CN106008408A - Carboxyl iron maltose injection and biomedical application thereof - Google Patents
Carboxyl iron maltose injection and biomedical application thereof Download PDFInfo
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- CN106008408A CN106008408A CN201610333666.8A CN201610333666A CN106008408A CN 106008408 A CN106008408 A CN 106008408A CN 201610333666 A CN201610333666 A CN 201610333666A CN 106008408 A CN106008408 A CN 106008408A
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- compound
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- maltose
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- cholelithiasis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
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- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses carboxyl iron maltose injection and biomedical application thereof. The carboxyl iron maltose injection contains carboxyl iron maltose and a compound (I). The compound (I) is a natural product and is of a novel structure. Effects of treating cholecystitis and cholelithiasis can be realized when the carboxyl iron maltose and the compound (I) are individually used; the effects of treating the cholecystitis and the cholelithiasis further can be improved when the carboxyl iron maltose and the compound (I) are jointly used, and accordingly the carboxyl iron maltose and the compound (I) can be developed to obtain the injection for treating the cholecystitis and the cholelithiasis. Compared with the prior art, the carboxyl iron maltose injection and the biomedical application have the advantages of outstanding substantial characteristics and obvious progress.
Description
Technical field
The invention belongs to biomedicine field, be specifically related to carboxyl maltose rail injection liquid and the application in biological medicine thereof.
Background technology
Carboxyl maltose ferrum is a kind of novel iron complex, with maltodextrin by iron ion stably complexation wherein, controls ferrum
Disengage, iron ion can be combined to play a role with iron transporter and ferritin, and prevents from discharging substantial amounts of free iron, reduce
Nitrous oxide is formed.Carboxyl maltose ferrum can be effectively improved mild to moderate Patients with iron deficiency anemia Hb and serum ferritin concentration.
Summary of the invention
It is an object of the invention to provide carboxyl maltose rail injection liquid and the application in biological medicine thereof.
The above-mentioned purpose of the present invention is achieved by techniques below scheme:
A kind of compound (I) with following structural formula,
A kind of carboxyl maltose rail injection liquid, including carboxyl maltose ferrum, compound as claimed in claim 1 (I) and medicine
Acceptable carrier on.
The preparation method of above-claimed cpd (I), comprises following operating procedure: Yunnan Caulis Spatholobi is pulverized by (a), with 65～75%
Alcohol heat reflux extracts, and united extraction liquid is concentrated into without alcohol taste, successively with petroleum ether, ethyl acetate and water saturated n-butyl alcohol
Extraction, respectively obtains petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；N-butyl alcohol in (b) step (a)
Take thing macroporous resin remove impurity, first with 9 column volumes of 20% ethanol elution, then with 10 column volumes of 65% ethanol elution, receive
Collecting 65% eluent, concentrating under reduced pressure obtains 65% ethanol elution concentrate；C in () step (b), 65% ethanol elution concentrate is used
Purification on normal-phase silica gel separates, and obtains 4 with the methylene chloride-methanol gradient elution that volume ratio is 65:1,35:1,15:1 and 7:1 successively
Component；D in () step (c), component 4 separates further by purification on normal-phase silica gel, be 12:1,7:1 and 1:1 by volume ratio successively
Methylene chloride-methanol gradient elution obtains 3 components；In (e) step (d) component 2 with octadecylsilane be bonded anti-phase
Silica gel separates, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 58%, collects 11～15 column volume eluents, washes
De-liquid is concentrated under reduced pressure to give compound (I).
Further, in the preparation method of compound (I), step (a) is extracted with 70% alcohol heat reflux, united extraction liquid.
Further, in the preparation method of compound (I), described macroporous resin is D101 type macroporous adsorbent resin.
Further, in the preparation method of compound (I), step (a) replace ethyl acetate to extract with dichloromethane,
Obtain dichloromethane extract.
The above-claimed cpd (I) application in the medicine of preparation treatment cholecystitis and cholelithiasis.
The application in the medicine of preparation treatment cholecystitis and cholelithiasis of the above-mentioned carboxyl maltose rail injection liquid.
Advantages of the present invention: containing carboxyl maltose ferrum and a kind of novel structure in the carboxyl maltose rail injection liquid that the present invention provides
Natural product, carboxyl maltose ferrum and during this natural product independent role, cholecystitis and cholelithiasis is had therapeutical effect；The two
During synergy, the therapeutic effect of cholecystitis and cholelithiasis is improved further, can be developed into the injection for the treatment of cholecystitis and cholelithiasis.
Detailed description of the invention
Further illustrate the essentiality content of the present invention below in conjunction with embodiment, but do not limit scope with this.
Embodiment 1: compound (I) separates preparation and structural identification
Separation method: Yunnan Caulis Spatholobi (2kg) is pulverized by (a), extracts (15L × 3 time) with 70% alcohol heat reflux, merges
Extracting solution, is concentrated into without alcohol taste (3L), satisfies with petroleum ether (3L × 3 time), ethyl acetate (3L × 3 time) and water successively
N-butyl alcohol (3L × 3 time) extraction of sum, respectively obtains petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；
Acetic acid ethyl ester extract D101 type macroporous resin remove impurity in (b) step (a), first with 9 column volumes of 20% ethanol elution,
Again with 10 column volumes of 65% ethanol elution, collecting 65% eluent, concentrating under reduced pressure obtains 65% ethanol elution concentrate；(c)
In step (b), 65% ethanol elution concentrate purification on normal-phase silica gel separates, and is 65:1 (9 column volumes), 35:1 by volume ratio successively
The methylene chloride-methanol gradient elution of (10 column volumes), 15:1 (8 column volumes) and 7:1 (8 column volumes) obtains 4
Individual component；D in () step (c), component 4 separates further by purification on normal-phase silica gel, be 12:1 (6 cylinders by volume ratio successively
Long-pending), the methylene chloride-methanol gradient elution of 7:1 (7 column volumes) and 1:1 (6 column volumes) obtain 3 components；(e)
The reverse phase silica gel that in step (d), component 2 is bonded by octadecylsilane separates, water-soluble with the methanol that concentration expressed in percentage by volume is 58%
Liquid isocratic elution, collects 11～15 column volume eluents, and eluent is concentrated under reduced pressure to give compound (I) (HPLC normalizing
Change purity more than 98%).
Structural identification: HR-ESI-MS shows [M+H]+For m/z 237.1775, can obtain molecular formula in conjunction with nuclear-magnetism feature is
C15H24O2, degree of unsaturation is 4.Hydrogen nuclear magnetic resonance modal data δH(ppm, CDCl3, 500MHz): H-1 β (2.23, m),
H-2 α (1.58, m), H-2 β (1.87, m), H-3 α (1.66, m), H-3 α (2.25, m), H-5 (2.32,
Br, t, J=7.8Hz), H-6 α (2.78, br, d, J=12.6Hz), H-6 β (2.33, ddd, J=12.6,7.8,1.8Hz),
H-8 α (1.96, m), H-8 β (1.94, m), H-9 α (5.79, dd, J=7.5,4.6Hz), H-12 (1.15, s),
H-13 (1.25, s), H-14 (1.87, s), H-15 (1.38, s)；Carbon-13 nmr spectra data δC(ppm, CDCl3,
125MHz): 55.5 (CH, 1-C), 30.4 (CH2, 2-C), 39.5 (CH2, 3-C), 94.9 (C, 4-C),
55.4 (CH, 5-C), 33.8 (CH2, 6-C), 93.7 (C, 7-C), 29.8 (CH2, 8-C), 124.1 (CH,
9-C), 135.8 (C, 10-C), 72.4 (C, 11-C), 24.2 (CH3, 12-C), 25.1 (CH3, 13-C),
23.5(CH3, 14-C), 29.6 (CH3, 15-C).Infrared spectrum (3374cm-1) show that this compound contains hydroxyl base
Group.The hydrogen spectrum of compound shows that this compound has four unimodal methyl signals (δH1.15,1.25,1.87 and 1.38), one
Olefinic methine proton signal [δH5.79 (1H, dd, J=7.5,4.6Hz)].Carbon spectrum 15 carbon signals of display of this compound,
Including four methyl, four methylene, three methines (an alkene carbon), three company's oxygen quaternary carbons and an alkene quaternary carbon.
Comprehensive high resolution mass spectrum and nuclear magnetic data, this compound may be a sesquiterpenoids.Consulting literatures can be seen that this
Compound and known compound 4 α, 7 α-Epoxyguaiane-10 α, 11-diol has similar structure.Relatively both nuclear magnetic datas
Finding, compared to 4 α in noval chemical compound, 7 α-Epoxyguaiane-10 α, 11-diol only difference is that and had more one group of double key carbon letter
Number.In the HMBC of noval chemical compound composes, H-9 Yu C-10 and C-14, and the dependency table of H-1 Yu C-10 and C-14
It it is double bond between bright C-9 and C-10.Therefore, this compound remains C-4, C-7 position and forms the guainane type of oxygen bridge
Sesquiterpene.In ROESY spectrum, H3-15/H-5, H3-15/H-1 and H-5/H3Relevant between-12 may infer that this compound
H-5, H-1, H3Fork propyl group on-15 and C-7 positions is beta comfiguration.Comprehensive hydrogen spectrum, carbon spectrum, HMBC spectrum and ROESY spectrum,
And document is about correlation type nuclear magnetic data, can substantially determine that this compound is as follows, spatial configuration passes through ECD further
Test determines, theoretical value is basically identical with experiment value.
This compound chemical formula and carbon atoms numbered are as follows:
Embodiment 2: pharmacological action
The present embodiment injects colibacillary method in using common bile duct Incomplete ligation and gallbladder and prepares cholecystitis and cholelithiasis rabbit model,
Observe medicine and reduce the anti-cholecystitis and cholelithiasis effect of the aspects such as local organization TNF-α, β-EP content, reduction bile viscosity.
1, materials and methods
1.1 animal
Select the healthy rabbits at monthly age in March-4, body weight 1.3kg-1.9kg, provided by the animal department of the Chinese Academy of Sciences of Hunan Medical University and raised.
1.2 reagent and sample
Carboxyl maltose ferrum is purchased from Nat'l Pharmaceutical & Biological Products Control Institute.Compound (I) is made by oneself, and preparation method is shown in embodiment 1.
TNF radioimmunological kit is provided by Beijing East biotechnology research, and EP radioimmunological kit is by the sharp biotechnology center of sea, Beijing section
There is provided.Escherichia coli are provided by Hunan Hygienic & Epidemic Prevention Station, are cultivated by cross infection section of Xiangya Hospital, Central-South China Univ. and are provided
5×106The Escherichia coli bacteria liquid of/L.
1.3 instrument
Hemorheology LGR-80 Serial blood viscosity tester (cone-plate formula) is provided by Beijing Steellex Scientific Instrument Company.
Prepared by 1.4 rabbit packets and model
Rabbit is randomly divided into 6 groups, often group 12, respectively Normal group, model control group, positive controls (Longdanxiegan
Soup group, 50mg kg-1) and carboxyl maltose ferrum group (80mg kg-1), compound (I) group (80mg kg-1), carboxyl wheat
Bud sugar ferrum and compound (I) compositions group [40mg kg-1Carboxyl maltose ferrum+40mg kg-1Compound (I)].Normally
Matched group: carry out sham-operation, and intravenous injection every day normal saline；Model control group: carry out modeling operation, and vein every day
Injecting normal saline；Decoction of Gentiana for Purging the Liver-fire group: carry out modeling operation, and intravenous injection every day Decoction of Gentiana for Purging the Liver-fire；Remaining group: carry out
Modeling is performed the operation, and the medicine of the above-mentioned dosage of intravenous injection every day.Administration time is from the beginning of Post operation d2, morning 09 every day:
30/10:30 is administered once, altogether 7d.
Modeling is performed the operation: put into 12 in common bile duct direction, rabbit common bile duct outer#Syringe needle, with 1#Extract syringe needle after silk thread ligation, cause gallbladder
House steward's local stenosis.Expose gallbladder again, at body inserting needle, inject 0.1mL concentration 5 × 106·L-IEscherichia coli bacteria liquid.Ligation
Pin mouth, muscle skin of sewing up the incision.
1.5 bile viscosity determination experiments
Each group rabbit is put to death after observing treatment 7d. and extraction bile lmL surveys bile viscosity.
1.6 tumor necrosis factors (TNF-α) and beta-endorphin (β-EP) determination experiment
Peel off gallbladder, take gallbladder tissue and weigh after drying about 200mg, add lmL normal saline homogenate.4000r min after homogenate-1
Centrifugal 20min, extracts supernatant and intends surveying tumor necrosis factor (TNF-α) and beta-endorphin (β-EP).
1.7 statistical method
Experimental data mean ± standard deviation (x ± s) represents, application SPSS18.0 version statistical software carry out one factor analysis of variance and
T checks, statistically significant for difference with P ＜ 0.05.
2, experimental result
2.1 impacts on cholecystitis and cholelithiasis rabbit model bile viscosity
With Normal group ratio, model control group lapin bile viscosity significantly raised (P ＜ 0.01)；With model control group ratio, carboxylic
Base maltose ferrum substantially reduces (P ＜ 0.01) with compound (I) compositions group and positive controls lapin bile viscosity；With mould
Type matched group ratio, carboxyl maltose ferrum group, compound (I) group lapin bile viscosity reduces (P ＜ 0.05).The results are shown in Table 1.
2.2 on cholecystitis and cholelithiasis rabbit model TNF-α, the impact of β-EP
With Normal group ratio, the TNF-α of model control group rabbit, β-EP significantly raised (P ＜ 0.01).With model control group ratio,
Carboxyl maltose ferrum significantly reduces (P ＜ 0.01) with compound (I) compositions group and positive controls TNF-α, β-EP；With
Model group ratio, carboxyl maltose ferrum group, compound (I) group TNF-α, β-EP reduce (P ＜ 0.05).The results are shown in Table 1.
Table 1 is on cholecystitis and cholelithiasis rabbit model bile viscosity and TNF-α, the impact of β-EP content
| Group | Bile viscosity (mPa) | TNF-α(ng/g) | β-EP(pg/g) |
| Normal group | 0.86±0.26 | 3.5±0.9 | 1762±98 |
| Model control group | 3.14±0.33 | 112.8±15.3 | 4939±213 |
| Positive controls | 0.93±0.14 | 32.9±3.1 | 2467±124 |
| Carboxyl maltose ferrum group | 2.06±0.24 | 67.3±9.3 | 3112±153 |
| Compound (I) group | 2.05±0.19 | 56.5±3.6 | 3073±131 |
| Carboxyl maltose ferrum and compound (I) compositions group | 1.03±0.27 | 17.9±1.8 | 2129±114 |
The pathogenic factor of cholecystitis and cholelithiasis is mainly cholestasis and antibacterial infects.Therefore at the animal model of cholecystitis and cholelithiasis
In, this is also two key factors.
The above results shows, when carboxyl maltose ferrum, compound (I) independent role, has treatment to cholecystitis and cholelithiasis and makees
With；When carboxyl maltose ferrum and compound (I) synergy, the therapeutic effect of cholecystitis and cholelithiasis is improved further, can
To develop into the injection for the treatment of cholecystitis and cholelithiasis.
The effect of above-described embodiment indicates that the essentiality content of the present invention, but does not limit protection scope of the present invention with this.
It will be understood by those within the art that, technical scheme can be modified or equivalent, and not take off
Essence and protection domain from technical solution of the present invention.
Claims (8)
1. a compound (I) with following structural formula,
2. a carboxyl maltose rail injection liquid, it is characterised in that: include carboxyl maltose ferrum, change as claimed in claim 1
Compound (I) and pharmaceutically acceptable carrier.
3. the preparation method of the compound (I) described in claim 1, it is characterised in that comprise following operating procedure: (a)
By Yunnan Caulis Spatholobi pulverize, with 65～75% alcohol heat reflux extract, united extraction liquid, be concentrated into without alcohol taste, successively use petroleum ether,
Ethyl acetate and water saturated n-butanol extraction, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；
B in () step (a), n-butyl alcohol takes thing macroporous resin remove impurity, first with 9 column volumes of 20% ethanol elution, then use 65% second
10 column volumes of alcohol eluting, collect 65% eluent, and concentrating under reduced pressure obtains 65% ethanol elution concentrate；In (c) step (b)
65% ethanol elution concentrate with purification on normal-phase silica gel separate, successively with the dichloromethane that volume ratio is 65:1,35:1,15:1 and 7:1-
Methanol elution gradient obtains 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, use volume successively
3 components are obtained than the methylene chloride-methanol gradient elution for 12:1,7:1 and 1:1；E in () step (d), component 2 is with ten
The reverse phase silica gel of eight alkyl silane bondings separates, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 58%, collects 11～15
Individual column volume eluent, eluent is concentrated under reduced pressure to give compound (I).
The preparation method of compound the most according to claim 3 (I), it is characterised in that: step (a) 70% second
Alcohol circumfluence distillation, united extraction liquid.
The preparation method of compound the most according to claim 3 (I), it is characterised in that: described macroporous resin is D101
Type macroporous adsorbent resin.
The preparation method of compound the most according to claim 3 (I), it is characterised in that: step (a) is used dichloromethane
Alkane replaces ethyl acetate to extract, and obtains dichloromethane extract.
7. the application in the medicine of preparation treatment cholecystitis and cholelithiasis of the compound (I) described in claim 1.
8. the application in the medicine of preparation treatment cholecystitis and cholelithiasis of the carboxyl maltose rail injection liquid described in claim 2.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106727662A (en) * | 2016-12-20 | 2017-05-31 | 南京恒生制药有限公司 | A kind of carboxyl maltose iron Pharmaceutical composition and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106727662A (en) * | 2016-12-20 | 2017-05-31 | 南京恒生制药有限公司 | A kind of carboxyl maltose iron Pharmaceutical composition and preparation method thereof |
| CN106727662B (en) * | 2016-12-20 | 2019-02-26 | 南京恒生制药有限公司 | A kind of carboxyl maltose iron Pharmaceutical composition and preparation method thereof |
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