CN108542884A - A kind of sensitive medicament-carried liposomes of pH of SPIO tracers and preparation method thereof - Google Patents

A kind of sensitive medicament-carried liposomes of pH of SPIO tracers and preparation method thereof Download PDF

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CN108542884A
CN108542884A CN201810417787.XA CN201810417787A CN108542884A CN 108542884 A CN108542884 A CN 108542884A CN 201810417787 A CN201810417787 A CN 201810417787A CN 108542884 A CN108542884 A CN 108542884A
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spio
tracers
liposomes
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sensitive
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CN108542884B (en
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李必波
罗治彬
何美
李必强
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People's Hospital Of Chongqing City
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Abstract

The invention discloses a kind of sensitive medicament-carried liposomes of pH of SPIO tracers, are obtained using following quality proportioning：1~10 part of bulk pharmaceutical chemicals, 1~50 part of phosphatidyl-ethanolamine, 1~30 part of cholesterol, 1~30 part of linoleic acid, 0~10 part of carboxymethyl chitosan, 0~10 part of SPIO nano particle.The invention also discloses a kind of preparation methods of the sensitive medicament-carried liposomes of pH of SPIO tracers：S1：Take phosphatidyl-ethanolamine, cholesterol and linoleic acid in flask, addition chloroform is dissolved, and water soluble drug solution is added and carries out being ultrasonically formed w/o type emulsion；S2：It is performed under reduced pressure and is evaporated to gel state；Buffer solution is added, continues evaporation and forms aqueous suspension；S3：By liposome turbid liquor freeze thawing 3 times after addition SPIO nano particle；It is centrifuged off the SPIO nano particle and water soluble drug that aqueous suspension is not packed in；S4：Carboxymethyl chitosan solution is added, is hydrated.

Description

A kind of sensitive medicament-carried liposomes of pH of SPIO tracers and preparation method thereof
Technical field
The present invention relates to pH sensitive liposome technical fields, and in particular to a kind of sensitive medicament-carried liposomes of pH of SPIO tracers And preparation method thereof.
Background technology
Liposome (liposome) means a kind of double-deck miniature vesicular body of fat molecule with similar biofilm structure, diameter 25~1000nm etc. can be used as hydrophily or/and hydrophobic pharmaceutical carrier.With targeting, lymph directionality, sustained release Property, reduce drug toxicity, improve medicine stability the characteristics of.
The quick unordered growth pattern of solid malignant, keeps its angiogenesis insufficient, blood oxygen supply is insufficient, causes to swell Occurs anoxic cell in tumor.The presence of anoxic cell causes the pH value (6.5 or less) at mesenchyma stroma of tumors compared with normal structure interstitial The pH value (7.4) at place is low, this provides theoretical foundation for pH sensitive liposomes (pH sensitive liposomes).PH is sensitive Liposome is a kind of liposome sensitive to pH, is made of the membrane material with pH sensibility, the lipid bilayer in structure The stability of layer changes with environment pH variations, while can also be called acid-sensitive polymer liposome.When drug-loaded liposome is with blood circulation When reaching tumor locus, since the reduction of pH at interstitial causes membrane material protonation that imitated vesicle structure is caused to destroy, drug is released, The targeting of tumour can be realized.
The research of early stage pH sensitive liposome mainly realizes liposome pH sensibility by selecting different phosphatide.This pH Sensitive liposome is mainly by pH sensitive compounds and unsaturated cephalin (phosphatidylethanolamine, PE) group At, wherein common PE is dioleoylphosphatidylethanolamine (dioleoylphosphatidylethanolamine, DOPE). And the hydrophilic segment of pH sensitive liposome compounds contains the pH sensitive groups such as carboxyl more, such as oleic acid (oleicacid, OA), courage Sterol hemisuccinic acid ester (cholesteryl hemisuccinate, CHEMS) and palmitoylhomocysteine (Palmitoyl Homocysteine, PHC) etc..Unsaturated cephalin is cone, and the small hydrophobic end of water-wet side is big, and pH sensitive liposome compounds Carboxylic acid group in neutral conditions, be inverted conical, the big hydrophobic end of water-wet side is small, both has then been complementarily shaped to liposome bilayer Film is simultaneously stable at neutral environment.When pH is reduced to acidity, carboxylic acid group will protonate, and water-wet side volume opposite will subtract It is small, liposome cannot be caused unstable with the complementation of unsaturated cephalin on three-dimensional conformation.The lipid of a variety of different pH sensitivities Body can be obtained by adjusting the composition ratio of lipid or changing membrane material type.Zhang hong etc. use PE/CHO/OA (6:2:It is 3W/W) membrane material, is prepared for taxol pH sensitive liposomes, what in vitro test showed in 5.0 solution of pH accumulative releases Degree of putting is at 1.3 times of 7.4 solution of pH.In-vivo test in mice shows：Its t1/2And AUC is 1.8 times and 2.6 of taxol respectively Times.Zuo Tiantian etc. substitutes oleic acid using linoleic acid, and (16 are combined in proportion with PE, CHO:24:8, W/W) it is prepared for docetaxel pH Sensitive liposome, vitro release experiment show that the accumulative releasing degree in 72h in 7.4 solution of 5.0 solution of pH and pH is respectively 87.81% and 65.21%, show it with apparent pH sensibility.Kim Min-Jung etc. are prepared for using DOPE and CHEMS Using EGF-R ELISA as the pH sensitivity long circulating immunoliposomes of target spot, when DOPE/CHEMS (molar ratio) is 6：When 4, Gained liposome shows stronger acid-sensitive in pH5.5 solution, and gemcitabine is wrapped in the pH sensitivity fat with antibody In plastid, inhibit A549Act as free drug 2 times of cancer cell multiplication.
In addition to pH sensitive compounds and unsaturated cephalin can realize the pH sensibility of liposome, containing amino and contain The pH sensibility high score materials of carboxylic acid group can also be used to structure pH sensitive liposomes, often by by pH Sensitive Polymer Materials Modification is formed in outer liposome surface or be embedded in liposome bilayer membrane.With amino high molecular material such as polyhistidyl and Polylysine, pH sensitive liposomes could be built by needing mutually to merge with negative charged lipid body.Contain the cationic (- NH) base of weak base Group, and the amphipathic electrolyte carboxymethyl chitosan containing weak acid anion (- COO-) group, lipid is wrapped in by aquation Body surface face, the liposome tablets in vitro after modification show that apparent pH sensibility, possible cause are carboxymethyl chitosan On amino group protonation campaign at a low ph so that the structure modified in the carboxymethyl chitosan of surface of liposome occurs Variation squeezes liposome bilayer and liposome is made to reset, in rearrangement process, by the drug quick release of encapsulating.Yang Shanxiang etc. It selects carboxymethyl chitosan as dressing agent, prepares pH sensitivity adriamycin nano liposomes, in vitro test shows adriamycin in Drug release under property and weak basic condition is relatively slow, drug accumulation release rate only 40% when 8h, close to tumour cell pH Solutions of weak acidity and acid condition under, drug accumulation release rate is up to 60% or more when 8h, and release amount of medicine is with absorption delaying agents PH is reduced and is increased, and illustrates that adriamycin nano liposome has pH sensibility after carboxymethyl chitosan is sugar-modified.
In conclusion passing through pH sensitive compounds, the group two-by-two of unsaturated cephalin and pH sensibility high score materials It closes or is used alone, manufactured drug-loaded liposome all has certain pH sensibility, but there are still required pH condition values too low, medicine The features such as object release time is too long, accumulative releasing degree is insufficient.
In addition, the height pH sensibility of liposome is to realize the premise of tumor-targeting, tumor-targeting how is confirmed again It is another challenge.Confirm that the method for tumor-targeting includes at present：Drug content in tissues measures, fluorescein develops, radioactivity Nucleic development etc..Fine jade etc. is prepared for the proliposome of height Lung targeting more than domestic scholars, is studied in rabbit body, by quiet After arteries and veins injecting lipid body, puts to death rabbit and obtain each organs and tissues, extract drug ingedient after tissue homogenate, tissue is carried out by HPLC The detection of drug concentration obtains pharmacokinetics and Tissue distribution data, it was demonstrated that the liposome has the lung tissue of height Targeting.Foreign scholar Hong Myo-Sook are wrapped up using the membrane material of pH sensitivities, are prepared for using fluorescer as developer PH sensitive liposomes, and liposome is placed in investigation pH sensibility in vitro human lung cancer tissue, as a result show the liposome in 2h The interior fluorescer by package is discharged up to 100%, and release shows that it has less than 30% in 8h in Isolated Rat normal liver tissue Height pH sensibility.Foreign scholar Vildete Carmo, using 99mTc as radioactive tracer developer, using the film of pH sensitivities Material is prepared for 99mTc-- hexamethylpropyleneamine oxime pH sensitive liposomes (99mTc--SpHL), and rat results from vivo experiments is aobvious Show, (after the 60h that is inflamed, the local pH of Inflamed tissue is from originally just in artificial constructed rat inflammation foot by 99mTc--SpHL 7.4 in the case of often are reduced to 18 times that 6.5) cumulative radiation level is simple drug, show that the pH sensitive liposomes have Height pH sensibility and targeting.The method that three of the above confirms targeting has distinct disadvantage, such as living tissue drug concentration Detection, can not carry out, can not detect each in vivo dynamic drug concentration change in real time；Fluorescer is developer mainly in body Outer cell or in vitro tissue development；99mTc has apparent radioactivity, and half-life short (6.02h).
Invention content
In view of the above shortcomings of the prior art, the technical problem to be solved by the present invention is to：It is sensitive how a kind of pH is provided Property it is apparent, tracer effect is good, preparation process is simple, the sensitive medicament-carried liposomes of pH of stable storing SPIO tracers and its preparation side Method.
In order to solve the above-mentioned technical problem, present invention employs the following technical solutions：Including bulk pharmaceutical chemicals, auxiliary material and tracer Agent, the bulk pharmaceutical chemicals are one kind in water soluble drug or fat-soluble medicine, and the auxiliary material includes that phosphatidyl-ethanolamine, courage are solid Alcohol, linoleic acid and carboxymethyl chitosan, the tracer are SPIO nano particle, and the pH of the SPIO tracers is quick Feel drug-loaded liposome to obtain using following quality proportioning：1~10 part of bulk pharmaceutical chemicals, 1~50 part of phosphatidyl-ethanolamine, cholesterol 1~ 30 parts, 1~30 part of linoleic acid, 0~10 part of carboxymethyl chitosan, 0~10 part of SPIO nano particle.
Wherein, the auxiliary material further includes dioleoylphosphatidylethanolamine, lecithin, hydrogenated soy phosphatidyl choline, phosphatidyl-4 Alcohol, Distearoyl Phosphatidylethanolamine, Pegylation Distearoyl Phosphatidylethanolamine, Cholesteryl hemisuccinate, palm It is one or any several in acyl homocysteine, oleic acid, vitamin E, metal chelating agent and butylated hydroxyarisol The combination of kind.
Wherein, the tracer is the SPIO nano particle of glucan package, ferric oxide nanometer particle grain Diameter 5nm, grain size is 30nm-35nm after wrapping up glucan, has superparamagnetism, water solubility, biocompatibility.Superparamagnetic iron oxide Nano particle is no radiography agent, under magnetic resonance in such a way that the T2 for reducing tissue is weighted as signal, makes the background of MRI Signal strength reduces, and pathological tissues is enable clearly to image, to carry out target area development, and can be by dynamically measuring different when Between the signal value put calculate targeting time distribution map.
In this way, the sensitive medicament-carried liposomes of pH of SPIO tracers of the present invention have, pH sensibility is apparent, tracer effect is good, prepares The advantages of simple for process, stable storing, can be used as water-soluble or fat-soluble medicine carrier, destroy in low ph conditions lower structure and The targeting of tumor locus is realized in drug release, and then increases absorption of the cancer cell to drug, reduces poisonous side effect of medicine, and can be real Existing "dead" tracer and dynamic monitoring.Wherein, liposome can be suspension, can also be freeze-dried.
The invention also discloses a kind of preparation methods of the sensitive medicament-carried liposomes of pH of SPIO tracers, include the following steps：
S1：It takes 1~30 part of 1~50 part of phosphatidyl-ethanolamine, 1~30 part of cholesterol and linoleic acid in flask, chlorine is added It is imitative to be dissolved, 1~10 part of water soluble drug solution is then added and carries out ultrasound, until forming uniform w/o type emulsion；
S2：Flask is connect with Rotary Evaporators, is performed under reduced pressure evaporation, forms gel state；Into flask The PBS buffer solution that 1~10 part of pH is 7.4 is added, continues evaporation under reduced pressure and forms aqueous suspension；
S3：It is added -80 DEG C, 50 DEG C of aqueous suspension elder generation postposition after 0~10 part of SPIO nano particle Freeze thawing is carried out, is repeated 3 times；Then the Superparamagnetic Iron Oxide nanometer that aqueous suspension is not packed in is removed using supercentrifugal process Grain and water soluble drug, obtain liposome turbid liquor；
S4：The carboxymethyl chitosan solution that 0~10 part of mass percent is 0.3% is added into liposome turbid liquor, into Capable hydration 30min, ultrasound and mistake miillpore filter obtain the sensitive medicament-carried liposomes of pH of SPIO tracers.
Wherein, the water soluble drug is Misonidazole, adriamycin, Epi-ADM, pyrrole adriamycin, vincristine, support Moor any one in glycosides, cis-platinum, Nedaplatin, carboplatin, gemcitabine and Hydroxycamptothecin.
Wherein, further include vitamin E as oxidant in step S1.
In conclusion the sensitive medicament-carried liposomes of pH of SPIO tracers provided by the present invention have pH sensibility high, super suitable Magnetic good advantage, to realize that tumor-targeting, reduction drug toxicity, "dead" tracer lay the foundation.Invention additionally discloses The preparation methods of the sensitive medicament-carried liposomes of pH of SPIO tracers can preferably wrap water-soluble or fat-soluble medicine It wraps up in, preparation method is simple, and particle diameter distribution is uniform, is conducive to industrialize.
Description of the drawings
Fig. 1 is the cumulative release of Misonidazole pH sensitive liposomes Misonidazole under condition of different pH of SPIO tracers Degree.
Fig. 2 be SPIO tracers Misonidazole pH sensitive liposomes under condition of different pH Superparamagnetic Iron Oxide nanometer The accumulative releasing degree of grain.
Fig. 3 is the Misonidazole pH sensitive liposome grain size distributions of SPIO tracers.
Fig. 4 is the Misonidazole pH sensitive liposome potential diagrams of SPIO tracers.
Fig. 5 is the Misonidazole pH sensitive liposome scanning electron microscope (SEM) photographs of SPIO tracers.
Fig. 6 is the Misonidazole pH sensitive liposome transmission electron microscope pictures of SPIO tracers.
Fig. 7 is the Misonidazole pH sensitive liposome magnetization curves of SPIO tracers.
Specific implementation mode
Part formulation embodiment is set forth below.
Embodiment 1：A kind of sensitive medicament-carried liposomes of pH of SPIO tracers are obtained using following quality proportioning：Misonidazole 2.5 parts, 30 parts of phosphatidyl-ethanolamine, 10 parts of cholesterol, 10 parts of linoleic acid, 0.5 part of carboxymethyl chitosan, Superparamagnetic Iron Oxide 0.5 part of nano particle, 2 parts of vitamin E.The wherein Misonidazole pH sensitive liposomes of SPIO tracers rice under condition of different pH The Accumulation dissolution of rope nitre azoles is as shown in Figure of description Fig. 1, and the Misonidazole pH sensitive liposomes of SPIO tracers are in different pH Under the conditions of SPIO nano particle accumulative releasing degree as shown in Figure of description Fig. 2, the misso nitre of SPIO tracers Azoles pH sensitive liposomes grain size distribution is as shown in Figure of description Fig. 3, the Misonidazole pH sensitive liposome electricity of SPIO tracers Bitmap is as shown in Figure of description Fig. 4, the Misonidazole pH sensitive liposomes scanning electron microscope (SEM) photograph such as Figure of description of SPIO tracers Shown in Fig. 5, the Misonidazole pH sensitive liposomes transmission electron microscope picture of SPIO tracers is as shown in Figure of description Fig. 6, SPIO tracers Misonidazole pH sensitive liposomes magnetization curve as shown in Figure of description Fig. 7.
A kind of pH sensitive liposomes of SPIO tracers and preparation method thereof, include the following steps：
S1：Take 10 parts of 30 parts of phosphatidyl-ethanolamine, 10 parts of cholesterol and linoleic acid molten in chloroform progress in flask, is added Solution carries out ultrasound 2min after the aqueous solution containing 2.5 parts of Misonidazole is then added, until forming uniform w/o type emulsion；
S2：Flask is connect with Rotary Evaporators, is performed under reduced pressure evaporation, forms gel state；Into flask The PBS buffer solution that 8ml pH are 7.4 is added, continues evaporation under reduced pressure and forms aqueous suspension；
S3：It is added -80 DEG C, the 50 DEG C progress freeze thawing of aqueous suspension elder generation postposition after 0.5 part of SPIO, is repeated 3 times；Then, The Misonidazole and SPIO that aqueous suspension is not packed in are removed using supercentrifugal process, obtains liposome turbid liquor；
S4：The carboxymethyl chitosan solution that 0.5 part of mass percent is 0.3% is added into liposome, is hydrated 30min, ultrasound and miillpore filter excessively obtain the pH sensitive liposomes of SPIO tracers.
Further, in step S1, further include certain mass proportioning vitamin E as antioxidant.
Embodiment two：
A kind of pH sensitive liposomes of SPIO tracers and preparation method thereof, include the following steps：
A1：It takes 10 parts of 5 parts of taxol, 30 parts of phosphatidyl-ethanolamine, 10 parts of cholesterol and linoleic acid in flask, then adds Enter chloroform to be dissolved, flask connect with Rotary Evaporators, and volatilizes chloroform under 37 DEG C, 100r/min, reduced pressure, Film is formed in beaker inner wall；
A2：The aqueous solution containing 0.5 part of SPIO is added into beaker, Rotary Evaporators are protected from light in 50 ± 1 DEG C, 100r/min Under the conditions of aquation 60min obtain liposome solutions；
A3：The taxol and SPIO that liposome is not packed in are removed using supercentrifugal process, obtains liposome turbid liquor；
A4：The carboxymethyl chitosan solution that 0.5 part of mass percent is 0.3% is added into liposome, is hydrated 30min obtains the pH sensitive liposomes of SPIO tracers.
Further, in step A1, further include certain mass proportioning vitamin E as antioxidant.
Embodiment three：
A kind of pH sensitive liposomes of SPIO tracers and preparation method thereof, include the following steps：
B1：It takes 10 parts of 30 parts of phosphatidyl-ethanolamine, 10 parts of cholesterol and linoleic acid in flask, it is mixed that dimethyl sulfoxide (DMSO) is added Cooperation is A phases, regard 0.5 part of pure water, glycerine, 5 parts of cis-platinum and SPIO mixing as B phases, after A phases and B are mixed, pours into It in blender, is stirred 3 minutes at 55 DEG C, then takes out to be put into mulser and emulsify 30 seconds, be put into later in high-pressure emulsification agent newborn Change 4 times；
B2：After products of the step B1 after being emulsified in high-pressure emulsification agent is put into the defoaming of supersonic oscillations machine, pH is added For 7.4 PBS buffer solution, liposome turbid liquor is formed；
B3：The cis-platinum and SPIO that liposome is not packed in are removed using supercentrifugal process, obtains liposome turbid liquor；To lipid Body suspension carries out ultrasound, and crosses miillpore filter and obtain liposome；
B4：The carboxymethyl chitosan solution that 0.5 part of mass percent is 0.3% is added into liposome, is hydrated 30min obtains the pH sensitive liposomes of SPIO tracers.
Further, in step B1, further include certain mass proportioning vitamin E as antioxidant.
Example IV：
A kind of pH sensitive liposomes of SPIO tracers and preparation method thereof, include the following steps：
C1：It takes 10 parts of 5 parts of adriamycin, 30 parts of phosphatidyl-ethanolamine, 10 parts of cholesterol and linoleic acid in flask, uncle is added Butanol is dissolved, and 200 parts of aqueous trehalose solutions are then added, and the carboxymethyl chitosan that 0.5 part of mass percent is 0.3% is molten Liquid, 0.5 part of SPIO solution, and be sub-packed in 100ml sterilizing cillin bottles after filtering with microporous membrane, it is placed in cold in freeze drier Be lyophilized it is dry, sealing, obtain the pH sensitivity proliposomes of SPIO tracers；
C2：Before use, 1 bottle of the pH sensitivities proliposome of SPIO tracers is taken, physiological saline 100ml is added, is shaken in 37 DEG C Bed shakes 30min, obtains the pH sensitive liposomes of SPIO tracers.
Further, in step C1, further include certain mass proportioning vitamin E as antioxidant.
When Clinical practice, injection or freeze-dried may be used.The pH of SPIO tracers provided by the present invention is sensitive medicament-carried Liposome has the advantages that pH sensibility is high, superparamagnetism is good, to realize tumor-targeting, reducing drug toxicity, "dead" Tracer lays the foundation.The invention also discloses the preparation methods of the sensitive medicament-carried liposomes of the pH of SPIO tracers, can be preferably right Water-soluble or fat-soluble medicine is wrapped up, and preparation method is simple, and particle diameter distribution is uniform, is conducive to industrialize.
Finally it should be noted that：The above embodiments are merely illustrative of the technical solutions of the present invention, rather than its limitations；Although Present invention has been described in detail with reference to the aforementioned embodiments, it will be understood by those of ordinary skill in the art that；It still may be used To modify to the technical solution recorded in previous embodiment, either which part or all technical features are equal It replaces；And these modifications or replacements, the model for technical solution of the embodiment of the present invention that it does not separate the essence of the corresponding technical solution It encloses, should all cover in the claim of the present invention and the range of specification.

Claims (5)

1. a kind of sensitive medicament-carried liposomes of pH of SPIO tracers, which is characterized in that described including bulk pharmaceutical chemicals, auxiliary material and tracer Bulk pharmaceutical chemicals are one kind in water soluble drug or fat-soluble medicine, and the auxiliary material includes phosphatidyl-ethanolamine, cholesterol, linoleic acid And carboxymethyl chitosan, the tracer are SPIO nano particle, the sensitive medicament-carried fat of pH of the SPIO tracers Plastid is obtained using following quality proportioning：1~10 part of bulk pharmaceutical chemicals, 1~50 part of phosphatidyl-ethanolamine, 1~30 part of cholesterol, sub- oil 1~30 part of acid, 0~10 part of carboxymethyl chitosan, 0~10 part of SPIO nano particle.
2. a kind of sensitive medicament-carried liposomes of pH of SPIO tracers as described in claim 1, which is characterized in that the water-soluble pesticide Object includes adriamycin, Epi-ADM, pyrrole adriamycin, vincristine, Etoposide, cis-platinum, Nedaplatin, carboplatin, gemcitabine, hydroxyl Camptothecine and Misonidazole；The fat-soluble medicine includes taxol, Docetaxel, camptothecine.
3. a kind of sensitive medicament-carried liposomes of pH of SPIO tracers as described in claim 1, which is characterized in that the auxiliary material also wraps It includes dioleoylphosphatidylethanolamine, lecithin, hydrogenated soy phosphatidyl choline, phosphatidylinositols, Distearoyl Phosphatidylethanolamine, gather Glycation Distearoyl Phosphatidylethanolamine, Cholesteryl hemisuccinate, palmitoylhomocysteine, oleic acid, vitamin E, one or any several combination in metal chelating agent and butylated hydroxyarisol.
4. a kind of preparation method of the sensitive medicament-carried liposomes of pH of SPIO tracers, which is characterized in that include the following steps：
S1：Take 1~30 part of 1~50 part of phosphatidyl-ethanolamine, 1~30 part of cholesterol and linoleic acid in flask, be added chloroform into Then row dissolving is added 1~10 part of water soluble drug solution and carries out ultrasound, until forming uniform w/o type emulsion；
S2：Flask is connect with Rotary Evaporators, is performed under reduced pressure evaporation, forms gel state；1 is added into flask The PBS buffer solution that~10 parts of pH are 7.4 continues evaporation under reduced pressure and forms aqueous suspension；
S3：It is added after 0~10 part of SPIO nano particle and carries out aqueous suspension elder generation postposition for -80 DEG C, 50 DEG C Freeze thawing is repeated 3 times；Then using supercentrifugal process remove the SPIO nano particle that is not packed in of aqueous suspension with And water soluble drug, obtain liposome turbid liquor；
S4：The carboxymethyl chitosan solution that 0~10 part of mass percent is 0.3% is added into liposome turbid liquor, carries out water 30min is closed, ultrasonic and miillpore filter excessively obtains the sensitive medicament-carried liposomes of pH of SPIO tracers.
5. a kind of preparation method of the sensitive medicament-carried liposomes of pH of SPIO tracers as claimed in claim 4, which is characterized in that step Further include vitamin E as oxidant in rapid S1.
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