CN109305938A - Norfloxacin metal complex and its preparation method and application - Google Patents
Norfloxacin metal complex and its preparation method and application Download PDFInfo
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- CN109305938A CN109305938A CN201710621874.2A CN201710621874A CN109305938A CN 109305938 A CN109305938 A CN 109305938A CN 201710621874 A CN201710621874 A CN 201710621874A CN 109305938 A CN109305938 A CN 109305938A
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- norfloxacin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
- A01N25/08—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing solids as carriers or diluents
- A01N25/10—Macromolecular compounds
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/60—1,4-Diazines; Hydrogenated 1,4-diazines
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N59/00—Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
- A01N59/16—Heavy metals; Compounds thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The present invention provides a kind of Norfloxacin metal complex, the complex forms with Norfloxacin and compound and polyacid compound containing B metal element, preparation method is as follows: Norfloxacin, the compound containing B metal element and polyacid compound are mixed, pH is adjusted, obtains Norfloxacin metal complex through post-processing after temperature reaction.The complex is applied to antibacterial a variety of daily implements surfaces, medical apparatus surface antibacterial and is carried out using a variety of pharmaceutical dosage forms antibacterial etc..In preparation method provided by the present invention, the easily controllable operation of reaction process, raw material are easy to get, and yield is high, is easy to purify.
Description
Technical field
The present invention relates to field of medicaments, in particular to a kind of Norfloxacin metal complex and its preparation method and application.
Background technique
Quinolone drugs is a kind of artificial synthesized antimicrobial.With remarkable advantages such as efficient, wide spectrums, so far
There are nearly 100,000 quinolone drugs and its derivative to be synthesized.Third generation quinolone medicine represents medicine as Norfloxacin
(Norfloxacin, orfloxacin), it is 4- quinolonyl structure of modification derivative, 6 it is upper add a fluorine (F), therefore also by
Referred to as fluoroquinolones (fluoroquinolones) are enhanced to histiocytic penetration power This structure increases fat-soluble,
Thus good absorbing, tissue concentration is high, and long half time more considerably increases antimicrobial spectrum and bactericidal effect.
Norfloxacin using more and more extensive, bacterium is extremely low to Norfloxacin natural resistance frequency, but with using
It is extensive, the drug resistance of bacterium is continuously improved.And Norfloxacin antibacterial is rapid-action, antimicrobial spectrum is wider, and its product development is more
Comprehensively, cheap, than convenient mass consumption.Therefore, its bioactivity and then reduction bacterium are improved to its drug resistance, is
Urgent problem to be solved.
It, can be significant partially studies have shown that after biologically active drug molecule and metal ion form complex
Ground improves the bioactivity of drug, and then reduces bacterium to the drug resistance of drug.But be only to a small number of simple complexs into
Row research, therefore the structure of matter novel Norfloxacin metal complex abundant is prepared, so that it is effectively improved drug
While bioactivity, and other treatment effect can be brought, and be efficiently applied in organism and in-vitro antibacterial, there is weight
Want meaning.
Summary of the invention
To solve the above-mentioned problems, present inventor has performed sharp studies, as a result, it has been found that: by Norfloxacin, contain subgroup
The compound and polyacid compound of metallic element mix, and adjust pH, obtain Norfloxacin metal after temperature reaction after post-processing
Complex.The complex has good bioactivity, so as to complete the present invention.
The purpose of the present invention is to provide following aspect:
In a first aspect, the present invention provides a kind of Norfloxacin metal complex, by Norfloxacin and contain B metal
The compound and polyacid compound of element cooperate, which can indicate as follows: (Z)z{X[MO(NF)n]m, wherein
Z indicates that cation, X indicate that polyoxoanion, M indicate B metal element.
Preferably,
Z be metal cation or ammonium ion,
X is the polyoxoanion containing transition metal element, preferably γ type polyoxoanion, more preferably contains VIB
The polyoxoanion of race's metallic element, one in polyoxoanion especially preferably containing chromium, molybdenum element or wolfram element
Kind,
M is VB race metallic element, preferably one of vanadium, niobium element, tantalum element,
Z is 1~4, preferably 1~3, such as 2；
N is 1~4, preferably 1~3, such as 2；
M is 1~4, preferably 1~3, such as 2.
Second aspect, the present invention provide the preparation method of Norfloxacin metal complex, method includes the following steps:
(1) Norfloxacin (NF), the compound containing B metal element and polyacid compound are mixed, is optionally stirred
It mixes；
(2) pH in mixture or its solution is adjusted to acidity；
(3) heating is reacted；
(4) after reaction, it is post-processed, obtains target product.
The third aspect, it is described anti-in particular for antibacterial according to the application of the Norfloxacin metal complex of first aspect
Bacterium is preferably antibacterial daily implements surface, medical apparatus surface antibacterial and is carried out using pharmaceutical dosage form antibacterial.
The Norfloxacin metal complex and polyalkenylalcohols progress are compound, are preferably formed as membrane structure, structure is preferred are as follows:
(Z)z{X[MO(NF)n]m- P, P represents polyalkenylalcohols, preferably polyvinyl alcohol (PVA).
The Norfloxacin metal complex is prepared as follows with polyalkenylalcohols compound:
(1) polyene alcoholic solution is prepared；
(2) Norfloxacin metal complex and its solution are prepared according to second aspect；
(3) Norfloxacin metal complex and polyalkenylalcohols compound are prepared.
The Norfloxacin metal complex provided according to the present invention, has the advantages that
(1) Norfloxacin metal complex provided by the invention, the structure of matter is abundant, and Norfloxacin passes through with metallic element
Synergistic effect enhances Norfloxacin bioactivity, and then reduces bacterium to the drug resistance of drug.
(2) the Norfloxacin metal complex can be applied to that a variety of daily implements surfaces are antibacterial, medical apparatus surface is anti-
Bacterium and use a variety of pharmaceutical dosage forms progress are antibacterial etc., have wide range of applications.
(3) Norfloxacin metal complex is loaded on high molecular material, especially on polyalkenylalcohols material, passes through hydrogen
The effect of key can reach the antibacterial effect of long-acting slow-release；
(4) preparation method of the invention is simple, and raw material is easy to get, and while easily operated, is conducive to the popularization of industrialization.
Detailed description of the invention
Fig. 1 shows the infrared spectrogram of raw material Norfloxacin and embodiment 1；
Fig. 2 shows the ultraviolet suctions in the embodiment 2 of 200~400nm of scanning range, comparative example 1, comparative example 2 and comparative example 3
Receive spectrogram；
Fig. 3 shows the uv absorption spectra of embodiment 2, comparative example 1, comparative example 2 under 275nm excitation wavelength；
Fig. 4 a shows embodiment 2 (S) and comparative example 2 (D) to the sustained-release antibacterial effect diagram of Escherichia coli；
Fig. 4 b shows embodiment 2 (S) and comparative example 2 (D) to the sustained-release antibacterial effect diagram of staphylococcus aureus.
Specific embodiment
Present invention will now be described in detail, and the features and advantages of the invention will become more with these explanations
It is clear, clear.
Dedicated word " exemplary " means " being used as example, embodiment or illustrative " herein.Here as " exemplary "
Illustrated any embodiment should not necessarily be construed as preferred or advantageous over other embodiments.Although each of embodiment is shown in the attached drawings
In terms of kind, but unless otherwise indicated, it is not necessary to attached drawing drawn to scale.
According to the first aspect of the invention, a kind of Norfloxacin metal complex is provided, by Norfloxacin and contains pair
The compound and polyacid compound of race's metallic element cooperate,
The Norfloxacin metal complex structure can indicate as follows: (Z)z{X[MO(NF)n]m,
Wherein, Z indicates that cation, X indicate that polyoxoanion, M indicate B metal element；Z be 1~4, preferably 1~
3, such as 2；N is 1~4, preferably 1~3, such as 2；M is 1~4, preferably 1~3, such as 2.
In one preferred embodiment, the polyoxoanion is the polyoxoanion containing transition metal element,
Preferably γ type polyoxoanion, the more preferably polyoxoanion containing group vib metallic element, especially preferably containing chromium member
One of element, molybdenum element or polyoxoanion of wolfram element are further preferably the polyoxoanion containing molybdenum element, such as
[γ-Mo8O26]4-。
In one preferred embodiment, X is the polyoxoanion containing molybdenum element, and molybdenum element has antitumor work
Property, toxicity is low and multivalent state variation so that the structure of complex more horn of plenty.
In one preferred embodiment, M is VB race metallic element, preferably vanadium, niobium element, in tantalum element
One kind, more preferably vanadium.
In one preferred embodiment, M is vanadium, with it is anti-inflammatory, sterilization etc. bioactivity, vfanadium compound
Physiological effect and toxicity are related with the total amount of vanadium, chemical combination characteristic and form, to the life of animal body in reasonable dosage range
Reason function plays a driving role, and such as maintains the growth of organism, promotes the absorption of glucose and shows the effect of para-insulin
Deng can be used for the certain diseases of diagnosing and treating also with preferable bioactivity after complex that it is formed with drug molecule
Disease.Vanadium adjust body metabolism of blood glucose, uropoiesis metabolism and in terms of also play an important role.
In one preferred embodiment, Z is metal cation or ammonium ion, more preferably ammonium ion (NH4 +)。
In one preferred embodiment, the structure of the Norfloxacin metal complex is during to be with polyoxoanion be
The heart is connected by end oxygen with the complex of Norfloxacin and B metal element.
In one preferred embodiment, the Norfloxacin metal complex leads to using Norfloxacin as organic ligand
The mode and B metal element for crossing chelating ligands are coordinated.
In one preferred embodiment, the carboxyl of Norfloxacin molecule and ketone carbonyl are matched with B metal element
Position, wherein carboxyl is coordinated in a manner of monodentate with metallic element.
According to the second aspect of the invention, the preparation method of above-mentioned Norfloxacin metal complex is provided comprising following
Step:
Step (1) mixes Norfloxacin (NF), the compound containing B metal element and polyacid compound,
Optionally stirring；
In one preferred embodiment, the polyacid compound is to contain transition metal element in polyoxoanion
Compound, the preferably compound containing group vib metallic element in polyoxoanion, more preferably contain chromium in polyoxoanion
One of element, molybdenum element or compound of wolfram element, further preferably contain the chemical combination of molybdenum element in polyoxoanion
Object, such as (NH4)6Mo7O24·4H2O。
In one preferred embodiment, the polyacid compound is template, and then can be formed with polyoxoanion
Centered on complex structure.
In the present invention, the compound containing B metal element is preferably the chemical combination containing Group VB metallic element
Object, more preferably containing one of vanadium, niobium element or compound of tantalum element, especially preferably containing the change of vanadium
Close object.
In one preferred embodiment, the compound containing B metal element is to contain B metal element
Oxide, the preferably oxide containing Group VB metallic element, more preferably containing vanadium, niobium element or tantalum element
One of oxide, especially preferably containing the oxide of vanadium, such as vanadic anhydride.
In one preferred embodiment, the compound containing B metal element can be by buying or testing
It is made, optimization experiment self-control, the purity of product is higher, is conducive to the generation of Norfloxacin metal complex.
In one preferred embodiment, the compound containing B metal element is to contain B metal element
Oxide, be made by the oxysalt accordingly containing B metal element, it is described to contain the oxygen-containing of B metal element
Hydrochlorate is the oxysalt containing Group VB metallic element, in the oxysalt for preferably comprising vanadium, niobium element or tantalum element
One kind, more preferably containing the oxysalt of vanadium, such as ammonium metavanadate,
Oxysalt containing B metal element is added in optional heatable container, is heated, optionally stirred
It mixes, cooling obtains the oxide containing B metal element after reaction, spare, wherein
The heatable container is preferably evaporating dish, and heating method is preferably sand-bath heating, heating water bath, heating mantle heats
Or electromagnetic oven heating etc., more preferable sand-bath heating；
Preferably, the molar ratio of the compound containing B metal element and Norfloxacin and polyacid compound is 1:
0.5~0.9:0.2~0.45, such as 1:0.7:0.35.
In one preferred embodiment, solvent is additionally added in step (1), the solvent is preferably water, You Jirong
The composition of agent or both, more preferably water and organic solvent composition, wherein
The organic solvent is preferably methanol, ethyl alcohol, isopropanol, acetone etc., preferably ethyl alcohol.
In the present invention, when the solvent is the composition of organic solvent and water, the volume ratio of organic solvent and water is
1:1~4, preferably 1:1.5~3, more preferably 1:2.
In the present invention, the w/v of Norfloxacin and institute's solubilizer is (0.12~0.30) parts by weight: (10~
30) parts by volume, more preferably (0.15~0.25) parts by weight: (12~20) parts by volume, such as 0.22 parts by weight: 15 parts by volume,
In, 1 parts by weight are calculated as based on 1g, 1 parts by volume is calculated as based on 1mL.
In one preferred embodiment, it is additionally added salt strong electrolytic solution in step (1), preferably KCl is molten
Liquid or NaCl solution etc., more preferably KCl solution.
Preferably, the concentration of salt strong electrolyte is 1~4molL-1, more preferable 1.5~3molL-1, such as 3molL-1。
In the present invention, salt strong electrolyte is added so that various electrolyte balances in solution, keep relative stability.
Preferably, the w/v of Norfloxacin and salt strong electrolytic solution is (0.12~0.30) parts by weight:
(1.6~4) parts by volume, more preferably (0.15~0.25) parts by weight: (2~3.2) parts by volume, such as 0.22 parts by weight: 3 volumes
Part, wherein 1 parts by weight are calculated as based on 1g, 1 parts by volume is calculated as based on 1mL.
In one preferred embodiment, the mixture in step (1) or its solution is at a set temperature while stirring
It is reacted, wherein
The set temperature is 15 DEG C~35 DEG C, preferably 20~30 DEG C, more preferably 25 DEG C；
Mixing time is 1~4h, preferably 1.5~3h, more preferably 2h.
The pH of mixture or its solution in step (1) is adjusted to acidity by step (2)；
In one preferred embodiment, it is described use weak acid for adjusting pH, the weak acid be formic acid, acetic acid, benzoic acid,
Ethanedioic acid etc., preferably acetic acid, further, the concentration of weak acid are 1~4molL-1, preferably 1.5~3molL-1, such as
2mol·L-1。
In one preferred embodiment, the pH of mixture or its solution is adjusted to 3.5~5.5, it is preferable that adjust
PH to 4.
Inventors have found that the piperazinyl and carboxyl of Norfloxacin are protonated in pH < 3, and in pH > 10, piperazine
Base and carboxyl are by deprotonation, and in neutral and alkalescent, the N atomic energy of piperazinyl is participated in the coordination of metal
It goes, but under mild acid conditions, the N atom of piperazinyl cannot participate in the coordination of metal, thus the preferred pH of the present invention is adjusted
To 3.5~5.5.
In one preferred embodiment, the solution in step (2) is stirred at 15 DEG C~30 DEG C 10min~
60min, it is preferable that further stir 30min at 25 DEG C controlled at 20~25 DEG C of 1~1.5h of stirring.
Step (3), heating are reacted；
In one preferred embodiment, the solution that step (3) obtains is transferred in reaction vessel, preferably poly- four
Vinyl fluoride low pressure reaction kettle, constant temperature is reacted under heating condition.
In one preferred embodiment, heating temperature be 100 DEG C~150 DEG C, preferably 110~130 DEG C, more preferably
It is 120 DEG C.
In one preferred embodiment, the reaction time is 2~5 days, preferably 4 days.
Step (4) is post-processed after reaction, obtains target product.
In one preferred embodiment, cool down after reaction, by substance after reaction be cooled to 10 DEG C~
50 DEG C, preferably 15 DEG C~40 DEG C, more preferably 20 DEG C~35 DEG C, such as 25 DEG C.
In the present invention, cooling method can use Temperature fall or Programmed cryopreservation, it is preferred to use Programmed cryopreservation, into
One step, with 5~20Kh-1Speed program cooling, it is preferred that cooling rate be 8~15Kh-1, more preferably
10K·h-1。
In one preferred embodiment, the product obtained after above-mentioned cooling is washed, removing its surface may adhere to
Soluble impurity, the cleaning solution for washing solid is preferably distilled water.
In one preferred embodiment, after being washed to the product after cooling, it is dried, is preferably made
It with boulton process, normal heating method, natural seasoning etc., is more preferably dried using boulton process, thus obtains this
The target product of invention, i.e. Norfloxacin metal complex, structure can indicate as follows: (Z)z{X[MO(NF)n]m, wherein
Z is 1~4, preferably 1~3, such as 2；N is 1~4, preferably 1~3, such as 2；M is 1~4, preferably 1~3, such as 2.
Z indicates cation, preferably metal cation or ammonium ion, more preferably ammonium ion；
X indicates polyoxoanion, preferably containing the polyoxoanion of transition metal element, more preferably γ type polyacid yin
Ion, the especially preferably polyoxoanion containing group vib metallic element, further preferably containing chromium, molybdenum element or
One of polyoxoanion of wolfram element most preferably contains the polyoxoanion containing molybdenum element, such as (γ-Mo8O26
)4-；
M indicates that B metal element, preferably M are VB race metallic element, more preferably vanadium, niobium element, in tantalum element
One kind, especially preferably vanadium；
Infrared spectrum analysis shows that the absorption peak of the complex and ligand Norfloxacin is different, and NF is in 1730cm-1Place
The carboxyl feature stretching vibration absworption peak (ν of appearanceC=O), after forming complex, absorption peak disappears at this, in 1556cm-1、
1393cm-1There is absorption peak, corresponds to asymmetric stretching vibration and the symmetrical stretching vibration of carboxyl, illustrate quinolone ring in NF
On carboxyl in a manner of monodentate with vanadium be coordinated, NF is in 1622cm-1Locate the carbonylic stretching vibration absorption peak (C=O) occurred, is being formed
After complex, absorption peak red shift is to 1630cm at this-1Place, illustrates that carbonyl has also assisted in coordination.In addition, when X is (γ-Mo8O26
)4-When, the infrared spectroscopy of gained complex is in 945cm-1、856cm-1、791cm-1Locate existing characteristics absorption peak, can be attributed to
γ-Mo8O26The vibration absorption peak of ν (Mo=O) and ν (Mo-O-Mo) in structure；
Complex is in 3440cm-1Nearby also show H2The strong stretching vibration absworption peak of O
Therefore, Norfloxacin metal complex of the invention is in 1556cm-1、1393cm-1、1630cm-1、945cm-1、
856cm-1、791cm-1And 3440cm-1There are absorption peaks at place.
In the present invention, there is synergistic effect between Norfloxacin and metal ion, the antibacterial activity of complex is caused to be better than
Norfloxacin, therefore significant the bioactivity for improving drug, and then bacterium is reduced to the drug resistance of drug.
According to the third aspect of the invention we, the application of above-mentioned Norfloxacin metal complex is provided, in particular for antibacterial.
The preferred in-vitro antibacterial of antibacterial, is more preferably used for that a variety of daily implements surfaces are antibacterial, medical apparatus surface antibacterial
It is antibacterial etc. with using a variety of pharmaceutical dosage forms to carry out.
In the application, the Norfloxacin metal complex can also carry out compound with polyalkenylalcohols, be preferably formed as membrane structure.
Its structure is preferred are as follows: (Z)z{X[MO(NF)n]m- P, wherein P represents polyalkenylalcohols, preferably polyvinyl alcohol (PVA)；
The above compound can be prepared in accordance with the following methods:
(1) polyene alcoholic solution is prepared
Polyalkenylalcohols is dissolved in solvent, solvent is preferably distilled water, it heats while stirring, so that polyalkenylalcohols all dissolves,
Preferably, heating temperature is 70~120 DEG C, more preferably 80~100 DEG C, such as 90 DEG C.
In a preferred embodiment, the polyalkenylalcohols is preferably polyvinyl alcohol, is that a kind of safe biology can
Degraded macromolecular organic matter, it is nontoxic to the human body, it is without side-effects, have good biocompatibility, adhesive strength is good, easily at
Film, and the good mechanical performance of film, tensile strength increase with the degree of polymerization, alcoholysis degree and are enhanced.
In a preferred embodiment, the w/v of above-mentioned polyalkenylalcohols and solvent is (1~5) parts by weight: (10
~50) parts by volume, more preferably (1.5~3) parts by weight: (15~30) parts by volume, such as 2 parts by weight: 20 parts by volume, wherein base
1 parts by weight are calculated as in 1g, 1 parts by volume is calculated as based on 1mL.
In a preferred embodiment, polyalkenylalcohols all dissolves, at this time solution jelly pellucidity, using machinery
The mode of agitating mode or supersonic oscillations handles above-mentioned polyene alcoholic solution, it is preferred to use the mode of ultrasonic vibration, to remove
Bubble in solution.
(2) Norfloxacin metal complex and its solution are prepared according to above-mentioned second aspect；
In a preferred embodiment, Norfloxacin metal complex obtained is dissolved in solvent and is uniformly mixed,
The solvent is preferably distilled water；
In a preferred embodiment, the w/v of above-mentioned Norfloxacin metal complex and solvent is
(0.0080~0.020) parts by weight: (2~6) parts by volume, more preferably (0.0100~0.0015) parts by weight: (2~4) volume
Part, such as 0.0126 parts by weight: 3 parts by volume, wherein 1 parts by weight are calculated as based on 1g, 1 parts by volume is calculated as based on 1mL.
Preferably, it is sufficiently mixed above-mentioned solution uniformly, more using the mode of mechanical stirring mode or supersonic oscillations
It is preferred that by the way of supersonic oscillations
Preferably, incorporation time is preferably 1~5h, and more preferable 2~4h, such as 3h keep Norfloxacin metal complex uniform
Dispersion in a solvent；
(3) compound (Z) is preparedz{X[MO(NF)n]m}-P
The solution that above-mentioned Norfloxacin metal complex is configured to is mixed with polyene alcoholic solution；
In one preferred embodiment, polyene alcoholic solution prepared by step (1) is added to promise made from step (2)
In Flucloxacillin metal complex solution, stirring is preferably vigorously stirred 1~4h, more preferable 1.5~3h, such as 3h, to make the two
Even mixing；
In one preferred embodiment, the Norfloxacin metal complex solution and polyalkenylalcohols measured in step (3)
The volume ratio of solution is 1:(0.5~2), more preferably 1:(0.8~1.5), such as 1:1；
In a preferred embodiment, above-mentioned promise is handled using the mode of mechanical stirring mode or supersonic oscillations
The mixed liquor of Flucloxacillin metal complex solution and polyene alcoholic solution, it is preferred to use the mode of ultrasonic vibration, to remove mixed liquor
In bubble.
In one preferred embodiment, mixed liquor is formed a film；
In a preferred embodiment, by mixed liquor drying and forming-film obtained above, preferably mixed liquor is poured into
Drying and forming-film is carried out after in film container further to be done using boulton process, normal heating method, natural seasoning etc.
Dry processing more preferably uses boulton process.
In a preferred embodiment, it is dried at 40 DEG C~80 DEG C, is more preferably carried out at 45 DEG C~60 DEG C
Dry, such as 50 DEG C, further, drying time is preferably 1~4h, more preferably 1.5~3h, such as 2h.
It further, is preferably glass container and plastic containers etc., more preferably plastic containers at film container, such as 96 is round
Orifice plate lid.
In a preferred embodiment, it by the compound film stripping of drying and moulding, collects, spare, which can table
It is shown as (Z)z{X[MO(NF)n]m- P, as detailed above.
The composite membrane has slow releasing function, the rate of release of Norfloxacin metal complex can be reduced, so that releasing
Medicine velocity-stabilization, drug effect improve, times for spraying is reduced.
In the present invention, inventor thinks due to (Z)z{X[MO(NF)n]mIn Norfloxacin piperazinyl on nitrogen can be with
Hydrogen bond is formed with the hydroxyl on the surface PVA, and the oxygen atom on polyoxoanion can also form hydrogen with the hydroxyl on polyalkenylalcohols surface
Key, and then (Z) can be reducedz{X[MO(NF)n]mFrom the rate of release on polyalkenylalcohols, to reach slow releasing function.
Embodiment
Embodiment 1
0.085mol ammonium metavanadate solid is added in evaporating dish, is placed in sand-bath and heats, be stirred continuously, it is solid to white
Body all becomes red brown solid and stops heating, obtains product vanadic anhydride (V2O5), it is cooling, for use.
By 1.00mmol vanadic anhydride obtained above, 0.70mmol Norfloxacin (NF) and 0.35mmol (NH4)6Mo7O24·4H2O mixing, is added 3mLKCl (3molL-1) solution, add 10mLH2O and 5mL ethyl alcohol, is stirred at room temperature
2h。
Use 2molL-1The pH of above-mentioned solution is adjusted to 4.0 by HAc solution, continues that 0.5h is stirred at room temperature
The turbid solution stirred evenly is transferred in the polytetrafluoroethylene (PTFE) low pressure reaction kettle of 25mL, it is permanent under the conditions of 120 DEG C
Temperature reaction 4 days.
With 10Kh-1Speed program be cooled to room temperature.Obtain green bulk crystals.Water washing is distilled, vacuum is placed
It is dry in drying box, obtain product (NH4)2{(γ-Mo8O26)[VO(NF)2]2Complex, yield is 34% (in terms of V), X-
Ray single crystal diffraction is as described in experimental example 1.
(NH is tested using elemental analyser4)2{(γ-Mo8O26)[VO(NF)2]2Complex structure in C, H and N member
Element, measured result are as follows: C 29.30, N 7.41, H 2.98 and calculated value C 29.26, N 7.47, H 2.92 preferably kiss
It closes.
Measure (NH made from raw material Norfloxacin and the present embodiment4)2{(γ-Mo8O26)[VO(NF)2]2Complex is infrared
Spectrogram, 4000~500cm of measurement range-1, as a result as shown in Figure 1, wherein
Curve a shows the infrared spectrogram that sample is made in raw material Norfloxacin；
Curve b shows the infrared spectrogram that sample is made in embodiment 1.
As shown in Figure 1:
Norfloxacin is in 1730cm-1Locate the carboxyl feature stretching vibration absworption peak (ν occurredC=O) disappear in embodiment 1；
And the carboxyl vibration peak of embodiment 1 is located at 1556cm-1And 1393cm-1.The two differs 163cm-1, because poor
Value is less than 200cm-1, illustrate that the carboxyl in NF on quinolone ring is coordinated in a manner of monodentate with vanadium；
Raw material NF is in 1622cm-1Locate the 3 carbonylic stretching vibration absorption peaks (C=O) occurred, red shift is extremely in embodiment 1
1630cm-1Place, illustrates that carbonyl has also assisted in coordination；
In addition, embodiment 1 is located at 945cm-1、856cm-1、791cm-1Characteristic absorption peak can be attributed to γ-Mo8O26Structure
The vibration absorption peak of middle ν (Mo=O) and ν (Mo-O-Mo)；Embodiment 1 is in 3440cm-1Nearby also show H2The strong flexible vibration of O
Dynamic absorption peak；
The presence of the characteristic absorption peak of above-mentioned infrared spectroscopy and variation tendency illustrate to have in structure the metal complex of NF with
And the presence of polyacid compound.
Embodiment 2
20.0mL distilled water will be added in 2.0g polyvinyl alcohol (PVA), it is all molten to solid PVA in 90 DEG C of heating stirrings
Change, jelly pellucidity is removed all bubbles, then using supersonic oscillations method so that it is molten to form polyvinyl alcohol solution
Liquid.PVA solution concentration obtained is 10% at this time.
Take (NH obtained in 0.0126g embodiment 14)2{(γ-Mo8O26)[VO(NF)2]2, 3mL distilled water is added, surpasses
Sound oscillation 3h, is uniformly dispersed, and forms Norfloxacin metal complex solution.
3mL poly-vinyl alcohol solution produced above is added in Norfloxacin metal complex solution produced above, it is acute
Strong stirring 2h, then carries out sonic oscillation, and bubbles all in mixed liquor are removed.
Using the circular groove of 96 orifice plate lids as template, taking in 30 μ l of mixed liquor injection groove, 50 DEG C of vacuum drying 2h take out,
By the composite membrane ((NH of drying and moulding4)2{(γ-Mo8O26)[VO(NF)2]2- PVA), it then removes, collects from orifice plate, it is standby
With.
Comparative example
Comparative example 1
It weighing 2.0g polyvinyl alcohol (PVA) and 20.0mL distilled water is added, 90 DEG C of heating stirrings to solid PVA are all dissolved,
Jelly pellucidity is removed all bubbles, then using supersonic oscillations method to form poly-vinyl alcohol solution solution.
PVA solution concentration obtained is 10% at this time.
3mL distilled water is measured, 3mL poly-vinyl alcohol solution obtained above is added, is vigorously stirred 2h, polyvinyl alcohol dispersion
After uniformly, sonic oscillation is then carried out, bubbles all in mixed liquor are removed.
Using the circular groove of 96 orifice plate lids as template, taking in 30 μ l of mixed liquor injection groove, 50 DEG C of vacuum drying 2h take out,
It by the polyvinyl alcohol film of drying and moulding, then removes, collects from orifice plate, it is spare.
Comparative example 2
It weighing 2.0g polyvinyl alcohol (PVA) and 20.0mL distilled water is added, 90 DEG C of heating stirrings to solid PVA are all dissolved,
Jelly pellucidity is removed all bubbles, then using supersonic oscillations method to form poly-vinyl alcohol solution solution.
Poly-vinyl alcohol solution concentration obtained is 10% at this time.
0.0066g Norfloxacin is weighed, 3mL distilled water is added, sonic oscillation 3h makes Norfloxacin be dispersed in water
In solution, Norfloxacin solution is formed.
3mL poly-vinyl alcohol solution obtained above is added in Norfloxacin solution obtained above, is vigorously stirred 2h, really
Protecting Norfloxacin aqueous solution and PVA can uniformly mix, and then carry out sonic oscillation, and bubbles all in mixed liquor are removed.
Using the circular groove of 96 orifice plate lids as template, taking in 30 μ l of mixed liquor injection groove, 50 DEG C of vacuum drying 2h take out,
It by the composite membrane (NF-PVA) of drying and moulding, then removes, collects from orifice plate, it is spare.
Comparative example 3
Method is identical as comparative example 2, is only distinguished as raw materials used not instead of Norfloxacin, (NH4)6Mo7O24·4H2O,
To which (NH be made4)6Mo7O24·4H2O solution carries out subsequent reactions, finally obtained [Mo8O26]4-- PVA composite membrane.
Experimental example
The X-ray single crystal diffraction of 1 sample of experimental example
This experimental example sample used is sample made from embodiment 1.
The X-ray single crystal diffraction data of sample are in the Agilent Super Nova type CCD X-ray for having multilayer film
Mo K alpha ray is used on single crystal diffractometer As incident radiation, diffraction is collected at a temperature of 293K
Data.
The data of collection use SHELXTL software Packet analyzing using direct method through the LP factor and empirical absorption correction, structure,
Optimized by complete matrix least square method, all non-hydrogen atom coordinates use anisotropic thermal parameters revision.Hydrogen on organic group
Atomic coordinates adds the method for hydrogen to obtain using geometry, wherein
The crystallographic data of sample is as shown in table 1:
Table 1
aR1=Σ | | Fo|-|Fc||/Σ|Fo|,bwR2=[Σ [w (Fo 2-Fc 2)2]/Σw(Fo 2)2]
The bond distance of sampleIt is as shown in table 2 with bond angle (°):
Table 2
By Tables 1 and 2 analysis it is found that
Embodiment 1 is by 2 monokaryon vanadium complex (abbreviation V-NF2), 1 [γ-Mo8O26]4-(abbreviation γ-Mo8) polyacid yin
Ion and 2 NH4 +Cation composition.
In monokaryon vanadium complex V-NF2In structure, V respectively with the hydroxyl on 2 Norfloxacins, 4 ketonic oxygens and 3 carboxylic acids
Base oxygen forms the { VO of a distortion by way of chelating ligands6Octahedra, wherein the bond distance of V=O key isAnd the distance of the bond distance of other V-O keys is located atIn range.
Polyanionic γ-Mo8Including six { MoO6Octahedra and two { MoO5Tetragonal pyramid, wherein in { MoO6Octahedral
The distance of Mo-O key is located in body structureBetween.
Two groups of { MoO6It is octahedra respectively with two { MoO5Tetragonal pyramid is connected by total side, it is interactive hexa-atomic foring
Ring.In γ-Mo8It include 14 end oxygen (O in unitt), 6 doube bridge oxygen (μ2- O), 4 three bridging oxygen (μ3- O) and 2 four bridging oxygen (μ4-
O)。Mo-OtAverage bond length existBetween.Mo-ObAverage bond length exist
Between.γ-Mo8Pass through two μ with two vanadium atoms respectively2- O, which is connected, constitutes the cellular construction of embodiment 1, wherein Mo-O-V
Bond angle be 147.3 (5)°.The overall structure of complex is with γ-[Mo8O26]4-Centered on, both ends pass through in symmetric position
End oxygen does not connect the sandwich-type structure to be formed with the vanadium atom on two vanadium-Norfloxacin complex.
The unit molecule of each embodiment 1 passes through γ-Mo8On end oxygen pass through and Norfloxacin molecule piperazine ring on nitrogen
The hydrogen bond (O1-HN3, O17-HN6) that atom is formed forms 1D organic supermolecular chain along b axis in space, separately
One side 1D chain is acted on by the π pi accumulation between NF ligand, and two aromatic rings centre distances areIn sky
Between form 2D molecular network structure.
The measurement of 2 sample anti-microbial property of experimental example
This experimental example sample used is sample made from embodiment 1 and raw material Norfloxacin.
Paper disk method is taken in the anti-microbial property experiment of sample, and experimental method is referring to national standard experimental method, respectively measurement pair
Escherichia coli and staphylococcus aureus bacteriostasis rate, as a result as shown in Table 3 and Table 4,
3 embodiment 1 of table and raw material NF are to Escherichia coli bacteriostasis rate
4 embodiment 1 of table and raw material NF are to staphylococcus aureus bacteriostasis rate
| Sample | 1st time | 2nd time | 3rd time | Average colony | Bacteriostasis rate |
| Blank | 135 | 128 | 131 | 131 | ---- |
| Raw material NF | 10 | 12 | 11 | 11 | 91.6 |
| Embodiment 1 | 14 | 13 | 13 | 13 | 90.1 |
Bacteriostasis rate=(blank group clump count-experimental group clump count)/(blank clump count).
It is found that embodiment 1 is close with the bacteriostatic activity of raw material Norfloxacin, but complex structure made from embodiment 1 is more
It is abundant.
The uv-vis spectra of 3 sample of experimental example measures
This experimental example sample used is embodiment 2, comparative example 1, sample made from comparative example 2 and comparative example 3.
It is the ultraviolet spectra that substrate measures laminated film, scanning with quartz using UV2550 UV, visible light spectrophotometer
200~400nm of range, as a result as shown in Figure 2, wherein
Curve a shows the uv absorption spectra that sample is made in embodiment 2；
Curve b shows the uv absorption spectra that sample is made in comparative example 1；
Curve c shows the uv absorption spectra that sample is made in comparative example 2；
Curve d shows the uv absorption spectra that sample is made in comparative example 3.
From the figure 3, it may be seen that
The prominent absorption bands of comparative example 2 (NF-PVA composite membrane) are 321nm and 335nm, for 2 ((NH of embodiment4)2
{(γ-Mo8O26)[VO(NF)2]2- PVA composite membrane) for, the either shape at the position of maximum absorption band, intensity or peak
Shape, it is all quite similar with NF-PVA composite membrane, it is clear that the absorption band should all be assigned as π → π * transition of NF；
Compared with comparative example 2, small violet shift is had occurred in 2 absorption maximum of embodiment, is not bound by any theory, the present inventor
Think, this is because ligand NF is macrocycle molecule, be not at molecule in approximately the same plane after being coordinated with vanadium ion, molecule is put down
Face degree reduces, and conjugacy is reduced；Simultaneously vanadium ion have certain sucking action again to big pi bond, after coordination, on ring electron cloud to vanadium from
Son is mobile, so that charge is unevenly distributed on ring, symmetry is reduced, and the conjugacy of ring accordingly reduces, and violet shift occurs for wavelength；
In addition, new characteristic absorption peak occurs near 201nm in embodiment 2, this feature peak and comparative example 3 are at this
Characteristic absorption is relatively coincide.
To sum up, raw material Norfloxacin and (NH4)2{(γ-Mo8O26)[VO(NF)2]2Successfully load on PVA film.
4 sample of experimental example is sustained release behavior measurement in vitro
This experimental example sample used is embodiment 2, sample made from comparative example 1 and comparative example 2.
The slow release effect of composite membrane is monitored by measuring the cumulative release amount of compound in each period.
Operating method: 10, sample are taken as made from embodiment 2, comparative example 1 and comparative example 2 to be placed in 20mL beaker respectively
In, 10mL distilled water is added, diaphragm is taken out after 37 DEG C of immersion 3h, is reapposed in new 20mL beaker, 10mL is added and steams
Distilled water continues under the conditions of 37 DEG C again to take out diaphragm after impregnating 3h, and it is primary to carry out aforesaid operations by every 3h in preceding 12h, and 12h~
Every 12h repeats to sample primary in 48h.It samples solution and collects the progress ultraviolet absorptivity test under 275nm excitation wavelength, as a result such as
Shown in Fig. 3, wherein
Curve a shows the uv absorption spectra that sample is made in embodiment 2；
Curve b shows the uv absorption spectra that sample is made in comparative example 1；
Curve c shows the uv absorption spectra that sample is made in comparative example 2.
From the figure 3, it may be seen that
In 0h~9h, after the Cumulative release amount of comparative example 2 has reached 91%, 9h, the burst size of NF in aqueous solution
It has almost no change, this shows that NF has the process of a burst release within preceding 9h, and in the process, the Cumulative release amount of NF reaches
Maximum value, after 9h, the burst size of NF is close to zero；
The burst release process of embodiment 2 is in 0h~12h, and maximum burst size about 28% during being somebody's turn to do, Cumulative release amount reaches
72%.There is the process of a slow release between 12h~48h, release cumulant is maintained between 10%~13%,
And embodiment 2 still keeps activity after 48h, bacteriostasis rate maintains 32%.
Compared with the comparative example 2 in this process release conditions of (0h-48h), embodiment 2 have in aqueous solution one it is more slow
Slow release process.
To sum up, 2 ((NH of embodiment4)2{(γ-Mo8O26)[VO(NF)2]2- PVA composite membrane) occur in aqueous solution it is slow
Phenomenon is released, is not bound by any theory, it has been recognised by the inventors that because containing polyacid group [γ-Mo in 2 structure of embodiment8O26]4-,
A large amount of oxygen atom is contained on polyacid surface, this makes γ-Mo8With an oxygen-enriched structure, in addition on the piperazinyl of Norfloxacin
Nitrogen other than, γ-Mo8On oxygen atom can also form a large amount of hydrogen bond with the oxygen atom on the surface PVA, reduce (NH4)2{(γ-
Mo8O26)[VO(NF)2]2From the rate of release on PVA, so that (NH4)2{(γ-Mo8O26)[VO(NF)2]2In aqueous solution
Solubility is substantially reduced, thus has reached slow releasing function.
The external sustained-release antibacterial determination of activity of 5 sample of experimental example
This experimental example sample used is sample made from embodiment 2 and comparative example 2.
The bacteriostatic activity test of composite membrane uses paper disk method, replaces the scraps of paper to carry out experimental implementation composite membrane, wherein
Fig. 4 a indicates embodiment 2 (S) and comparative example 2 (D) to the sustained-release antibacterial effect of Escherichia coli；
Fig. 4 b indicates embodiment 2 (S) and comparative example 2 (D) to the sustained-release antibacterial effect of staphylococcus aureus.
By in Fig. 4 a it is found that embodiment 2 and comparative example 2 are respectively 25mm and 31mm for the bacteriostatic diameter of Escherichia coli
(for PVA film without bacteriostasis, the diameter after water absorption and swelling is 11mm).
For the antibacterial activity of further comparative example 2 and comparative example 2, loop test three times has been carried out again.
As shown in Fig. 4 a II, in II, embodiment 2 and comparative example 2 are respectively 29mm for the bacteriostatic diameter of Escherichia coli
And 27mm, compared with I, the bacteriostatic diameter of comparative example 2 reduces 13%, and the bacteriostatic diameter of embodiment 2 increases 16%；
In III, the bacteriostatic diameter for Escherichia coli of comparative example 2 is identical as the bacteriostatic diameter of PVA film, and as zero,
And embodiment 2 declines 20% to the bacteriostatic diameter of Escherichia coli compared with II；
In IV, 39% is declined compared with III to the bacteriostatic diameter (14nm) of Escherichia coli to embodiment 2, downward trend phase
To slow.
It is described the invention in detail above in conjunction with detailed description and exemplary example, but these explanations are simultaneously
It is not considered as limiting the invention.It will be appreciated by those skilled in the art that without departing from the spirit and scope of the invention,
Can be with various equivalent substitutions, modifications or improvements are made to the technical scheme of the invention and its embodiments, these each fall within the present invention
In the range of.Scope of protection of the present invention is subject to the appended claims.
Claims (10)
1. a kind of Norfloxacin metal complex, which is characterized in that the complex is by Norfloxacin and contains B metal element
Compound and polyacid compound cooperate, which indicates as follows: (Z)z{X[MO(NF)n]m, wherein Z is indicated
Cation, X indicate that polyoxoanion, M indicate B metal element.
2. complex according to claim 1, which is characterized in that Z be metal cation or ammonium ion,
X is the polyoxoanion containing transition metal element, preferably γ type polyoxoanion, more preferably containing group vib gold
The polyoxoanion of category element, one of the polyoxoanion especially preferably containing chromium, molybdenum element or wolfram element,
M is VB race metallic element, preferably one of vanadium, niobium element, tantalum element,
Z is 1~4, preferably 1~3, such as 2；
N is 1~4, preferably 1~3, such as 2；
M is 1~4, preferably 1~3, such as 2.
3. the preparation method of the Norfloxacin metal complex of claims 1 or 2, which is characterized in that this method includes following step
It is rapid:
(1) Norfloxacin (NF), the compound containing B metal element and polyacid compound are mixed, is optionally stirred；
(2) pH of mixture or its solution is adjusted to acidity；
(3) heating is reacted；
(4) after reaction, it is post-processed, obtains target product.
4. preparation method according to claim 3, which is characterized in that in step (1),
The compound containing B metal element is the compound containing Group VB element, preferably comprises vanadium, niobium member
One of element or the compound of tantalum element,
Compound containing B metal element be selected from the oxide containing B metal element, such as vanadic anhydride,
The polyacid compound is the compound containing transition metal element in polyoxoanion, is preferably contained in polyoxoanion
There are the compound of group vib metallic element, the more preferably compound containing chromium, molybdenum element or wolfram element in polyoxoanion
One of, the compound of molybdenum element, such as (NH are contained further preferably in polyoxoanion4)6Mo7O24·4H2O,
The molar ratio of the compound containing B metal element and Norfloxacin and polyacid compound is 1:0.5~0.9:
0.2~0.45.
5. preparation method according to claim 3, which is characterized in that
In step (1),
Salt strong electrolytic solution, preferably KCl solution or NaCl solution is added,
Solvent is added, the solvent is preferably the composition of water, organic solvent or both, more preferably the group of water and organic solvent
Close object, wherein the organic solvent is preferably methanol, ethyl alcohol, isopropanol or acetone.
6. preparation method according to claim 3, which is characterized in that
In step (2), using weak acid for adjusting pH, weak acid is formic acid, acetic acid, benzoic acid or ethanedioic acid, preferably acetic acid, will be mixed
The pH of object or its solution is adjusted to 3.5~5.5.
7. preparation method according to claim 3, which is characterized in that
In step (4), cool down after reaction, using Temperature fall or Programmed cryopreservation, it is preferred to use Programmed cryopreservation, into one
Step ground, with 5~20Kh-1Speed program cooling, it is preferred that cooling rate be 8~15Kh-1, preferably reaction is terminated
Substance afterwards is cooled to 10 DEG C~50 DEG C, more preferably 15 DEG C~40 DEG C, further preferably 20 DEG C~35 DEG C.
8. the application of the Norfloxacin metal complex of claims 1 or 2, in particular for antibacterial, the antibacterial is preferably day
Normal implements surface is antibacterial, medical apparatus surface antibacterial and is carried out using pharmaceutical dosage form antibacterial.
9. the application of claim 8, the Norfloxacin metal complex and polyalkenylalcohols progress are compound, are preferably formed as membrane structure,
Its structure is preferred are as follows: (Z)z{X[MO(NF)n]m- P, P represents polyalkenylalcohols, preferably polyvinyl alcohol (PVA).
10. the application of claim 8, which is characterized in that the Norfloxacin metal complex and polyalkenylalcohols compound are by as follows
It is prepared by method:
(1) polyene alcoholic solution is prepared；
(2) Norfloxacin metal complex and its solution are prepared according to one of claim 3 to 7；
(3) Norfloxacin metal complex and polyalkenylalcohols compound are prepared.
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| CN113384735A (en) * | 2020-03-11 | 2021-09-14 | 华南理工大学 | Silver ion controlled-release antibacterial dressing and preparation method and application thereof |
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