol | 18g | 0.68％ |
| Glucose | 30g | 1.13％ |
| Water for injection | 2500g | 94.48％ |
2, preparation technology:, make the meropenem lipidosome freeze-dried preparation that does not contain NaTDC and vitamin E with embodiment 1.
Comparative Examples 1B: the meropenem lipidosome freeze-dried preparation that does not contain vitamin E
1, prescription:
| Component | Weight | Percentage by weight (%) |
| Meropenem | 8g | 0.27％ |
| Ovum Gallus domesticus Flavus lecithin | 60g | 2.01％ |
| Two stearic acid phosphatidyl glycerols | 30g | 1.00％ |
| Cholesterol | 60g | 2.01％ |
| NaTDC | 300g | 10.04％ |
| Glucose | 30g | 1.00％ |
| Water for injection | 2500g | 83.67％ |
2, preparation technology:, make the meropenem lipidosome freeze-dried preparation that does not contain vitamin E with embodiment 1.
Embodiment 2: the meropenem liposome freeze-drying powder injection
1, prescription:
| Component | Weight | Percentage by weight (%) |
| Meropenem | 13g | 0.39％ |
| Soybean lecithin | 100g | 3.00％ |
| Two stearic acid phosphatidyl glycerols | 55g | 1.65％ |
| Cholesterol | 103g | 3.09％ |
| Vitamin E | 250mg | 0.01％ |
| NaTDC | 515g | 15.44％ |
| Glucose | 50g | 1.50％ |
| Water for injection | 2500g | 74.93％ |
2, preparation technology
1) preparation of blank liposome: take by weighing the soybean lecithin of said amount, two stearic acid phosphatidyl glycerol, cholesterol, vitamin E and NaTDC; Add an amount of chloroform-dehydrated alcohol mixed solvent (volume ratio 5: 1) dissolving; Remove solvent under reduced pressure, process even exsiccant lipid membrane, add 0.1mol/L citric acid-sodium citrate buffer then and regulate pH to 3.9; Make the complete aquation of lipid membrane; Through after the high pressure homogenize emulsifying, through the filtering with microporous membrane of 0.8 and 0.45 μ m, promptly get blank liposome turbid liquor successively then;
2) preparation contains the liposome of meropenem: meropenem is dissolved in the water for injection; Then the blank liposome suspension slowly is added drop-wise in the meropenem medicinal liquid; And, be incubated 20 minutes down at 48 ℃ with 0.2mol/L phosphate buffer adjusting pH to 7.0, promptly get the pastille liposome;
3) preparation meropenem liposome turbid liquor: regulate pH value to 6.3 by weight the D/W of preparation 8% and the glycine solution that adds 2.5mol/L; Get Liposomal dispersion; With this dispersion liquid washing pastille liposome, make the meropenem liposome solutions be replaced into the meropenem liposome turbid liquor of pH value 6.3 then.
4) standardize solution, degerming, packing, lyophilizing: add the injection water and be settled to 2500ml, the meropenem liposome suspension is used the filtering with microporous membrane degerming, packing, lyophilization gets finished product.
Comparative Examples 2A: the meropenem lipidosome freeze-dried preparation that does not contain NaTDC and vitamin E
1, prescription:
| Component | Weight | Percentage by weight (%) |
| Meropenem | 13g | 0.47％ |
| Soybean lecithin | 100g | 3.64％ |
| Two stearic acid phosphatidyl glycerols | 55g | 2.00％ |
| Cholesterol | 31g | 1.13％ |
| Glucose | 50g | 1.82％ |
| Water for injection | 2500g | 90.94％ |
2, preparation technology:, make the meropenem lipidosome freeze-dried preparation that does not contain NaTDC and vitamin E with embodiment 2.
Comparative Examples 2B: the meropenem lipidosome freeze-dried preparation that does not contain vitamin E
1, prescription:
| Component | Weight | Percentage by weight (%) |
| Meropenem | 13g | 0.39％ |
| Soybean lecithin | 100g | 3.00％ |
| Two stearic acid phosphatidyl glycerols | 55g | 1.65％ |
| Cholesterol | 103g | 3.09％ |
| NaTDC | 515g | 15.44％ |
| Glucose | 50g | 1.50％ |
| Water for injection | 2500g | 74.94％ |
2, preparation technology:, make the meropenem lipidosome freeze-dried preparation that does not contain vitamin E with embodiment 2.
Embodiment 3: the meropenem liposome freeze-drying powder injection
1, prescription:
| Component | Weight | Percentage by weight (%) |
| Meropenem | 13g | 0.40％ |
| Ovum Gallus domesticus Flavus lecithin | 96g | 2.92％ |
| Two myristic acid phosphatidyl glycerols | 50g | 1.52％ |
| Cholesterol | 97.5g | 2.96％ |
| Vitamin E | 500mg | 0.02％ |
| NaTDC | 487.5g | 14.81％ |
| Glucose | 46.25g | 1.41％ |
| Water for injection | 2500g | 75.97％ |
2, preparation technology
1) preparation of blank liposome: take by weighing the Ovum Gallus domesticus Flavus lecithin of said amount, two myristic acid phosphatidyl glycerol, cholesterol, vitamin E and NaTDC; Add an amount of chloroform-dehydrated alcohol mixed solvent (volume ratio 5.5: 1) dissolving; Remove solvent under reduced pressure, process even exsiccant lipid membrane, add 0.1mol/L citric acid-sodium citrate buffer then and regulate pH to 3.6; Make the complete aquation of lipid membrane; Through after the high pressure homogenize emulsifying, through the filtering with microporous membrane of 0.8 and 0.45 μ m, promptly get blank liposome turbid liquor successively then;
2) preparation contains the liposome of meropenem: meropenem is dissolved in the water for injection; Then the blank liposome suspension slowly is added drop-wise in the meropenem medicinal liquid; And, be incubated 20 minutes down at 42 ℃ with 0.2mol/L phosphate buffer adjusting pH to 7.0, promptly get the pastille liposome;
3) preparation meropenem liposome turbid liquor: regulate pH value to 6.2 by weight the D/W of preparation 8% and the glycine solution that adds 2.5mol/L; Get Liposomal dispersion; With this dispersion liquid washing pastille liposome, make the meropenem liposome solutions be replaced into the meropenem liposome turbid liquor of pH value 6.2 then.
4) standardize solution, degerming, packing, lyophilizing: add the injection water and be settled to 2500ml, the meropenem liposome suspension is used the filtering with microporous membrane degerming, packing, lyophilization gets finished product.Comparative Examples 3A: the meropenem lipidosome freeze-dried preparation that does not contain NaTDC and vitamin E
1, prescription:
| Component | Weight | Percentage by weight (%) |
| Meropenem | 13g | 0.48％ |
| Ovum Gallus domesticus Flavus lecithin | 96g | 3.51％ |
| Two myristic acid phosphatidyl glycerols | 50g | 1.83％ |
| Cholesterol | 29g | 1.06％ |
| Glucose | 46.25g | 1.69％ |
| Water for injection | 2500g | 91.43％ |
2, preparation technology:, make the meropenem lipidosome freeze-dried preparation that does not contain NaTDC and vitamin E with embodiment 3.
Comparative Examples 3B: the meropenem lipidosome freeze-dried preparation that does not contain vitamin E
1, prescription:
| Component | Weight | Percentage by weight (%) |
| Meropenem | 13g | 0.40％ |
| Ovum Gallus domesticus Flavus lecithin | 96g | 2.92％ |
| Two myristic acid phosphatidyl glycerols | 50g | 1.52％ |
| Cholesterol | 97.5g | 2.96％ |
| NaTDC | 487.5g | 14.82％ |
| Glucose | 46.25g | 1.41％ |
| Water for injection | 2500g | 75.98％ |
2, preparation technology:, make the meropenem lipidosome freeze-dried preparation that does not contain vitamin E with embodiment 3.
Embodiment 4: the meropenem lipidosome freeze-dried preparation
1, prescription:
| Component | Weight | Percentage by weight (%) |
| Meropenem | 12g | 0.38％ |
| Ovum Gallus domesticus Flavus lecithin | 96g | 3.04％ |
| Two stearic acid phosphatidyl glycerols | 48g | 1.52％ |
| Cholesterol | 80g | 2.53％ |
| Vitamin E | 250mg | 0.01％ |
| NaTDC | 360g | 11.41％ |
| Lactose | 60g | 1.90％ |
| Water for injection | 2500g | 79.21％ |
2, preparation technology
Operate with reference to embodiment 1 each step; Wherein step 3) prepares the meropenem liposome turbid liquor: be to regulate pH value to 6.0 by weight preparation 9% lactose aqueous solution and the glycine solution that adds 2.5mol/L; Get Liposomal dispersion; With this dispersion liquid washing pastille liposome, make the meropenem liposome solutions be replaced into the meropenem liposome turbid liquor of pH value 6.0 then.
Comparative Examples 4A: the meropenem lipidosome freeze-dried preparation that does not contain NaTDC and vitamin E
1, prescription:
| Component | Weight | Percentage by weight (%) |
| Meropenem | 12g | 0.44％ |
| Ovum Gallus domesticus Flavus lecithin | 96g | 3.50％ |
| Two stearic acid phosphatidyl glycerols | 48g | 1.75％ |
| Cholesterol | 24g | 0.88％ |
| Lactose | 60g | 2.19％ |
| Water for injection | 2500g | 91.24％ |
2, preparation technology:, make the meropenem lipidosome freeze-dried preparation that does not contain NaTDC and vitamin E with embodiment 4.
Comparative Examples 4B: the meropenem lipidosome freeze-dried preparation that does not contain vitamin E
1, prescription:
| Component | Weight | Percentage by weight (%) |
| Meropenem | 12g | 0.38％ |
| Ovum Gallus domesticus Flavus lecithin | 96g | 3.04％ |
| Two stearic acid phosphatidyl glycerols | 48g | 1.52％ |
| Cholesterol | 80g | 2.53％ |
| NaTDC | 360g | 11.41％ |
| Lactose | 60g | 1.90％ |
| Water for injection | 2500g | 79.21％ |
2, preparation technology:, make the meropenem lipidosome freeze-dried preparation that does not contain vitamin E with embodiment 4.
Embodiment 5: the meropenem lipidosome freeze-dried preparation
1, prescription:
| Component | Weight | Percentage by weight (%) |
| Meropenem | 10g | 0.32％ |
| Ovum Gallus domesticus Flavus lecithin | 78g | 2.47％ |
| Two stearic acid phosphatidyl glycerols | 42g | 1.33％ |
| Cholesterol | 75g | 2.38％ |
| Vitamin E | 500mg | 0.02％ |
| NaTDC | 360g | 11.41％ |
| Trehalose | 90g | 2.85％ |
| Water for injection | 2500g | 79.23％ |
2, preparation technology
Operate with reference to embodiment 1 each step; Wherein step 3) prepares the meropenem liposome turbid liquor: be to regulate pH value to 6.0 by weight preparation 6% aqueous trehalose solution and the glycine solution that adds 2.5mol/L; Get Liposomal dispersion; With this dispersion liquid washing pastille liposome, make the meropenem liposome solutions be replaced into the meropenem liposome turbid liquor of pH value 6.0 then.
Comparative Examples 5A: the meropenem lipidosome freeze-dried preparation that does not contain NaTDC and vitamin E
1, prescription:
| Component | Weight | Percentage by weight (%) |
| Meropenem | 10g | 0.36％ |
| Ovum Gallus domesticus Flavus lecithin | 78g | 2.84％ |
| Two stearic acid phosphatidyl glycerols | 42g | 1.53％ |
| Cholesterol | 21.82g | 0.80％ |
| Trehalose | 90g | 3.28％ |
| Water for injection | 2500g | 91.18％ |
2, preparation technology:, make the meropenem lipidosome freeze-dried preparation that does not contain NaTDC and vitamin E with embodiment 5.
Comparative Examples 5B: the meropenem lipidosome freeze-dried preparation that does not contain vitamin E
1, prescription:
| Component | Weight | Percentage by weight (%) |
| Meropenem | 10g | 0.32％ |
| Ovum Gallus domesticus Flavus lecithin | 78g | 2.47％ |
| Two stearic acid phosphatidyl glycerols | 42g | 1.33％ |
| Cholesterol | 75g | 2.38％ |
| NaTDC | 360g | 11.41％ |
| Trehalose | 90g | 2.85％ |
| Water for injection | 2500g | 79.24％ |
2, preparation technology:, make the meropenem lipidosome freeze-dried preparation that does not contain vitamin E with embodiment 5.
Test Example 1: the investigation of liposome
Prepared sample among embodiment 1-5 and Comparative Examples 1-5A, the 1-5B is carried out quality investigation, mainly carry out the mensuration of the observation of liposome outward appearance, particle size determination, envelop rate and percolation ratio.Wherein particle size determination adopts multi-angle nanoparticle analyzer to detect.Envelop rate and percolation ratio adopt column chromatography for separation to combine spectrophotography to measure.The result sees the following form:
Table 1: the envelop rate of embodiment 1-5 and Comparative Examples 1-5A, 1-5B and percolation ratio are investigated
| Outward appearance | Mean diameter | Envelop rate | Percolation ratio | |
| Embodiment 1 | Block loose | 108 | 95.6％ | 0.22％ |
| Comparative Examples 1A | Block loose | 290 | 68.3％ | 2.35％ |
| Comparative Examples 1B | Block loose | 186 | 83.9％ | 1.16％ |
| Embodiment 2 | Block loose | 120 | 92.7％ | 0.38％ |
| Comparative Examples 2A | Block loose | 430 | 58.7％ | 2.78％ |
| Comparative Examples 2B | Block loose | 229 | 79.2％ | 1.49％ |
| Embodiment 3 | Block loose | 116 | 93.5％ | 0.33％ |
| Comparative Examples 3A | Block loose | 370 | 61.9％ | 2.62％ |
| Comparative Examples 3B | Block loose | 214 | 80.7％ | 1.36％ |
| Embodiment 4 | Atrophy | 111 | 94.9％ | 0.29％ |
| Comparative Examples 4A | Atrophy | 330 | 65.1％ | 2.49％ |
| Comparative Examples 4B | Atrophy | 202 | 82.0％ | 1.26％ |
| Embodiment 5 | Atrophy | 110 | 95.3％ | 0.25％ |
| Comparative Examples 5A | Atrophy | 320 | 67.2％ | 2.41％ |
| Comparative Examples 5B | Atrophy | 197 | 83.1％ | 1.20％ |
Above result shows:
The mean diameter little (100nm-120nm) that contains the meropenem lipidosome freeze-dried preparation of NaTDC and vitamin E; Envelop rate high (more than 90%); Percolation ratio low (more than 0.4%), quality obviously is superior to not containing the meropenem lipidosome freeze-dried preparation of NaTDC and vitamin E.And the meropenem lipidosome freeze-dried preparation (about mean diameter 200nm, envelop rate about 80%, percolation ratio is more than 1.5%) that does not more contain vitamin E is also more excellent.
Simultaneously, adopt glucose better, be block open structure as the liposome outward appearance of freeze drying protectant preparation, and bad with lactose or trehalose as the liposome outward appearance of freeze drying protectant preparation, be the atrophy shape.
Test Example 2: study on the stability
The sample prepared among embodiment 1-5 and Comparative Examples 1-5A, the Comparative Examples 1-5B and the meropenem common flour pin (Zhongnuo Pharmaceutical (Shijiazhuang) Co., Ltd., Shiyao Group) of listing are diluted to 100ml with 0.9% sodium chloride injection respectively, the stability data in the measuring cell relaxing the bowels with purgatives of warm nature 12 hours.Percolation ratio adopts column chromatography for separation to combine spectrophotography to measure, and the detection method of content, relevant thing is official method (two ones of Chinese Pharmacopoeia versions in 2010, appendix VD HPLC), and the result sees the following form:
Table 2: the study on the stability of embodiment 1-5 and Comparative Examples 1-5A, solution that 1-5B disposes
| Time | Sample | Percolation ratio | Relevant thing | Content |
| 0 hour | Embodiment 1 | 0.23％ | 0.9％ | 101.2％ |
| Comparative Examples 1A | 2.33％ | 0.9％ | 100.9％ | |
| Comparative Examples 1B | 1.17％ | 0.9％ | 101.0％ | |
| Embodiment 2 | 0.37％ | 1.1％ | 100.6％ | |
| Comparative Examples 2A | 2.79％ | 1.2％ | 100.2％ | |
| Comparative Examples 2B | 1.48％ | 1.0％ | 100.4％ | |
| Embodiment 3 | 0.33％ | 1.0％ | 100.8％ | |
| Comparative Examples 3A | 2.64％ | 1.1％ | 100.4％ | |
| Comparative Examples 3B | 1.35％ | 1.1％ | 100.7％ | |
| Embodiment 4 | 0.30％ | 1.1％ | 101.0％ | |
| Comparative Examples 4A | 2.48％ | 1.1％ | 100.7％ | |
| Comparative Examples 4B | 1.26％ | 1.1％ | 100.8％ | |
| Embodiment 5 | 0.27％ | 1.0％ | 101.1％ | |
| Comparative Examples 5A | 2.42％ | 1.0％ | 100.8％ | |
| Comparative Examples 5B | 1.21％ | 1.1％ | 101.0％ | |
| The listing injectable powder | 1.2％ | 100.0％ | ||
| 2 hours | Embodiment 1 | 0.25％ | 0.9％ | 100.8％ |
| Comparative Examples 1A | 2.38％ | 1.0％ | 99.3％ | |
| Comparative Examples 1B | 1.20％ | 0.9％ | 100.1％ | |
| Embodiment 2 | 0.42％ | 1.2％ | 100.0％ | |
| Comparative Examples 2A | 2.93％ | 1.4％ | 98.0％ | |
| Comparative Examples 2B | 1.58％ | 1.1％ | 99.1％ |
| Embodiment 3 | 0.37％ | 1.1％ | 100.3％ | |
| Comparative Examples 3A | 2.75％ | 1.3％ | 98.4％ | |
| Comparative Examples 3B | 1.42％ | 1.2％ | 99.5％ | |
| Embodiment 4 | 0.33％ | 1.1％ | 100.6％ | |
| Comparative Examples 4A | 2.56％ | 1.2％ | 99.0％ | |
| Comparative Examples 4B | 1.31％ | 1.1％ | 99.7％ | |
| Embodiment 5 | 0.29％ | 1.0％ | 100.7％ | |
| Comparative Examples 5A | 2.49％ | 1.1％ | 99.1％ | |
| Comparative Examples 5B | 1.25％ | 1.1％ | 100.0％ | |
| The listing injectable powder | 1.5％ | 95.9％ | ||
| 4 hours | Embodiment 1 | 0.28％ | 1.0％ | 100.2％ |
| Comparative Examples 1A | 2.47％ | 1.1％ | 97.1％ | |
| Comparative Examples 1B | 1.25％ | 1.0％ | 98.9％ | |
| Embodiment 2 | 0.53％ | 1.3％ | 99.1％ | |
| Comparative Examples 2A | 3.25％ | 1.5％ | 94.8％ | |
| Comparative Examples 2B | 1.78％ | 1.2％ | 97.3％ | |
| Embodiment 3 | 0.45％ | 1.2％ | 99.5％ | |
| Comparative Examples 3A | 2.98％ | 1.5％ | 95.5％ | |
| Comparative Examples 3B | 1.56％ | 1.3％ | 97.8％ | |
| Embodiment 4 | 0.38％ | 1.2％ | 100.0％ | |
| Comparative Examples 4A | 2.73％ | 1.3％ | 96.5％ | |
| Comparative Examples 4B | 1.41％ | 1.2％ | 98.2％ | |
| Embodiment 5 | 0.33％ | 1.1％ | 100.1％ | |
| Comparative Examples 5A | 2.61％ | 1.2％ | 96.7％ | |
| Comparative Examples 5B | 1.32％ | 1.2％ | 98.7％ | |
| The listing injectable powder | 2.0％ | 89.0％ | ||
| 8 hours | Embodiment 1 | 0.33％ | 1.1％ | 99.3％ |
| Comparative Examples 1A | 2.69％ | 1.3％ | 93.9％ | |
| Comparative Examples 1B | 1.35％ | 1.2％ | 97.2％ | |
| Embodiment 2 | 0.71％ | 1.4％ | 97.6％ | |
| Comparative Examples 2A | 3.75％ | 1.9％ | 89.7％ | |
| Comparative Examples 2B | 2.09％ | 1.4％ | 94.4％ |
| Embodiment 3 | 0.59％ | 1.3％ | 98.2％ | |
| Comparative Examples 3A | 3.37％ | 1.8％ | 90.9％ | |
| Comparative Examples 3B | 1.79％ | 1.5％ | 95.1％ | |
| Embodiment 4 | 0.48％ | 1.3％ | 98.9％ | |
| Comparative Examples 4A | 3.04％ | 1.5％ | 92.6％ | |
| Comparative Examples 4B | 1.58％ | 1.4％ | 95.9％ | |
| Embodiment 5 | 0.40％ | 1.2％ | 99.1％ | |
| Comparative Examples 5A | 2.87％ | 1.4％ | 93.1％ | |
| Comparative Examples 5B | 1.45％ | 1.3％ | 96.8％ | |
| The listing injectable powder | 3.4％ | 80.7％ | ||
| 12 hours | Embodiment 1 | 0.41％ | 1.2％ | 97.9％ |
| Comparative Examples 1A | 3.03％ | 1.5％ | 89.1％ | |
| Comparative Examples 1B | 1.51％ | 1.3％ | 94.7％ | |
| Embodiment 2 | 0.95％ | 1.4％ | 95.1％ | |
| Comparative Examples 2A | 4.44％ | 2.3％ | 81.3％ | |
| Comparative Examples 2B | 2.50％ | 1.6％ | 89.5％ | |
| Embodiment 3 | 0.77％ | 1.4％ | 95.9％ | |
| Comparative Examples 3A | 3.93％ | 2.1％ | 83.4％ | |
| Comparative Examples 3B | 2.11％ | 1.8％ | 90.6％ | |
| Embodiment 4 | 0.62％ | 1.4％ | 96.9％ | |
| Comparative Examples 4A | 3.50％ | 1.7％ | 86.3％ | |
| Comparative Examples 4B | 1.83％ | 1.5％ | 92.2％ | |
| Embodiment 5 | 0.51％ | 1.3％ | 97.3％ | |
| Comparative Examples 5A | 3.26％ | 1.6％ | 87.5％ | |
| Comparative Examples 5B | 1.65％ | 1.4％ | 93.8％ | |
| The listing injectable powder | 5.9％ | 69.5％ |
Visible by above data, after being configured to transfusion, at room temperature the stability of placement improves the meropenem lipidosome freeze-dried preparation that contains NaTDC and vitamin E greatly than the common flour injection; Place after 12 hours, contain the requirement (relevant thing 1.5%, content 90.0-110.0%) that transfusion that the meropenem lipidosome freeze-dried preparation of NaTDC and vitamin E is made into still meets quality standard; Relevant thing is less than 1.5%; Content is higher than 95%, and the transfusion that the common flour injection is made into has not just met the requirement of quality standard when at room temperature being placed into 4 hours; Relevant thing is 2.0%, and content is 89.0%.In addition; When not containing transfusion that the meropenem lipidosome freeze-dried preparation of NaTDC and vitamin E is made into and at room temperature being placed into 8 hours; The undesirable situation of quality standard occurs, the relevant thing of Comparative Examples 2A and Comparative Examples 3A is greater than 1.5%, and the content of Comparative Examples 2A is less than 90%.And the transfusion that the meropenem lipidosome freeze-dried preparation that does not contain vitamin E is made into is when at room temperature being placed into 12 hours; The undesirable situation of quality standard appears; The relevant thing of Comparative Examples 2B and Comparative Examples 3B is greater than 1.5%, and the content of Comparative Examples 2B is less than 90%.
This shows; The meropenem lipidosome freeze-dried preparation that contains NaTDC and vitamin E provided by the invention; The problem of unstable that has been occurred when having solved the at room temperature long-time infusion of this medicine; Have conspicuous effect, this provides better choice for meropenem in the application aspect the clinical continuous transfusion.
Test Example 3: the embodiment 1 meropenem lipidosome freeze-dried preparation test of pesticide effectiveness
Get 50 of Kunming mouses, male and female half and half, body weight 20-30g.Mouse peritoneal is fixed on the workbench after injecting the anesthesia of 6% chloral hydrate 0.05mL/10g body weight, and cisternal puncture is removed 2 μ L cerebrospinal fluid, injects streptococcus pneumoniae bacteria suspension 2 μ L, sews up scalp.Mice is divided into 5 groups at random, 10 every group.Drug treatment after 24 hours, one group gives embodiment the sample of 1 preparation, and one group gives Comparative Examples 1A the sample of preparation, and one group gives Comparative Examples 1B the sample of preparation, one group of injectable powder that goes on the market, last group is the blank group.Before the administration, earlier the sample of each group is diluted to the solution of suitable concentration respectively with 0.9% sodium chloride injection, dosage is 250mg/kg, divides five injections with the medicinal liquid for preparing then, and injection in 4 hours finishes.Dosing in per 8 hours once, with the method administration.Observe the dead mouse situation then every day, write down mouse death rate in 14 days, result such as following table:
Table 3 infects after the dead mouse situation of embodiment, Comparative Examples and the treatment of listing article
| Mortality rate (%) | The 1st day | The 2nd day | The 3rd day | The 4th day | The 5th day | The 6th day | The 7th day |
| Embodiment 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Comparative Examples 1A | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Comparative Examples 1B | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| The listing injectable powder | 0 | 0 | 0 | 0 | 0 | 0 | 10 |
| Matched group | 0 | 0 | 0 | 10 | 10 | 20 | 30 |
| The 8th day | The 9th day | The 10th day | The 11st day | The 12nd day | The 13rd day | The 14th day | |
| Embodiment 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Comparative Examples 1A | 0 | 10 | 10 | 20 | 20 | 30 | 40 |
| Comparative Examples 1B | 0 | 0 | 0 | 10 | 10 | 20 | 30 |
| The listing injectable powder | 10 | 20 | 20 | 30 | 30 | 40 | 50 |
| Matched group | 30 | 40 | 50 | 50 | 60 | 70 | 80 |
Through respectively organizing mortality rate data contrasts and learn to above:
The mice of blank group begins dead successively after 3 days the intracerebroventricular streptococcus pneumoniae, mortality rate reached 80% in the 14th day;
Listing injectable powder group began to occur dead at the 7th day, mortality rate was 50% in the 14th day;
The mice of Comparative Examples 1A group began to occur dead at the 9th day, mortality rate was 40% in the 14th day;
It is later that death time appears in Comparative Examples 1B group, and the 11st day begins to occur, and the 14th day mortality rate is merely 30%;
Embodiment death record do not occur for 1 group.
This shows that the meropenem lipidosome freeze-dried preparation that contains phospholipid, cholesterol and NaTDC and the suitable compatibility of vitamin E is remarkable to the meningitic therapeutic effect of mice.
Though, used general explanation, the specific embodiment and test in the preceding text, the present invention has been done detailed description, on basis of the present invention, can to some modifications of do or improvement, this will be apparent to those skilled in the art.Therefore, these modifications or the improvement on the basis of not departing from spirit of the present invention, made all belong to the scope that requirement of the present invention is protected.
Claims (5)
1. meropenem lipidosome freeze-dried preparation; It is characterized in that this injection is grouped into by the one-tenth of following weight portion: meropenem 5-15 part, phospholipid 80-160 part, cholesterol 50-110 part, vitamin E 0.15-0.50 part, NaTDC 300-550 part and sugared 30-100 part;
Wherein, phospholipid is selected from Ovum Gallus domesticus Flavus lecithin and two stearic acid phosphatidyl glycerols; Said sugar is selected from glucose, lactose or trehalose;
The method for preparing of above-mentioned meropenem lipidosome freeze-dried preparation may further comprise the steps:
1) preparation of blank liposome: take by weighing phospholipid, cholesterol, vitamin E and the NaTDC of said amount, add an amount of chloroform-dehydrated alcohol mixed solvent dissolving, remove solvent under reduced pressure; Process even exsiccant lipid membrane; Add 0.1mol/L citric acid-sodium citrate buffer then, make the complete aquation of lipid membrane, then through after the high pressure homogenize emulsifying; Through the filtering with microporous membrane of 0.8 and 0.45 μ m, promptly get blank liposome turbid liquor successively;
2) preparation contains the liposome of meropenem: meropenem is dissolved in the water for injection; Then the blank liposome suspension slowly is added drop-wise in the meropenem medicinal liquid; And, be incubated 20 minutes down at 40-50 ℃ with 0.2mol/L phosphate buffer adjusting pH to 7.0, promptly get the pastille liposome;
3) preparation meropenem liposome turbid liquor: by weight compound concentration is that the sugar aqueous solution of 5-10% and the glycine solution that adds 2.5 mol/L are regulated pH value to 6.0-6.5; Get Liposomal dispersion; Use this dispersion liquid washing step 2 then) preparation the pastille liposome, make the meropenem liposome solutions be replaced into the meropenem liposome turbid liquor of pH value 6.0-6.5;
4) standardize solution, degerming, packing, lyophilizing: add injection water standardize solution, the meropenem liposome suspension is used the filtering with microporous membrane degerming, packing, lyophilization gets finished product.
2. meropenem lipidosome freeze-dried preparation according to claim 1; It is characterized in that this injection is grouped into by the one-tenth of following weight portion: 30 parts of 8 parts of meropenems, 90 parts in phospholipid, 60 parts in cholesterol, 0.15 part of vitamin E, 300 parts of NaTDCs and sugar.
3. meropenem lipidosome freeze-dried preparation according to claim 1 is characterized in that, the volume ratio of chloroform and dehydrated alcohol is 1:1-15:1 in said chloroform-dehydrated alcohol mixed solvent.
4. meropenem lipidosome freeze-dried preparation according to claim 1 is characterized in that, step 1) adds 0.1mol/L citric acid-sodium citrate buffer, makes pH value be controlled at 3.0-4.0.
5. meropenem lipidosome freeze-dried preparation according to claim 1; It is characterized in that, said high pressure homogenize emulsifying be adopt high pressure homogenizer with above-mentioned blank liposome suspension under 110-120MPa pressure, homogenizing 5 times; The mean diameter of gained liposome is 100-120nm; Narrow diameter distribution, between 60-250nm, the liposome particle diameter and the uniformity detect with multi-angle nanoparticle analyzer.
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