CN102391499A - Preparation method of polymer for quickly releasing active components of masticinic acid under exciting of reduction - Google Patents
Preparation method of polymer for quickly releasing active components of masticinic acid under exciting of reduction Download PDFInfo
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Abstract
The invention belongs to the fields of high molecular materials and biomedical engineering, and particularly relates to a preparation method of polymer for quickly releasing active components of masticinic acid under the exciting of reduction. The preparation method comprises the following steps: the two ends of polyethylene glycol are connected with the active components of the masticinic acid by disulfide bonds; the active components exist stably in common body-fluid environment; due to hydrophobicity, the active components of the masticinic acid form a hydrophobic kernel; a shell is hydrophilic polyethylene glycol; once the active components reach the lesion position, due to exciting of the reduction environment, the disulfide bonds start to be fractured, so that the active components of the masticinic acid in the kernel can be quickly released, further the treating effect of medicines is improved and the toxic and side effects are reduced.
Description
Technical field
The invention belongs to macromolecular material and biomedical engineering field, be specifically related to the preparation method of the polymkeric substance of snap-out release masticinic acid activeconstituents under a kind of also primary stimuli.
Background technology
The olibanum resinoid natural gum ester that is called as salai is used as anti-inflammatory agent in traditional India herbalist medicine.Ancient India herbalist's medicine document description its therepic use.The clinical trail test of being undertaken by India CSIR laboratory has clearly illustrated in 88% patient and has reached good level; And there are not adverse side effect (Singh, G.B., Status report; Anti-inflammatory drugs from plant sources, 1982).On the patient who suffers from the key smoking cessation of knee, carry out at random, double blinding, placebo shown (Kimmatkar, Phytomedicine, 2003,10,3 ~ 7) such as the significant pain improvement of statistics, detumescence and knee bends increases to good clinical trial.The result of treatment that Boswellia serrata extract is shown the intestines colitis patient that bursts can (Gupta, I wait people, Eur) J.Med with the comparison of sulfasalazine and mesalazine; Res., 1998,3,511-14 and Gerhardt; H., wait people, Gastroenterol; 2001,39,11 ~ 17).
And USP (patent No.: WO 00/66111) report; Four kinds of compounds (beta boswellic acid, beta boswellic acid ethyl ester, 11-carbonyl-beta boswellic acid, 11-carbonyl-beta boswellic acid ethyl ester) are wherein mixed by a certain percentage, as the treatment autoimmune disorder; Patent (the patent No.: 200810201528.X) show that 11-carbonyl-beta-acetyl masticinic acid can suppress the growth of tumour cell; (patent No. is patent: 200480017755.7) show and utilize masticinic acid activeconstituents treatment of arthritis effectively.Therefore the masticinic acid activeconstituents is because its potential effect to illnesss such as treatment cancer, psoriasis, sacroiliitis has become the target of concentrating research.
Metabolism is fast in vivo to medicine at present, and the transformation period is short, needs frequent a large amount of administration, and the shortcoming of target property difference, and pharmaceutical carrier begins by broad research.After medicine and carrier formed drug-loading system, the absorption of medicine and distribution received the influence of the physico-chemical property of carrier.Select the appropriate carriers material according to clinical requirement, not only can conduct drugs to target organ, and also play useful effect for pharmaceutical carrier character and pharmacologically active.And product of the present invention does not need pharmaceutical carrier, in the time of can in human body, touching lesion locations, under the stimulation of reducing environment, can discharge the masticinic acid activeconstituents, thus the treatment disease, and these all are based on the characteristic of disulfide linkage.
Sulfydryl-disulfide exchange reaction is quick, reversible, is bringing into play important effect in (like protein structure, enzymic activity, oxidation-reduction balance etc.) aspect the many biological functions that keep active somatic cell.Gsh is a kind of small-molecular peptides of being made up of three amino acid that contains sulfydryl; Reduced form (GSH) and two kinds of forms of oxidized form (GSSG) are arranged; They are that topmost oxidation-reduction is right in the zooblast; There is the mutual transformation between NADPH-GSSG reductase catalysis amphitypy in most forms with reduced glutathion under physiological condition.In plastosome, tenuigenin, nucleus, Secretory Pathway and extracellular space, keeping a kind of nonequilibrium state of uniqueness between the GSH/GSSG.Reduced glutathion (GSH) is very big in the concentration difference of partes corporis humani position; For example has only 2 ~ 20uM at body fluid (like blood) and extracellular; Cell interior but can be reached for more than the 0.5mM, and the concentration of tumour cell inside is Normocellular especially more than at least 4 times.The existence of high density GSH in the tumour cell; For it has created a kind of inside reductibility environment of uniqueness; This provides corresponding signal with regard to the polymkeric substance that connects for disulfide linkage, and the research that therefore is directed against the reduction-sensitive polymer micelle of drug delivery in the cell becomes noticeable gradually.For example, people such as Zhong have prepared with the di-block copolymer (Dextran-S-S-PCL) of biomacromolecule VISOSE (Dextran) as hydrophilic chain, (Biomacromolecules, 2010,11 (4): 848-854); People such as Li have then prepared to gather the di-block copolymer that leucine is a hydrophobic segment (PEG-S-S-Pleu) (Polymer, 2011,52 (16): 3580-3586).
Summary of the invention
The object of the present invention is to provide the preparation method of the polymkeric substance of snap-out release masticinic acid activeconstituents under a kind of also primary stimuli.
The objective of the invention is to connect the masticinic acid activeconstituents through disulfide linkage, make it have good environment-responsive, improve the result of treatment of medicine, alleviate toxic side effect at the two ends of polyoxyethylene glycol.
The preparation method of the polymkeric substance of snap-out release masticinic acid activeconstituents under a kind of also primary stimuli provided by the invention, concrete steps are following:
With molecular weight is that 1000 ~ 10000 polyoxyethylene glycol adds reaction kettle, and dispersing and dissolving adds the caustic alkali A aqueous solution of weight percentage 40% in the solvent methyl-sulphoxide, and the stirring at normal temperature reaction is after 0.5 ~ 3 hour; Add the Mono Chloro Acetic Acid of 5 ~ 10 times of amounts of polyoxyethylene glycol terminal hydroxy group total mole number, temperature of reaction is 50 ~ 75 ℃, and the reaction times is 24 ~ 48 hours; Regulate PH to neutral, suction filtration, concentrated solvent; In deionized water, dialyse, freeze-drying must be arrived two ends and contained the polyoxyethylene glycol of holding carboxyl; The polyoxyethylene glycol of holding carboxyl is contained at resulting two ends be dissolved in the solvent anhydrous methylene chloride, add the N of 1 ~ 5 times of amount of polyoxyethylene glycol terminal hydroxy group total mole number, the N'-NSC 57182, and according to N; N'-NSC 57182 mole number adds N-hydroxy-succinamide, and system is room temperature reaction under argon gas or nitrogen protection, reacts after 12 ~ 24 hours; This solution is slowly dropped in the dichloromethane solution of cystamine of 5 ~ 10 times of amounts of polyoxyethylene glycol terminal hydroxy group total mole number, room temperature reaction, the reaction times is 12 ~ 24 hours; Through suction filtration, deposition, concentrated solvent; In deionized water, dialyse, freeze-drying obtains containing the amino polyoxyethylene glycol of end; This masticinic acid activeconstituents that contains 1.5 ~ 3 times of amino total amounts of the amino polyoxyethylene glycol of end is added another reaction kettle, and dispersing and dissolving adds the N of 1 ~ 5 times of amino total amount of polyoxyethylene glycol in the dissolving methyl-sulphoxide; The N'-NSC 57182, and according to N, N'-NSC 57182 mole number adds N-hydroxy-succinamide; System is room temperature reaction under argon gas or nitrogen protection, reacts after 12 ~ 24 hours, and the dimethyl sulfoxide solution that will contain the amino polyoxyethylene glycol of end slowly drops in the above-mentioned solution; Room temperature reaction, the reaction times is 12 ~ 24 hours, through suction filtration; Deposition, concentrated solvent is dialysed in deionized water; Freeze-drying promptly obtains required product.
Among the present invention, described caustic alkali A is one or both in sodium hydroxide or the Pottasium Hydroxide.
Among the present invention; Described masticinic acid activeconstituents is α-masticinic acid, beta boswellic acid, α-masticinic acid ethyl ester, beta boswellic acid ethyl ester, 11-carbonyl-beta boswellic acid, 11-carbonyl-beta boswellic acid ethyl ester, γ-masticinic acid, 2 α, 3 α-two hydroxyls-12-alkene-24-carboxylic acid, 3 Alpha-hydroxies-9; 12-diene-24-carboxylic acid, 3-carbonyl-root of gansui-8; 24-diene-21 acid, the 3 Alpha-hydroxy roots of gansui-8; 24-diene-21 acid, the 3 beta-hydroxy roots of gansui-8,24-diene-21 acid or 3 α-carboxyl root of gansui-8, a kind of in 24-diene-21 acid.
Among the present invention, described product is to connect the masticinic acid activeconstituents at the polyoxyethylene glycol two ends through disulfide linkage, and this product can decompose in reducing environment and come off and discharge the masticinic acid activeconstituents, and the molecular weight of this product is 1500 ~ 10000.
The invention has the advantages that: the polymkeric substance of snap-out release masticinic acid activeconstituents under a kind of also primary stimuli of the present invention's preparation is to connect the masticinic acid activeconstituents through disulfide linkage at the two ends of polyoxyethylene glycol, in general body fluid environment, is stable existence; The masticinic acid activeconstituents is because hydrophobicity constitutes hydrophobic inner core; Shell is hydrophilic polyoxyethylene glycol, in case arrive lesion locations, because the stimulation of reducing environment; Disulfide linkage begins fracture; Thereby snap-out release goes out the masticinic acid activeconstituents in the kernel, thereby has improved the result of treatment of medicine, alleviates toxic side effect.
Embodiment
Following examples are to further specify of the present invention, rather than limit scope of the present invention.
Embodiment 1
2g adds reaction kettle with polyoxyethylene glycol (molecular weight is 1000), and dispersing and dissolving is in solvent methyl-sulphoxide (DMSO), adds the NaOH aqueous solution of weight percentage 40%, and the stirring at normal temperature reaction is after 0.5 hour; Add the total 2g Mono Chloro Acetic Acid of polyoxyethylene glycol terminal hydroxy group, temperature of reaction is 50 ℃, and the reaction times is 24 hours; Regulate PH to neutral, suction filtration, concentrated solvent; In deionized water, dialyse, freeze-drying must be arrived two ends and contained the polyoxyethylene glycol of holding carboxyl; The polyoxyethylene glycol of holding carboxyl is contained at resulting two ends be dissolved in the solvent anhydrous methylene chloride, add 1.65g N, N'-NSC 57182 (DCC); 0.92g N-hydroxy-succinamide (NHS), system is room temperature reaction under argon gas or nitrogen protection, reacts after 12 hours; This solution is slowly dropped in the dichloromethane solution of cystamine (1.2g), room temperature reaction, the reaction times is 12 hours; Through suction filtration, deposition, concentrated solvent; In deionized water, dialyse, freeze-drying obtains containing the amino polyoxyethylene glycol of end; 4g α-masticinic acid is added another reaction kettle, and dispersing and dissolving adds 1.65g N, N'-NSC 57182 (DCC) in dissolving methyl-sulphoxide (DMSO); 0.92g N-hydroxy-succinamide (NHS), system is room temperature reaction under argon gas or nitrogen protection, reacts after 12 hours; The dimethyl sulfoxide solution that will contain the amino polyoxyethylene glycol of end slowly drops in the above-mentioned solution, room temperature reaction, and the reaction times is 12 hours; Through suction filtration, deposition, concentrated solvent; Be used in the deionized water and dialyse, freeze-drying promptly obtains required product.
Embodiment 2
2g adds reaction kettle with polyoxyethylene glycol (molecular weight is 2000), and dispersing and dissolving is in solvent methyl-sulphoxide (DMSO), adds the KOH aqueous solution of weight percentage 40%, and the stirring at normal temperature reaction is after 1 hour; Add the total 1.5g Mono Chloro Acetic Acid of polyoxyethylene glycol terminal hydroxy group, temperature of reaction is 55 ℃, and the reaction times is 24 hours; Regulate PH to neutral, suction filtration, concentrated solvent; In deionized water, dialyse, freeze-drying must be arrived two ends and contained the polyoxyethylene glycol of holding carboxyl; The polyoxyethylene glycol of holding carboxyl is contained at resulting two ends be dissolved in the solvent anhydrous methylene chloride, add 0.83g N, N'-NSC 57182 (DCC); 0.46g N-hydroxy-succinamide (NHS), system is room temperature reaction under argon gas or nitrogen protection, reacts after 18 hours; This solution is slowly dropped in the dichloromethane solution of cystamine (1.5g), room temperature reaction, the reaction times is 18 hours; Through suction filtration, deposition, concentrated solvent; In deionized water, dialyse, freeze-drying obtains containing the amino polyoxyethylene glycol of end; 1.5g11-carbonyl-beta boswellic acid is added another reaction kettle, and dispersing and dissolving adds 0.83g N, N'-NSC 57182 (DCC) in dissolving methyl-sulphoxide (DMSO); 0.46 g N-hydroxy-succinamide (NHS), system is room temperature reaction under argon gas or nitrogen protection, reacts after 12 hours; The dimethyl sulfoxide solution that will contain the amino polyoxyethylene glycol of end slowly drops in the above-mentioned solution, room temperature reaction, and the reaction times is 18 hours; Through suction filtration, deposition, concentrated solvent; Be used in the deionized water and dialyse, freeze-drying promptly obtains required product.
Embodiment 3
4g adds reaction kettle with polyoxyethylene glycol (molecular weight is 4000), and dispersing and dissolving is in solvent methyl-sulphoxide (DMSO), adds the KOH aqueous solution of weight percentage 40%, and the stirring at normal temperature reaction is after 2 hours; Add the total 2.5g Mono Chloro Acetic Acid of polyoxyethylene glycol terminal hydroxy group, temperature of reaction is 60 ℃, and the reaction times is 24 hours; Regulate PH to neutral, suction filtration, concentrated solvent; In deionized water, dialyse, freeze-drying must be arrived two ends and contained the polyoxyethylene glycol of holding carboxyl; The polyoxyethylene glycol of holding carboxyl is contained at resulting two ends be dissolved in the solvent anhydrous methylene chloride, add 2.1g N, N'-NSC 57182 (DCC); 1.2g N-hydroxy-succinamide (NHS), system is room temperature reaction under argon gas or nitrogen protection, reacts after 24 hours; This solution is slowly dropped in the dichloromethane solution of cystamine (0.5g), room temperature reaction, the reaction times is 36 hours; Through suction filtration, deposition, concentrated solvent; In deionized water, dialyse, freeze-drying obtains containing the amino polyoxyethylene glycol of end; The 2.5g 3 beta-hydroxy roots of gansui-8 are added another reaction kettle, and dispersing and dissolving adds 2.1g N, N'-NSC 57182 (DCC) in dissolving methyl-sulphoxide (DMSO); 1.2g N-hydroxy-succinamide (NHS), system is room temperature reaction under argon gas or nitrogen protection, reacts after 24 hours; The dimethyl sulfoxide solution that will contain the amino polyoxyethylene glycol of end slowly drops in the above-mentioned solution, room temperature reaction, and the reaction times is 18 hours; Through suction filtration, deposition, concentrated solvent; Be used in the deionized water and dialyse, freeze-drying promptly obtains required product.
Embodiment 4
10g adds reaction kettle with polyoxyethylene glycol (molecular weight is 5000), and dispersing and dissolving is in solvent methyl-sulphoxide (DMSO), adds the NaOH aqueous solution of weight percentage 40%, and the stirring at normal temperature reaction is after 3 hours; Add the total 3g Mono Chloro Acetic Acid of polyoxyethylene glycol terminal hydroxy group, temperature of reaction is 65 ℃, and the reaction times is 48 hours; Regulate PH to neutral, suction filtration, concentrated solvent; In deionized water, dialyse, freeze-drying must be arrived two ends and contained the polyoxyethylene glycol of holding carboxyl; The polyoxyethylene glycol of holding carboxyl is contained at resulting two ends be dissolved in the solvent anhydrous methylene chloride, add 3g N, N'-NSC 57182 (DCC); 1.7g N-hydroxy-succinamide (NHS), system is room temperature reaction under argon gas or nitrogen protection, reacts after 24 hours; This solution is slowly dropped in the dichloromethane solution of cystamine (3g), room temperature reaction, the reaction times is 12 hours; Through suction filtration, deposition, concentrated solvent; In deionized water, dialyse, freeze-drying obtains containing the amino polyoxyethylene glycol of end; With the 4g 3 Alpha-hydroxy roots of gansui-8,24-diene-21 acid adds another reaction kettle, and dispersing and dissolving adds 3g N in dissolving methyl-sulphoxide (DMSO); N'-NSC 57182 (DCC), 2g N-hydroxy-succinamide (NHS), system is room temperature reaction under argon gas or nitrogen protection, reacts after 12 hours; The dimethyl sulfoxide solution that will contain the amino polyoxyethylene glycol of end slowly drops in the above-mentioned solution, room temperature reaction, and the reaction times is 12 hours; Through suction filtration, deposition, concentrated solvent; Be used in the deionized water and dialyse, freeze-drying promptly obtains required product.
Embodiment
5In order further to understand the drug action of this product, carry out the test of following animal acute toxicity test and general pharmacology, to prove the security of medicine according to the invention.
Animal acute toxicity test
The product that will make by method provided by the present invention, through rat and mouse oral administration, find that the result is following:
1) mouse is adopted when containing 50 milligrams/kilogram of masticinic acid activeconstituentss (be equivalent to clinical recommended dose 250 times), any toxic reaction and death do not occur, prove that this product does not have acute toxicity to mouse.
2) rat is adopted when containing 20 milligrams/kilogram of masticinic acid activeconstituentss (be equivalent to clinical recommended dose 100 times), any toxic reaction and death do not occur, prove that this product does not have acute toxicity to rat.
The general pharmacology test
Adopt the Beagle dog that this product is carried out general pharmacology and learn research.
The Beagle dog is oral contain the masticinic acid activeconstituents be respectively low (5 milligrams/kilogram), in this product and the zero(ppm) water (control experiment) of (15 milligrams/kilogram), high (25 milligrams/kilogram) three dosage; Totally 4 groups are observed cardiovascular systems, respiratory system.
The result: this product does not all have obvious influence to the P wave voltage of Beagle dog systolic pressure, diastolic pressure, mean arterial pressure, heart rate, the rhythm of the heart, ECG, T wave voltage, QRS time, PR interval, QT interval, ST section, respiratory rate, the rhythm and pace of moving things and amplitude.
The result shows that this product does not have obvious influence to Beagle dog cardiovascular systems, respiratory system.
Embodiment 6The useful medicinal effect that following clinical application research and conclusion further illustrate product of the present invention.
15 ~ 40 years old psoriatic of selected altogether 15 examples of test.The patient goes to a doctor and did not use any oral and external medication in previous month.Patient's this product all for oral use, after 1 month, observing effect.The patient all has no adverse reaction, and after the treatment unusual effect is arranged.
Typical case
Liu's surname patient, the male sex, 22 years old.
Before the prescription on individual diagnosis, the skin of back papule was shown effect 3 years repeatedly, and fash shows as surplus the red papule 50 of shoulder, skin of back grain of rice size, and the scales of skin that peel off is many and come off easily, often had the sensation of itch during touch, was diagnosed as the vulgaris psoriasis.Go to a doctor and do not use any oral or externally applied agent treatment in preceding 1 month.Give oral this product, sooner or later each is with once, two week the back observing effects, finds no new rash appearance, and papule quantity reduces to 15, color is tending towards light color.After continuing medication to 4 week, papule is dwindled, and reduces to 4, fades away.To 6 all further consultations, papule all disappears.This routine patient's therapeutic evaluation is for curing.Part and systemic adverse reactions do not appear during the medication.
Claims (4)
1. preparation method of the polymkeric substance of snap-out release masticinic acid activeconstituents under the primary stimuli also is characterized in that concrete steps are following:
(1) be that 1000 ~ 10000 polyoxyethylene glycol adds reaction kettle with molecular weight, and dispersing and dissolving is in the solvent methyl-sulphoxide,
The caustic alkali A aqueous solution that adds weight percentage 40%, stirring at normal temperature reaction added the Mono Chloro Acetic Acid of 5 ~ 10 times of amounts of polyoxyethylene glycol terminal hydroxy group total mole number after 0.5 ~ 3 hour; Temperature of reaction is 50 ~ 75 ℃, and the reaction times is 24 ~ 48 hours, regulates PH to neutral; Suction filtration, concentrated solvent is dialysed in deionized water; Freeze-drying must be arrived two ends and contained the polyoxyethylene glycol of holding carboxyl;
(2) polyoxyethylene glycol of holding carboxyl is contained at resulting two ends and be dissolved in the solvent anhydrous methylene chloride, add the polyoxyethylene glycol end
The N of 1 ~ 5 times of amount of hydroxyl total mole number, the N'-NSC 57182, and according to N; N'-NSC 57182 mole number adds N-hydroxy-succinamide, and system is room temperature reaction under argon gas or nitrogen protection, reacts after 12 ~ 24 hours; This solution is slowly dropped in the dichloromethane solution of cystamine of 5 ~ 10 times of amounts of polyoxyethylene glycol terminal hydroxy group total mole number, room temperature reaction, the reaction times is 12 ~ 24 hours; Through suction filtration, deposition, concentrated solvent; In deionized water, dialyse, freeze-drying obtains containing the amino polyoxyethylene glycol of end;
(3) this masticinic acid activeconstituents that contains 1.5 ~ 3 times of amino total amounts of the amino polyoxyethylene glycol of end is added another reaction
Still, and dispersing and dissolving adds the N of 1 ~ 5 times of amino total amount of polyoxyethylene glycol, the N'-NSC 57182 in the dissolving methyl-sulphoxide; And according to N, N'-NSC 57182 mole number adds N-hydroxy-succinamide, and system is room temperature reaction under argon gas or nitrogen protection, reacts after 12 ~ 24 hours; The dimethyl sulfoxide solution that will contain the amino polyoxyethylene glycol of end slowly drops in the above-mentioned solution, room temperature reaction, and the reaction times is 12 ~ 24 hours; Through suction filtration, deposition, concentrated solvent; In deionized water, dialyse, freeze-drying promptly obtains required product.
2. the preparation method of the polymkeric substance of snap-out release masticinic acid activeconstituents is characterized in that described caustic alkali A is one or both in sodium hydroxide or the Pottasium Hydroxide under a kind of also primary stimuli according to claim 1.
3. the preparation method of the polymkeric substance of snap-out release masticinic acid activeconstituents under a kind of also primary stimuli according to claim 1; It is characterized in that described masticinic acid activeconstituents is α-masticinic acid, beta boswellic acid, α-masticinic acid ethyl ester, beta boswellic acid ethyl ester, 11-carbonyl-beta boswellic acid, 11-carbonyl-beta boswellic acid ethyl ester, γ-masticinic acid, 2 α, 3 α-two hydroxyls-12-alkene-24-carboxylic acid, 3 Alpha-hydroxies-9; 12-diene-24-carboxylic acid, 3-carbonyl-root of gansui-8; 24-diene-21 acid, the 3 Alpha-hydroxy roots of gansui-8; 24-diene-21 acid, the 3 beta-hydroxy roots of gansui-8,24-diene-21 acid or 3 α-carboxyl root of gansui-8, a kind of in 24-diene-21 acid.
4. the preparation method of the polymkeric substance of snap-out release masticinic acid activeconstituents under a kind of also primary stimuli according to claim 1; It is characterized in that described product is to be connected with the masticinic acid activeconstituents at the polyoxyethylene glycol two ends by disulfide linkage; This product can decompose in reducing environment and come off and discharge the masticinic acid activeconstituents, this product molecular weight be 1500 ~ 10000.
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| CN103160711A (en) * | 2011-12-19 | 2013-06-19 | 通用电气公司 | Nickel-cobalt-based alloy and bond coat and bond coated articles incorporating the same |
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| CN1615888A (en) * | 2004-08-31 | 2005-05-18 | 凌沛学 | Medicine composition and its use |
| WO2006117184A2 (en) * | 2005-05-03 | 2006-11-09 | Novartis Ag | Veterinary composition |
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| CN103160711A (en) * | 2011-12-19 | 2013-06-19 | 通用电气公司 | Nickel-cobalt-based alloy and bond coat and bond coated articles incorporating the same |
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