CN102327236B - Esomeprazole sodium liposome injection - Google Patents
Esomeprazole sodium liposome injection Download PDFInfo
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- CN102327236B CN102327236B CN 201110196429 CN201110196429A CN102327236B CN 102327236 B CN102327236 B CN 102327236B CN 201110196429 CN201110196429 CN 201110196429 CN 201110196429 A CN201110196429 A CN 201110196429A CN 102327236 B CN102327236 B CN 102327236B
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- esomeprazole sodium
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- esomeprazole
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Abstract
The invention discloses an esomeprazole sodium liposome injection. The esomeprazole sodium liposome injection is characterized by being mainly prepared from esomeprazole sodium, phosphatidylcholine, cholesterol, myelin, antioxygen and a protective agent. The prepared liposome injection is high in dissolvability, stability and entrapment rate and is small in a side effect, improves quality of preparation products, reduces toxic and side effects, improves bioavailability, and has an obvious curative effect.
Description
Technical field
The present invention relates to a kind of novel formulation of Esomeprazole sodium, particularly relate to esomeprazole sodium liposome injection and method for making thereof.
Background technology
Esomeprazole sodium (Esomeprazole), chemical name is: 5-methoxyl group-2-II (4-methoxyl group-3.5 dioxy base-2-pyridine radicals)-1H-benzimidazole sodium, molecular formula: C
17H
18N
3O
3SNa, molecular weight: 344.1, structural formula is:
Esomeprazole sodium is a kind of proton pump inhibitor, reduces gastric acid secretion by the H+/Na+-ATP enzyme that suppresses parietal cell.Esomeprazole is the s isomer of omeprazole, that first can be used for clinical proton pump inhibitor (ppi) individual isomer, it has the not available materia medica of omeprazole raceme and clinical advantages, compare with omeprazole, esomeprazole has higher with more consistent bioavailability, area is also larger under the plasma concentration time graph, area determines that they arrive the amount of parietal cell under the plasma concentration time graph of esomeprazole and omeprazole, therefore controls the gastric acid secretion degree that reaches.The same with other proton pump inhibitor, esomeprazole has higher specificity to the parietal cell sour environment, and gathering in this environment, activation and covalency inhibition proton pump, and the proton pump at other positions of human body does not reach the esomeprazole gathering and activates needed acidity.Esomeprazole sodium is mainly used in the treatment of erosive reflux esophagitis clinically, the long term maintenance treatment that the esophagitis patient who has cured prevents from recurring, the symptom control of gastro oesophageal reflux disease (GORD) (GERD) is with suitable antimicrobial therapy drug combination eradicate helicobacter pylori.
Patent documentation CN 101513387A discloses a kind of esomeprazole magnesium injection, mainly by esomeprazole magnesium or its officinal salt, antioxidant and solvent for injection form, the method adopts routine prescription and the production technology of this area, and the sample of preparation, less stable is unfavorable for long-term storage, bioavailability is low, has greatly affected the curative effect of medicine.
Patent documentation CN101269037A discloses a kind of esomeprazole magnesium oral sustained release drop pill, it is characterized in that by esomeprazole magnesium, glyceryl monostearate or stearic acid or hypromellose or their compositions of mixtures and vitamin E form, yet the esomeprazole sodium dropping balls can produce catabiosis in long term store, the related substance of medicine increases.
The product of the esomeprazole class medicine of listing has injection and tablet at present, and the esomeprazole bioavailability of these two kinds of dosage forms is low.
Liposome (liposomes) is dispersed in water phospholipid by British scholar Bangham and Standish at first and finds when carrying out electron microscopic observation.Liposome is a kind of novel Target Particles drug administration carrier, is the bimolecular folliculus with similar biofilm structure.Liposome can be divided into unilamelar liposome and multilamelar liposome according to the double-deck immobilized artificial membrane number of plies that its structure comprises, and the vesicle that contains the double-deck immobilized artificial membrane of monolayer is called unilamelar liposome, and the vesicle that contains the double-deck immobilized artificial membrane of multilamellar is called multilamelar liposome.General particle diameter is less than the small unilamellar vesicle that is called of 100nm, and the unilamelar liposome of particle diameter between 100nm-1000nm is called large unilamellar vesicle, and the particle diameter of multilamelar liposome is between 1-5 μ m.
In order to improve the bioavailability of esomeprazole, strengthen its targeting, the inventor studies esomeprazole sodium liposome injection, strengthens the effect of Esomeprazole sodium.
Summary of the invention
The purpose of this invention is to provide a kind of esomeprazole sodium liposome injection, the liposome excipient by Esomeprazole sodium and particular combinations makes the esomeprazole sodium lipidosome, and again lyophilization is aseptic subpackaged, makes lipidosome injection.
The stability of liposome is the major issue of restriction liposome development, and the liposome ubiquity is easily assembled, merged, and causes the entrapped drug seepage.The present invention has not only solved stability and the not good technical problem of envelop rate of liposome by the combination of particular excipient, has also obtained beyond thought preparation effect, thereby superior in quality liposome is provided.Although do not want to be bound by theory, the common and/or synergistic result that effect of the present invention may be.
The esomeprazole sodium liposome injection solubility that the present invention makes is good, good stability, and envelop rate is high, has improved the formulation products quality, has reduced toxic and side effects, and bioavailability improves greatly, more remarkable treatment effect.
Preparation liposome membrane material commonly used is phospholipid and additives.Phospholipid for the preparation of liposome has at present: natural phospholipid such as lecithin and fabaceous lecithin, synthetic phospholipid such as dipalmitoyl phosphatidyl choline and distearoyl phosphatidylcholine.Above-mentioned phospholipid all has two hydrophobic chains, no matter its hydrophilic group structure is how, and the formation lipid bilayer that they all can be spontaneous in water; Additives are commonly used cholesterol, 18-amine., a phosphatidic acid etc., and cholesterol can the bilayer flowability, permeability etc., and 18-amine. and phosphatidic acid can change the charge property of surface of liposome.
Bound by theory not; the inventor is through the long-term unexpected discovery of test; can obtain the esomeprazole sodium lipidosome of excellent in stability with the combination of Yolk lecithin, cholesterol and sphingo; it has good stability; add again specific freeze drying protectant; liposome can not break because of dehydration, fusion, ice crystal generation etc. in the freeze-drying process thereby make, and the lipid physical ability kept good envelop rate after aquation was redissolved.
The invention provides a kind of esomeprazole sodium liposome injection, mainly made by the composition of following ratio of weight and number:
In a preferred embodiment of the present invention, each composition weight umber of esomeprazole sodium liposome injection is:
Antioxidant can prevent the oxidation of liposome substrate, increases the stability of blank liposome, is the adjuvant a kind of commonly used of preparation liposome.In the preferred embodiments of the invention, antioxidant can be selected from propyl gallate.
When not full or atrophy becomes granule when the freeze-dried products external form, add protective agent, play the solid supporting function, make dried residue can substantially keep original volume, and keep enough intensity, fragmentation when avoiding storing.The protective agent that uses also should possess and draw moist littlely except the General Requirements that must possess injection supplementary material, and eutectic point is high, dissolution velocity is fast, outward appearance is pure white, even, fine and smooth, cheap and easy to get etc. after the lyophilizing.
In the preferred embodiments of the invention, protective agent is selected from the combination of sorbitol and dextran, and most preferably being weight ratio is the combination of 1: 1 sorbitol and dextran.
The particle diameter of liposome of the present invention can be controlled between the 50-300nm between 20nm-400nm further, and envelop rate can reach more than 85%.Simultaneously, use Freeze Drying Technique to carry out lyophilization, make freeze-dried powder, remove the water in the liposome, further strengthened the stability of esomeprazole sodium lipidosome, preservation condition is also more wide in range.In addition, redissolve after the various physicochemical properties of liposome be as good as with lyophilizing before.
The present invention also provides a kind of method for preparing above-mentioned esomeprazole sodium liposome injection, may further comprise the steps:
(1) Yolk lecithin, cholesterol, sphingo and antioxidant are added in an amount of organic solvent, heated and stirred is uniformly dispersed, and organic solvent is removed in decompression on rotary evaporator, makes immobilized artificial membrane;
(2) add an amount of buffer solution, jolting is stirred, and makes the complete aquation of immobilized artificial membrane, the homogeneous emulsifying of high speed, and filtering with microporous membrane makes the blank liposome suspension;
(3) Esomeprazole sodium is water-soluble, filtering with microporous membrane, filtrate adds in the blank liposome suspension, is incubated 45-60 ℃ and stirs 20-40 minute, adds protective agent again, stirs and makes its dissolving, and then cool to room temperature gets the Esomeprazole sodium liposome solutions;
(4) with mentioned solution through ultrafilter membrane except degerming and thermal source, then flowing steam sterilization, lyophilization under aseptic condition, packing makes esomeprazole sodium liposome injection.
In the preparation method of the present invention, organic solvent can be selected from one or more in n-butyl alcohol, the tert-butyl alcohol, isopropyl alcohol and the acetonitrile, and preferred volume ratio is 4: 1 n-butyl alcohol and the mixed solvent of acetonitrile.
In the preparation method of the present invention, buffer solution is selected from one or more in citrate buffer solution, borate buffer solution and the carbonate buffer solution, is preferably PH and is 6.4 citrate buffer solution.
Compared with prior art, esomeprazole sodium liposome injection provided by the invention and preparation method thereof has the following advantages: envelop rate is high, stability is high, has improved the therapeutic index of medicine, has reduced the toxicity of medicine, reduce toxic and side effects, improved the formulation products quality; The inventive method preparation technology is simple, is suitable for industrialized great production.
The specific embodiment
Further elaborate the present invention below with reference to embodiment, but it will be appreciated by those skilled in the art that the present invention is not limited to the preparation method of these embodiment and use.And those skilled in the art can carry out it is equal to replacement, combination, improvement or modification to the present invention according to description of the invention, but these all will comprise within the scope of the invention.
The preparation of embodiment 1 Esomeprazole sodium lipidosome freeze-dried injection
Prescription (1000 bottles):
Preparation technology:
(1) 120g Yolk lecithin, 20g cholesterol, 4g sphingo and 2g propyl gallate being added the 600ml volume ratio is in 4: 1 the n-butyl alcohol and acetonitrile, heated and stirred is uniformly dispersed, n-butyl alcohol and acetonitrile are removed in decompression on rotary evaporator, make immobilized artificial membrane;
(2) PH of adding 600ml is 6.4 citrate buffer solution, and jolting is stirred, and makes the complete aquation of immobilized artificial membrane, the homogeneous emulsifying of high speed, and filtering with microporous membrane makes the blank liposome suspension;
(3) the 40g Esomeprazole sodium is water-soluble, filtering with microporous membrane, filtrate adds in the blank liposome suspension, being incubated 45-60 ℃ stirred 20-40 minute, add again 100g sorbitol and 100g dextran, stirring makes its dissolving, and then cool to room temperature gets the Esomeprazole sodium liposome solutions;
(4) with mentioned solution through ultrafilter membrane except degerming and thermal source, then the flowing steam sterilization is 30 minutes, lyophilization under the aseptic condition, packing makes the Esomeprazole sodium lipidosome freeze-dried injection.
The preparation of embodiment 2 Esomeprazole sodium lipidosome freeze-dried injections
Prescription (1000 bottles):
Preparation technology:
(1) 240g Yolk lecithin, 160g cholesterol, 40g sphingo and 20g propyl gallate being added the 3000ml volume ratio is in 4: 1 the n-butyl alcohol and acetonitrile, heated and stirred is uniformly dispersed, n-butyl alcohol and acetonitrile are removed in decompression on rotary evaporator, make immobilized artificial membrane;
(2) adding 3000mlPH is 6.4 citrate buffer solution, and jolting is stirred, and makes the complete aquation of immobilized artificial membrane, the homogeneous emulsifying of high speed, and filtering with microporous membrane makes the blank liposome suspension;
(3) the 40g Esomeprazole sodium is water-soluble, filtering with microporous membrane, filtrate adds in the blank liposome suspension, being incubated 45-60 ℃ stirred 20-40 minute, add again 300g sorbitol and 300g dextran, stirring makes its dissolving, and then cool to room temperature gets the Esomeprazole sodium liposome solutions;
(4) with mentioned solution through ultrafilter membrane except degerming and thermal source, then the flowing steam sterilization is 30 minutes, lyophilization under the aseptic condition, packing makes the Esomeprazole sodium lipidosome freeze-dried injection.
Embodiment 3
Prescription (1000 bottles):
Preparation technology:
(1) 160g Yolk lecithin, 80g cholesterol, 20g sphingo and 10g propyl gallate being added the 1000ml volume ratio is in 4: 1 the n-butyl alcohol and acetonitrile, heated and stirred is uniformly dispersed, n-butyl alcohol and acetonitrile are removed in decompression on rotary evaporator, make immobilized artificial membrane;
(2) adding 1000mlPH is 6.4 citrate buffer solution, and jolting is stirred, and makes the complete aquation of immobilized artificial membrane, the homogeneous emulsifying of high speed, and filtering with microporous membrane makes the blank liposome suspension;
(3) the 40g Esomeprazole sodium is water-soluble, filtering with microporous membrane, filtrate adds in the blank liposome suspension, being incubated 45-60 ℃ stirred 20-40 minute, add again 200g sorbitol and 200g dextran, stirring makes its dissolving, and then cool to room temperature gets the Esomeprazole sodium liposome solutions;
(4) with mentioned solution through ultrafilter membrane except degerming and thermal source, then the flowing steam sterilization is 30 minutes, lyophilization under the aseptic condition, packing makes the Esomeprazole sodium lipidosome freeze-dried injection.
Embodiment 4 preparation Comparative Examples 1-3
| Form | Embodiment 1 | Comparative Examples 1 | Comparative Examples 2 | Comparative Examples 3 |
| Esomeprazole sodium | 40g | 40g | 40g | 40g |
| Yolk lecithin | 120g | 120g | 120g | 120g |
| Cholesterol | 20g | / | 20g | 20g |
| 18-amine. | / | 20g | ||
| Sphingo | 4g | 4g | 4g | 4g |
| Propyl gallate | 2g | / | 2g | / |
| Vitamin C | 2g | / | 2g | |
| Sorbitol | 100g | 100g | / | 100g |
| Dextran | 100g | 100g | / | 100g |
| Mannitol | / | / | 100g | / |
Above Comparative Examples is finished according to the technique of embodiment 1.
The mensuration of test example 1 particle diameter
Under the room temperature condition, get the Esomeprazole sodium lipidosome freeze-dried injection of embodiment and Comparative Examples, be made into 0.1% solution with normal saline, place the sample cell of Submicron Particle Sizer Model 370 particle diameter detectors, measure particle size distribution and mean diameter; Observe particle shape with projection electron microscope.Result such as table 1:
Table 1 particle diameter testing result
| Embodiment | Mean diameter | Outward appearance |
| Embodiment 1 | 252.7±20.3nm | Spherical, evenly |
| Comparative Examples 1 | 430.6±26.7nm | Inhomogeneous, mixed and disorderly |
| Embodiment 2 | 230.3±19.8nm | Spherical, evenly |
| Comparative Examples 2 | 426.6±20.9nm | Inhomogeneous, mixed and disorderly |
| Embodiment 3 | 205.4±18.0nm | Spherical, evenly |
| Comparative Examples 3 | 217.5±16.1nm | Spherical, more inhomogeneous |
By above result as can be known, the solid lipid nanoparticle particle diameter that embodiment 1-3 makes is even, and is aobvious spherical, big or small homogeneous; The solid lipid nanoparticle particle diameter that Comparative Examples 1-2 makes is inhomogeneous, and shape is indefinite, and is not of uniform size; Although the particle diameter of Comparative Examples 3 Liposomal formulations meets the requirements, the liposome particle size distribution is uneven as described in Example 3.
The mensuration of test example 2 envelop rates
The Esomeprazole sodium Liposomal formulation of embodiment and Comparative Examples preparation is dissolved in water is diluted to 0.1% solution, high speed centrifugation, 5000r/min, centrifugal 20 minutes, get supernatant, use dissolve with methanol, the HPLC method is measured the esomeprazole sodium content, the computational envelope rate, and result such as table 2:
Table 2 entrapment efficiency determination result
By above result as can be known, the envelop rate of the Liposomal formulation of embodiment 1-3 preparation is higher than the envelop rate of the Liposomal formulation of Comparative Examples 1-3 significantly, illustrates that product of the present invention has unforeseeable effect.
Test example 3 study on the stability
With the sample of embodiment of the invention 1-3 and Comparative Examples 1-3 preparation and listing injection Esomeprazole sodium (lot number: place respectively lower 6 months of the condition of 40 ℃ of high temperature, relative humidity 75% H20093314 AstraZeneca pharmaceutical Co. Ltd), carry out accelerated test and investigate experimental result such as table 3:
Table 3 accelerated test result
By above result as can be known, when accelerating June, the listing preparation becomes pale yellow powder, content, and related substance raises; The product content of Comparative Examples reduces, and related substance raises; And sample property of the present invention, content and related substance variation are all not obvious, illustrate that product stability of the present invention is good.
The test of test example 4 percolation ratios
Get the sample of test example 1-3 and Comparative Examples 1-3 preparation, under the room temperature condition, respectively at 0 day, 30 days, 60 days, 90 days and 180 days, make regular check on respectively, measure envelop rate, with the dose of sealing in 0 day relatively, calculate percolation ratio, the results are shown in Table 4
Table 4 percolation ratio result of the test
| Time | Embodiment 1 | Embodiment 2 | Embodiment 3 | Comparative Examples 1 | Comparative Examples 2 | Comparative Examples 3 |
| 0 day | 0.34 | 0.33 | 0.32 | 0.79 | 0.86 | 1.20 |
| 30 days | 0.39 | 0.37 | 0.36 | 1.34 | 1.67 | 2.34 |
| 60 days | 0.60 | 0.56 | 0.54 | 3.72 | 3.65 | 5.02 |
| 90 days | 0.66 | 0.64 | 0.65 | 5.04 | 4.95 | 10.44 |
| 180 days | 0.71 | 0.72 | 0.69 | 6.56 | 6.88 | 19.56 |
By above result of the test as can be known, the sample of embodiment of the invention preparation changes little in the long middle percolation ratio of long term storage, and the sample percolation ratio of Comparative Examples increases gradually, and the liposome seepage is serious, and the esomeprazole sodium liposome injection of this explanation the present invention preparation has higher stability.
The test of test example 4 bioavailability
24 1 years old left and right sides beasle dogs are divided into 4 groups at random, vein gives the Esomeprazole sodium 0.04g of embodiment 1 and Comparative Examples 1-, administration finishes rear 0,0.25,0.5,1,1.5,2.5,3.5 5.5 and 7.5 gather venous blood 1ml, inject and get blood vessel, the high speed centrifugation separation of serum, accurately draw blood serum sample 190 μ L and place 1.5mL Eppendorf microcentrifugal tube, add the saturated methotrexate solution of mark in the 10 μ L, add again methanol 400 μ L, vortex mixed 1min, 16000rpm high speed centrifugation 5min gets supernatant 200 μ L and adds 200 μ L water, 2500rpm vortex 30s mixing, carry out HPLC and analyze, carry out pharmacokinetic data available with WinNonline version5.2 program and process.Result of the test such as following table:
Relevant pharmacokinetic parameters
Can be found out by above experimental data, the esomeprazole sodium liposome injection of embodiment of the invention preparation is compared with Comparative Examples, bioavailability improves greatly, proved absolutely the present invention because the esomeprazole sodium liposome injection of making of excipient and active component, has synergism, the injection of preparation improves bioavailability widely, has obtained unexpected technical effect.
Claims (3)
1. esomeprazole sodium liposome injection is characterized in that mainly being made by the composition of following ratio of weight and number:
Wherein, described antioxidant is selected from propyl gallate; Protective agent is selected from the combination that weight ratio is 1: 1 sorbitol and dextran.
2. esomeprazole sodium liposome injection according to claim 1 is characterized in that mainly being made by the composition of following ratio of weight and number:
3. a method for preparing claim 1 or 2 each described esomeprazole sodium liposome injections is characterized in that comprising the steps:
(1) Yolk lecithin, cholesterol, sphingo and antioxidant are added in an amount of organic solvent, heated and stirred is uniformly dispersed, and organic solvent is removed in decompression on rotary evaporator, makes immobilized artificial membrane;
(2) add an amount of buffer solution, jolting is stirred, and makes the complete aquation of immobilized artificial membrane, the homogeneous emulsifying of high speed, and filtering with microporous membrane makes the blank liposome suspension;
(3) Esomeprazole sodium is water-soluble, filtering with microporous membrane, filtrate adds in the blank liposome suspension, is incubated 45-60 ℃ and stirs 20-40 minute, adds protective agent again, stirs and makes its dissolving, and then cool to room temperature gets the Esomeprazole sodium liposome solutions;
(4) with mentioned solution through ultrafilter membrane except degerming and thermal source, then flowing steam sterilization, lyophilization under the aseptic condition, packing makes esomeprazole sodium liposome injection;
Wherein, to be selected from volume ratio be 4: 1 n-butyl alcohol and the mixed solvent of acetonitrile to organic solvent; It is 6.4 citrate buffer solution that buffer solution is selected from PH.
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| CN101513387A (en) * | 2008-11-20 | 2009-08-26 | 李铁军 | Esomeprazole magnesium injection liquid |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101513387A (en) * | 2008-11-20 | 2009-08-26 | 李铁军 | Esomeprazole magnesium injection liquid |
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