CN102633817A - Cefoxitin esterified prodrug compound and oral preparations - Google Patents
Cefoxitin esterified prodrug compound and oral preparations Download PDFInfo
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- CN102633817A CN102633817A CN2012100885913A CN201210088591A CN102633817A CN 102633817 A CN102633817 A CN 102633817A CN 2012100885913 A CN2012100885913 A CN 2012100885913A CN 201210088591 A CN201210088591 A CN 201210088591A CN 102633817 A CN102633817 A CN 102633817A
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- cefoxitin
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Abstract
The invention discloses an esterified prodrug compound and salt forming compounds and oral preparations thereof. The prodrug compound is shown in the structural formula (IV) in the specification, takes cefoxitin as an active ingredient and can exist in the form of salts. The prodrug compound has the following advantages that a lipophilic group acetoxy-1-halothane is introduced on the basis of cefoxitin to esterify carboxyl to become the esterified prodrug, thus providing an active pharmaceutical ingredient changing the original dosage forms; orally taken, the esterified prodrug not only relieves pains suffered by the patients during injection but also is not only used in professional organizations, thus saving time and widening the application range of the drug; and the esterified prodrug has a confirmed curative effect.
Description
Technical field
The present invention relates to one type with second generation cephalosporin antibiotics cefoxitin be effective constituent esterification prodrug compound and salt-forming compound thereof with and oral prepns, belong to the medical compounds field.
Background technology
MK-306 is the semi-synthetic cynnematin of the s-generation (belonging to the cephamycin-type microbiotic); Develop listing in 1974, more than 20 country's listings in the world subsequently by U.S. MSD Corp.; Injection went on the market in China in 1992, and bulk drug went on the market in China in 2002.At the cefoxitin sodium for injection commodity of U.S.'s listing " MEFXOIN by name
" (or claim " Cefoxitin
"), the specification of FDA approval is 1.0,2.0g.Be mainly used in peritonitis and other intraperitoneal, interior, the gynecological infection of pelvic cavity that sensitive organism (as: streptococcus aureus, intestinal bacteria, pneumobacillus, proteus, morganella morganii strain, providencia, Peptostreptococcus, Bacteroides etc.) causes clinically; Septicemia; Endocarditis, urinary tract infections (comprising gonorrhoea), respiratory tract infection; Bone joint infection, skin soft-tissue infection.These article are powder injection, can quiet notes or intravenous drip or intramuscular injection.MK-306 is strong than other cephalosporins to the effect of anerobes, especially bacteroides fragilis.Because cefoxitin has the high-efficiency antimicrobial effect to anerobes; Also kept extremely strong anti-microbial activity to aerophil; This a pair of aerophil and anerobes all have stronger active broad spectrum antibiotic in clinical treatment anaerobic infection or polyinfection, possibly become a kind of selection promising and the alternative present drug combination of conduct.Therefore, can treat responsive microbial peritonitis and other intraperitoneal, interior, the gynecological infection of pelvic cavity clinically effectively, septicemia, endocarditis, urinary tract infections (comprising gonorrhoea), respiratory tract infection, bone joint infection, skin soft-tissue infection, total effective rate is 74%.
MK-306 is a kind of cephamycin derivant, is to contain a methoxyl group on No. 7 positions of its beta-lactam nucleus with the cynnematin difference.This structural difference makes cefoxitin different with existing cephalosporins derivatives aspect the Degradation of the tolerance β-Nei Xiananmei that gram-negative bacteria produced.The Production by Bacteria β-Nei Xiananmei is its drug-fast main mechanism, and is to the drug-fast major cause of β-Nei Xiananleikangshengsu of new generation by plasmid-mediated extended spectrum (ESBLs).Experiment shows that cefoxitin sodium is 94.88% to the responsive rate of producing the ESBLs bacterium, is to tackle the most effectively one of the medicine that produces the ESBLs bacterium.Because anti-enzyme ability and powerful in short-term sterilizing ability that MK-306 is remarkable, make it in zymogenic bacteria strain infection and intractable, complicacy infectation of bacteria, show splendid result of treatment.
MK-306 is semi-synthetic cephamycin-type microbiotic; Because having suppressed bacteria cell wall synthesizes and kill bacteria; Its structure is the same with cefotetan and cefmetazole, on 7 C atoms, has a trans methoxyl group, thereby has strengthened producing the resistivity of β ?lactamase bacterium enzymolysis.Cefoxitin is to many G-and G+ is aerobic and anerobes all has anti-microbial activity, and clinical efficacy is high, and toxic side effect is low, and anaphylaxis is few, is comparatively ideal anti-infectives, can be widely used in the control of clinical various infection.
These article absorb rapidly, and Plasma Concentration is high, and tissue permeability is good.Each internal organs and body fluid (as, urine, bile, sputum, ascites) in higher drug concentration is all arranged, thereby improved sterilizing power greatly.This not metabolism of article is mainly drained with original shape from urine through kidney.Plasma Concentration and drug eliminated half life then obviously increase with the renal dysfunction degree.
Tests such as the MK-306 acute toxicity test of in multiple animal body, carrying out, specific toxicity show; Have only when its consumption surpasses human dosage; When giving 1-7 that rat and injected in mice be about the human maximal dose and 1.5 times; Just observe fetal weight and slightly descend, but do not see teratogenecity or fetotoxicity.Do not see other serious adverse effects report.In addition, safety testing is the result show, MK-306 vein and administered intramuscular can not cause IRs such as vascular degeneration and muscular death, also can not cause the transformation reactions of cavy, do not see aggegation and haemolysis yet.Therefore, these article have shown good security aspect toxicology.Having characteristics such as wide spectrum, efficient, anti-enzyme, low toxicity, is the anti-infective oral pharmaceutical of widespread use clinically.
As clinical therapeutic efficacy cephalosporin compound preferably, in existing structure, have only cefoxitin sodium for injection at present, do not see the report of other structure.As powder injection, quiet only notes or intravenous drip or intramuscular injection, but the local pain of its maximum shortcoming when being administration; Give patient's physiology and cause great misery mentally; And all need arrive professional institution and just can carry out, it is also longer that intravenous drip accounts for the time, can't satisfy the demand of different crowd.Expansion cephalo west class D compound structure is to expand the problem that its purposes has become urgent need to solve.
Summary of the invention
It is single that the present invention is intended to overcome the cefoxitin sodium for injection usage, uses inconvenience, can't satisfy the defective of different crowd demand, and a kind of cefoxitin esterification prodrug compound and salt-forming compound and oral prepns are provided.This medical compounds can be used as oral prepns and uses, thereby the misery when having reduced patient because of injecting drug use has been expanded purposes, makes medication safer.
The present invention realizes the object of the invention through implementing following technical scheme:
The invention is characterized in: what represent with the structure formula IV is the esterification prodrug compound of effective constituent with the cefoxitin:
（Ⅳ）
Chemistry is by name: (6R, 7S)-assorted nitrogen dicyclo [4.2.0] oct-2-ene of 3-(carbamyl oxygen methyl)-7-methoxyl group-8-oxo-7-[2-(2-thienyl) kharophen]-5-thia-1--2-carboxylic acid-1-acetoxyl group ethyl ester.
The form of all right salt of medicinal compound of the present invention exists, and the form of its medicinal compound salt shows as hydrochloride, vitriol, methane sulfonates and PHENRAMINE MALEATE.
The preparation method of said cefoxitin esterification prodrug compound is following:
In reaction flask, cefoxitin salt is present in the polar solvent, be cooled to-20 ~ 25 ℃ after, added 1-acetyl oxygen-1-halogen ethane controlled temperature-20 ~ 25 ℃ condensation reaction 30 ~ 60 minutes;, add extraction after having reacted successively with organic solvent and sodium bicarbonate aqueous solution, extract; Organic phase is washed with sodium bicarbonate aqueous solution again, behind the concentrating under reduced pressure, adds recrystallisation solvent; Crystallization, filtration, 40 ℃ ~ 60 ℃ of controlled temperature, pressure≤0.01MPa vacuum-drying gets the targeted thing.
Its chemical reaction general formula is following:
R wherein
1For K, Na,
,
Said cefoxitin salt is sodium salt, the sylvite that cefoxitin and alkali metal cpd form, with the quaternary amine of triethylamine or DBU formation.
Said alkali metal cpd is selected from sodium hydrogencarbonate, saleratus, yellow soda ash, salt of wormwood, sodium hydroxide, Pottasium Hydroxide or Sodium isooctanoate.
The mol ratio of said cefoxitin and alkali metal cpd, triethylamine or DBU is 1:1 ~ 2, preferred 1:1.02 ~ 1.20.
Said polar solvent is N, dinethylformamide, DMAC N,N, or both are by the mixed solvent of any weight ratio.
Said 1-acetyl oxygen-1-halogen ethane is 1-acetyl oxygen-1-monochloroethane, 1-acetyl oxygen-1-monobromethane, 1-acetyl oxygen-1-iodoethane, preferred 1-acetyl oxygen-1-monobromethane.The mol ratio of said 1-acetyl oxygen-1-halogen ethane and cefoxitin salt is 1 ~ 2:1, preferred 1.05 ~ 1.25:1.
Said extraction uses organic solvent to be methylene dichloride, trichloromethane, ETHYLE ACETATE, methyl acetate or isopropyl acetate.
Cefoxitin salt and organic solvent weightmeasurement ratio are 1:7 ~ 14 during said extraction.
It is 1 ~ 10wt% that sodium bicarbonate aqueous solution concentration is used in said extraction, preferred 3 ~ 5wt%.
Said cefoxitin salt and sodium bicarbonate aqueous solution weightmeasurement ratio are 1:8 ~ 15.
It is 1 ~ 10wt% that sodium bicarbonate aqueous solution concentration is used in said washing, preferred 3 ~ 5wt%.
Said cefoxitin salt uses the sodium bicarbonate aqueous solution weightmeasurement ratio to be 1:4 ~ 8 with washing.
Said crystallization uses organic solvent to be ethanol, a kind of in Virahol, ether, isopropyl ether, DIPE, acetone, toluene, hexanaphthene, normal hexane, the sherwood oil, or any two or more mixed solvent with arbitrary proportion in them.
Cefoxitin salt and crystallization use the weight of solvent volume ratio to be 1:8 ~ 15 during said crystallization.
Cefoxitin esterification prodrug salt-forming compound according to the invention obtains through following manner:
The cefoxitin ester is present in the organic solvent, under-10 ℃ ~ 30 ℃ temperature, adds acid, after crystallization, solid-liquid separation, with 40 ℃ ~ 60 ℃ of solid controlled temperature, pressure≤0.01MPa vacuum-drying gets the targeted thing.
Said organic solvent is selected from methyl alcohol, ethanol; A kind of in Virahol, methylene dichloride, ETHYLE ACETATE, ether, isopropyl ether, DIPE, acetone, toluene, hexanaphthene, normal hexane, the sherwood oil, or any two or more the mixed solvent in them with any weight ratio.
The weightmeasurement ratio of said cefoxitin ester and organic solvent is 1:5 ~ 10.
Said acid is hydrochloric acid, sulfuric acid, methanesulfonic or toxilic acid.
Said cefoxitin ester is 1:1 ~ 2 with the mol ratio of acid.
Cefoxitin esterification prodrug compound of the present invention, its route of administration is oral, formulation comprises tablet, dispersible tablet, chewable tablet, orally disintegrating tablet, granule, capsule and dry suspensoid etc.
Oral prepns of the present invention is to be made by the universal method on the technology of pharmaceutics by cefoxitin esterification prodrug compound and auxiliary material; Said auxiliary material comprises on the technology of pharmaceutics necessary, like thinner, tackiness agent, disintegrating agent, lubricant, correctives, perfume compound and the sanitas etc. of tablet.
The invention has the advantages that:
The present invention finds in a large amount of tests that cephalo west class D compound is carried out in the structure of modification process; Cefoxitin through on 2 carboxyls with 1-acetyl oxygen-1-halogen ethane condensation after; Just become an esterification prodrug, thereby a kind of bulk drug that changes original formulation is provided.The maximum characteristics of esterification prodrug are to overcome the shortcoming that cefoxitin sodium for injection exists in clinical application, and it is oral changing injection, and its formulation comprises tablet, dispersible tablet, chewable tablet, orally disintegrating tablet, granule, capsule and dry suspensoid etc.; Administered through oral; Not only reduce the misery that patient brings when injection, and need not and to use in professional institution, both saved the time; Also expanded the range of application of medicine greatly; Curative effect is sure, and aspect medicine stability, is superior to MK-306, makes medication safer.
The present invention can adopt following specific embodiment to be described in detail, and should be appreciated that these embodiment are only used for purposes of illustration, and also limits protection scope of the present invention never in any form.Those skilled in the art can make multiple modification or change to embodiment of the present invention under spirit of the present invention and purport under the instruction of this specification sheets, these all will comprise within the scope of the invention.
Embodiment
Embodiment 1: (6R, 7S)-preparation of assorted nitrogen dicyclo [4.2.0] oct-2-ene of 3-(carbamyl oxygen methyl)-7-methoxyl group-8-oxo-7-[2-(2-thienyl) kharophen]-5-thia-1--2-carboxylic acid-1-acetoxyl group ethyl ester (compd A).
Cefoxitin 20g is joined in the reaction flask, add DMAC N,N 50ml; Cool to-20 ℃ and add DBU 7.3g reaction 10 minutes, added 1-acetyl oxygen-1-iodoethane 11.5g reaction 30 minutes, add ETHYLE ACETATE 180ml successively, 4% sodium bicarbonate aqueous solution 220ml extracts; Get organic phase, wash with 4% sodium bicarbonate aqueous solution 110ml, the organic phase concentrating under reduced pressure; Add ether 200ml, crystallization is filtered; 40 ℃ ~ 60 ℃ of controlled temperature, pressure≤0.01MPa vacuum-drying gets compd A 18.7g.Content 99.32%, yield 77.8%.
C
20H
23N
3O
9S
2The ultimate analysis value is: C, 46.77%; H4.51%; N, 8.18%; S, 12.49%.The practical measurement value is: C, 46.85%; H4.55%; N, 8.12%; S, 12.39%.
Embodiment 2: (6R, 7S)-preparation of assorted nitrogen dicyclo [4.2.0] oct-2-ene of 3-(carbamyl oxygen methyl)-7-methoxyl group-8-oxo-7-[2-(2-thienyl) kharophen]-5-thia-1--2-carboxylic acid-1-acetoxyl group ethyl ester (compd A).
Cefoxitin 20g is joined in the reaction flask, add N, dinethylformamide 80ml; Cool to-10 ℃ and add triethylamine 4.9g reaction 20 minutes, add 1-acetyl oxygen-1-monobromethane 8.6g, reaction is 60 minutes under this temperature; Add methylene dichloride 200ml respectively, 5% sodium bicarbonate aqueous solution 240ml extracts, and gets organic phase, wash with 5% sodium bicarbonate aqueous solution 120ml; With the organic phase concentrating under reduced pressure, add hexanaphthene 180ml, crystallization; Filter, 40 ℃ ~ 60 ℃ of controlled temperature, pressure≤0.01MPa vacuum-drying gets compd A 20.1g.Content 99.39%, yield 83.6%.
Embodiment 3: (6R, 7S)-preparation of assorted nitrogen dicyclo [4.2.0] oct-2-ene of 3-(carbamyl oxygen methyl)-7-methoxyl group-8-oxo-7-[2-(2-thienyl) kharophen]-5-thia-1--2-carboxylic acid-1-acetoxyl group ethyl ester (compd A).
MK-306 20g is joined in the reaction flask, add N, dinethylformamide 100ml adds 1-acetyl oxygen-1-monobromethane 8.2g at-15 ℃ and reacted 45 minutes; Add methyl acetate 180ml respectively, 4% sodium bicarbonate aqueous solution 220ml extracts, and gets organic phase, wash with 3% sodium bicarbonate aqueous solution 110ml; With the organic phase concentrating under reduced pressure, add toluene 160ml, crystallization; Filter, 40 ℃ ~ 60 ℃ of controlled temperature, pressure≤0.01MPa vacuum-drying gets compd A 18.2g.Content 99.53%, yield 79.6%.
Embodiment 4: (6R, 7S)-preparation of assorted nitrogen dicyclo [4.2.0] oct-2-ene of 3-(carbamyl oxygen methyl)-7-methoxyl group-8-oxo-7-[2-(2-thienyl) kharophen]-5-thia-1--2-carboxylic acid-1-acetoxyl group carbethoxy hydrochloride (compd B).
Cefoxitin 20g is joined in the reaction flask, add DMAC N,N 80ml; Cool to-10 ℃ and add triethylamine 5.6g reaction 10 minutes, added 1-acetyl oxygen-1-monobromethane 9.7g reaction 30 minutes, add methylene dichloride 180ml successively, 4% sodium bicarbonate aqueous solution 220ml extracts; Get organic phase, wash, with the organic phase concentrating under reduced pressure with 4% sodium bicarbonate aqueous solution; Add Virahol 200ml, 10 ℃ add 30% isopropanol solution of hydrogen chloride 5.7g, crystallization; Filter, 40 ℃ ~ 60 ℃ of controlled temperature, pressure≤0.01MPa vacuum-drying gets compd B 18.8g.Content 99.25%, yield 73.1%.
C
20H
24N
3O
9S
2Cl ultimate analysis value is: C, 43.67%; H, 4.40%; N, 7.64%; S, 11.66%; Cl, 6.45%.The practical measurement value is: C, 44.02%; H, 4.35%; N, 7.55%; S, 11.73%; Cl, 6.54%.
Embodiment 5: (6R, 7S)-preparation of assorted nitrogen dicyclo [4.2.0] oct-2-ene of 3-(carbamyl oxygen methyl)-7-methoxyl group-8-oxo-7-[2-(2-thienyl) kharophen]-5-thia-1--2-carboxylic acid-1-acetoxyl group carbethoxy hydrochloride (compd B)
Get embodiment 2 gained compound 10g and join in the reaction flask, add ether 80ml, 0 ℃ adds 30% isopropanol solution of hydrogen chloride 3.3g down, and crystallization is filtered, 40 ℃ ~ 60 ℃ of controlled temperature, and pressure≤0.01MPa vacuum-drying gets compd B 9.7g.Content 99.59%, yield 90.6%
Embodiment 6: (6R, 7S)-preparation of assorted nitrogen dicyclo [4.2.0] oct-2-ene of 3-(carbamyl oxygen methyl)-7-methoxyl group-8-oxo-7-[2-(2-thienyl) kharophen]-5-thia-1--2-carboxylic acid-1-acetoxyl group carbethoxy hydrochloride (compd B)
MK-306 20g is joined in the reaction flask, add N, dinethylformamide 50ml and DMAC N,N 50ml; Added 1-acetyl oxygen-1-monobromethane 8.9g reaction 60 minutes at-15 ℃, add trichloromethane 180ml successively, 1% sodium bicarbonate aqueous solution 220ml extracts, and gets organic phase, wash with 1% sodium bicarbonate aqueous solution 110ml; With the organic phase concentrating under reduced pressure, add Virahol 50ml, add isopropyl ether 50ml; Be cooled to 5 ℃, add 30% isopropanol solution of hydrogen chloride 10.8g, crystallization; Filter, 40 ℃ ~ 60 ℃ of controlled temperature, pressure≤0.01MPa vacuum-drying gets compound B-11 7.9g.Content 99.46%, yield 73.1%.
Embodiment 7: (6R, 7S)-preparation of assorted nitrogen dicyclo [4.2.0] oct-2-ene of 3-(carbamyl oxygen methyl)-7-methoxyl group-8-oxo-7-[2-(2-thienyl) kharophen]-5-thia-1--2-carboxylic acid-1-acetoxyl group ethyl ester vitriol (Compound C).
With embodiment 1 gained compound 15g, join in the reaction flask, add isopropyl ether 150ml, 5 ℃ add 3.2g sulfuric acid down, and crystallization is filtered, 40 ℃ ~ 60 ℃ of controlled temperature, pressure≤0.01MPa vacuum-drying gets 16.0g.Content 99.47%, yield 89.6%
C
20H
25N
3O
13S
3The ultimate analysis value is C, 39.27%; H, 4.12%; N, 6.87%; S, 15.73%.The practical measurement value is: C, 38.88%; H, 4.15%; N, 6.90%; S, 15.84%.
Embodiment 8: (6R, 7S)-preparation of assorted nitrogen dicyclo [4.2.0] oct-2-ene of 3-(carbamyl oxygen methyl)-7-methoxyl group-8-oxo-7-[2-(2-thienyl) kharophen]-5-thia-1--2-carboxylic acid-1-acetoxyl group ethyl ester methane sulfonates (Compound D)
MK-306 20g is joined in the reaction flask, add N, dinethylformamide 90ml; Add 1-acetyl oxygen-1-monobromethane 8.5g at 25 ℃ and reacted 45 minutes, add isopropyl acetate 180ml, add 8% sodium bicarbonate aqueous solution 220ml and extract; Get organic phase, wash with 8% sodium bicarbonate aqueous solution 110ml, the organic phase concentrating under reduced pressure; Add Virahol 200ml, add methanesulfonic 4.7g crystallization, filter; 40 ℃ ~ 60 ℃ of controlled temperature, pressure≤0.01MPa vacuum-drying gets Compound D 20.4g.Content 99.36%, yield 75.2%.
C
21H
27N
3O
12S
3The ultimate analysis value is: C, 41.37 %; H, 4.46%; N, 6.89%; S, 15.78%.The practical measurement value is: C, 41.59 %; H, 4.41%; N, 6.86%; S, 15.66%.
Embodiment 9: (6R, 7S)-preparation of assorted nitrogen dicyclo [4.2.0] oct-2-ene of 3-(carbamyl oxygen methyl)-7-methoxyl group-8-oxo-7-[2-(2-thienyl) kharophen]-5-thia-1--2-carboxylic acid-1-acetoxyl group ethyl ester PHENRAMINE MALEATE (compd E).
20g joins in the reaction flask with the cephalo cefoxitin, adds DMAC N,N 60ml, cools to-15 ℃ and adds DBU7.6g reaction 15 minutes; Add 1-acetyl oxygen-1-monobromethane 8.6g and reacted 60 minutes, add ETHYLE ACETATE 180ml successively, add 4% sodium bicarbonate aqueous solution 220ml and extract; Get organic phase, wash, with the organic phase concentrating under reduced pressure with 4% sodium bicarbonate aqueous solution; Add acetone 180ml, add toxilic acid 8.2g, crystallization; Filter, 40 ℃ ~ 60 ℃ of controlled temperature, pressure≤0.01MPa vacuum-drying gets compd E 21.3g.Content 99.28%, yield 72.1%.
C
24H
27N
3O
13S
2The ultimate analysis value is C, 45.78%; H4.32%; N, 6.68%; S, 10.18%.The practical measurement value is: C46.18%; H4.30%; N, 6.61%; S, 10.11%.
Embodiment 10: the method for preparing tablet thereof of compd A
Prescription is formed:
Compd A 100g
Starch 25g
Microcrystalline Cellulose 50g
Cross-linked carboxymethyl cellulose sodium 15g
5% farinaceous size 50ml
Magnesium Stearate 2.0g
Process 1000
Preparation technology: take by weighing recipe quantity compd A, starch, Microcrystalline Cellulose, cross-linked carboxymethyl cellulose sodium respectively, pulverize the back and cross 80 eye mesh screens, mix; Add 5% farinaceous size system softwood; The wet grain of the 20 eye mesh screen systems of crossing, 50 ℃ of dryings 3 hours add Magnesium Stearate and cross the whole grain of 18 mesh sieves; Compressing tablet, every heavily about 0.19g.
Prescription is formed:
Compd B 100g
Lactose 50g
Microcrystalline Cellulose 36g
PVPP 15g
10% 30 POVIDONE K 30 BP/USP
30Solution 40ml
Sodium lauryl sulphate 1.5g
Process 1000
Preparation technology: take by weighing compd B, lactose, Microcrystalline Cellulose, PVPP respectively, pulverize the back and cross 80 eye mesh screens, mix, add 10% 30 POVIDONE K 30 BP/USP
30Solution system softwood, the wet grain of the 30 eye mesh screen systems of crossing, 50 ℃ of dryings 3 hours add sodium lauryl sulphate and cross the whole grain of 20 mesh sieves, the heavily about 0.21g of compressing tablet, sheet.
Embodiment 12: the capsule preparation method thereof of Compound C
Prescription is formed:
Compound C 100g
Microcrystalline Cellulose 50g
Carboxymethylstach sodium 15g
2% hypromellose solution 25ml
Magnesium Stearate 2.0g
Process 1000
Preparation technology: take by weighing recipe quantity Compound C, Microcrystalline Cellulose, carboxymethylstach sodium respectively, pulverize the back and cross 80 eye mesh screens, mix; Add 2% hypromellose solution system softwood; The wet grain of the 20 eye mesh screen systems of crossing, 50 ℃ of dryings 3 hours add Magnesium Stearate and cross the whole grain of 18 mesh sieves; The heavily about 0.17g of filled capsules, capsule 's content.
Embodiment 13: the process for producing granula of Compound D
Prescription is formed:
Compound D 100g
Sucrose 525g
N.F,USP MANNITOL 495g
70% syrup solution 40ml
Lemon flavour 2ml
Process 1000 bags
Preparation technology: take by weighing Compound D, sucrose, N.F,USP MANNITOL respectively, pulverize the back and cross 60 eye mesh screens, mix, add 70% syrup solution system softwood; The wet grain of the 14 eye mesh screen systems of crossing, 50 ℃ of dryings 3 hours are crossed the whole grain of 10 mesh sieves, spray into lemon flavour; Mix packing, every bag of heavily about 1.15g of content.
Embodiment 14: the chewable tablet preparation method of compd A
Prescription is formed:
Compd A 100g
Sucrose 122g
10% starch slurry 40ml
Lemon flavour 2ml
Micropowder silica gel 15g
Magnesium Stearate 2g
Process 1000
Preparation technology: take by weighing compd A, sucrose respectively, pulverize the back and cross 80 eye mesh screens, mix, add 10% starch slurry system softwood; The wet grain of the 20 mesh sieve systems of crossing, 50 ℃ of dryings 3 hours add micropowder silica gel, Magnesium Stearate is crossed the whole grain of 18 mesh sieves, sprays into essence; Mix the heavily about 0.24g of compressing tablet, sheet.
Embodiment 15: the Orally disintegrating piece preparation method of compd A
Prescription is formed:
Compd A 100g
Microcrystalline Cellulose 40g
Lactose 50g
N.F,USP MANNITOL 20g
PVPP 20g
Low-substituted hydroxypropyl cellulose 20g
Magnesium Stearate 2g
Micropowder silica gel 5g
Preparation technology: it is subsequent use that each supplementary material was pulverized 100 mesh sieves, takes by weighing by recipe quantity, mixes, and directly pressed powder promptly gets the heavily about 0.26g of sheet.
Embodiment 16: the dry suspensoid preparation method of compd E
Prescription is formed:
Compd E 100g
Sucrose 900g
Xylo-Mucine 0.6g
Sodium Citrate 0.4g
Citric Acid 0.2g
Flavoring orange essence 2ml
Sodium lauryl sulphate 1g
Process 1000 bags
Preparation technology: compd E is pulverized, made particle diameter below 75 microns, with the abundant mixing of the sucrose of pulverizing 80 mesh sieves.With 50ml purified water dissolving Sodium Citrate, Citric Acid, sodium lauryl sulphate, add Xylo-Mucine then, it is subsequent use to be made into rubber cement.The rubber cement system softwood of full dose, with the wet grain of 30 mesh sieve systems, 50 ℃ of dryings 3 hours, the whole grain of 20 mesh sieves sprayed into flavoring orange essence, mixing, packing promptly gets, every bag of heavily about 1g.
Comparison example
Listing MK-306 and cefoxitin ester of the present invention stability simultaneous test
Press commercially available back, the accelerated tests condition: 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5% in sampling in 0,1,2,3 month, detects its polymkeric substance, related substance and sign content, and the result sees the following form
Accelerated test result
Can find out that from last table the stability of cefoxitin ester under high temperature, super-humid conditions is superior to MK-306.
Claims (10)
- One kind what represent with the structure formula IV is the esterification prodrug compound of effective constituent with the cefoxitin:
（Ⅳ）Chemistry is by name: (6R, 7S)-assorted nitrogen dicyclo [4.2.0] oct-2-ene of 3-(carbamyl oxygen methyl)-7-methoxyl group-8-oxo-7-[2-(2-thienyl) kharophen]-5-thia-1--2-carboxylic acid-1-acetoxyl group ethyl ester. - 2. according to claim 1 is the esterification prodrug compound of effective constituent with the cefoxitin; It is characterized in that: said medical compounds exists with the form of salt; Its medicinal salt-forming compound shows as hydrochloride, vitriol, methane sulfonates or PHENRAMINE MALEATE.
- 3. according to claim 1 is the esterification prodrug compound of effective constituent with the cefoxitin, it is characterized in that: the preparation method of said cefoxitin esterification prodrug compound is following:In reaction flask, cefoxitin salt is present in the polar solvent, be cooled to-20 ~ 25 ℃ after, added 1-acetyl oxygen-1-halogen ethane controlled temperature-20 ~ 25 ℃ condensation reaction 30 ~ 60 minutes;, add extraction after having reacted successively with organic solvent and sodium bicarbonate aqueous solution, extract; Organic phase is washed with sodium bicarbonate aqueous solution again, behind the concentrating under reduced pressure, adds recrystallisation solvent; Crystallization, filtration, 40 ℃ ~ 60 ℃ of controlled temperature, pressure≤0.01MPa vacuum-drying gets the targeted thing;Said cefoxitin salt is sodium salt, the sylvite that cefoxitin and alkali metal cpd form, or the quaternary amine that forms with triethylamine or DBU.
- 4. according to claim 3 is the esterification prodrug compound of effective constituent with the cefoxitin, it is characterized in that: said polar solvent is N, dinethylformamide, DMAC N,N, or both are by the mixed solvent of any weight ratio.
- 5. according to claim 3 is the esterification prodrug compound of effective constituent with the cefoxitin; It is characterized in that: said 1-acetyl oxygen-1-halogen ethane is 1-acetyl oxygen-1-monochloroethane, 1-acetyl oxygen-1-monobromethane or 1-acetyl oxygen-1-iodoethane, and the mol ratio of said 1-acetyl oxygen-1-halogen ethane and cefoxitin or cefoxitin salt is 1 ~ 2:1.
- 6. according to claim 3 is the esterification prodrug compound of effective constituent with the cefoxitin, it is characterized in that: said extraction uses organic solvent to be methylene dichloride, trichloromethane, ETHYLE ACETATE, methyl acetate or isopropyl acetate.
- 7. according to claim 3 is the esterification prodrug compound of effective constituent with the cefoxitin, it is characterized in that: the concentration of said sodium bicarbonate aqueous solution is 1 ~ 10 wt %.
- 8. according to claim 3 is the esterification prodrug compound of effective constituent with the cefoxitin; It is characterized in that: said recrystallisation solvent is selected from a kind of in ethanol, Virahol, ether, isopropyl ether, DIPE, acetone, toluene, hexanaphthene, normal hexane, the sherwood oil or any two or more mixed solvent with any weight ratio in them.
- 9. according to claim 1 is the esterification prodrug compound of effective constituent with the cefoxitin, it is characterized in that: said cefoxitin esterification prodrug salt-forming compound obtains through following manner:The cefoxitin ester is present in the organic solvent, under-10 ℃ ~ 30 ℃ temperature, adds acid, after crystallization, solid-liquid separation, with 40 ℃ ~ 60 ℃ of solid controlled temperature, pressure≤0.01MPa vacuum-drying gets the targeted thing;Said organic solvent is selected from methyl alcohol, ethanol; Virahol, methylene dichloride, ETHYLE ACETATE, ether, isopropyl ether, DIPE, acetone, toluene, hexanaphthene, normal hexane; A kind of in the sherwood oil, or any two or more the mixed solvent in them with any weight ratio;The weightmeasurement ratio of said cefoxitin ester and organic solvent is 1:5 ~ 10;Said acid is hydrochloric acid, sulfuric acid, methanesulfonic or toxilic acid;Said cefoxitin ester is 1:1 ~ 2 with the mol ratio of acid.
- 10. according to claim 1 is the esterification prodrug compound of effective constituent with the cefoxitin; It is characterized in that: described cefoxitin esterification prodrug compound; Its route of administration is oral, and formulation comprises tablet, dispersible tablet, chewable tablet, orally disintegrating tablet, granule, capsule and dry suspensoid;Said oral prepns is to be made by the universal method on the technology of pharmaceutics by activated feedstock cefoxitin esterification prodrug compound and auxiliary material, and said auxiliary material comprises the essential thinner of institute, tackiness agent, disintegrating agent, lubricant, correctives, perfume compound or sanitas on the technology of pharmaceutics.
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| CN101235045A (en) * | 2008-02-26 | 2008-08-06 | 芦红代 | Method for preparing cefoxitin sodium |
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| US4014873A (en) * | 1973-05-03 | 1977-03-29 | Merck & Co., Inc. | Process for the production of 7-acylamidocephalosporins |
| US4891370A (en) * | 1981-12-14 | 1990-01-02 | Merck & Co., Inc. | Cephalosporin derivatives as anti-inflammatory agents |
| CN1199735A (en) * | 1997-05-15 | 1998-11-25 | 第一制糖株式会社 | Preparation of highly pure crystalline form of cefuroxime axetil |
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Application publication date: 20120815 |