CN105712983A - Pharmaceutical composition of ciclopirox olamine and medical application of pharmaceutical composition - Google Patents
Pharmaceutical composition of ciclopirox olamine and medical application of pharmaceutical composition Download PDFInfo
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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
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
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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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
The invention discloses a pharmaceutical composition of ciclopirox olamine and a medical application of the pharmaceutical composition. The pharmaceutical composition of the ciclopirox olamine contains ciclopirox olamine and a natural product compound (I) of a novel structure, wherein the ciclopirox olamine and the compound (I) can protect the antioxidase activity of rats, can eliminate free radicals and can inhibit the peroxidation of lipid, prompting that the oxidation resistance is one of mechanisms of the ciclopirox olamine and the compound (I) protecting the kidney of the DM rats. After the ciclopirox olamine and the compound (I) are collectively used, the effect for adjusting the blood fat and the effect for protecting the kidney of the type-II diabetic rats are further improved, when the pharmaceutical composition is used at the early stage, the occurrence and development of the diabetic kidney disease can be effectively retained, and the pharmaceutical composition can be developed into a drug treating the diabetic kidney disease. Compared with the prior art, the substantive characteristics and the progress are remarkable.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of ciclopirox olamine, be specifically related to pharmaceutical composition and the medical usage thereof of a kind of ciclopirox olamine.
Background technology
Ciclopirox olamine is broad-spectrum antifungal medicine, mainly through changing the integrity of fungal cell membrane, causes intracellular matter to outflow, and the picked-up of blocking protein precursor substance, causing that fungal cell is dead, dermatophytosis, yeast, mycete etc. are had stronger antibacterial and bactericidal action, permeability is strong.Various actinomycetes, Grain-positive and gram-negative bacteria and mycoplasma, chlamydia, trichomonacide etc. also there is certain inhibitory action.
Up to now, there is not yet the dependency of ciclopirox olamine and pharmaceutical composition thereof and diabetic cardiomyopathy report.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of ciclopirox olamine, containing ciclopirox olamine and a kind of natural product in this pharmaceutical composition, ciclopirox olamine and this natural product can Synergistic treatment diabetic nephropathyes.
The above-mentioned purpose of the present invention is achieved by the techniques below scheme:
A kind of compound (I) with following structural formula,
The pharmaceutical composition of a kind of ciclopirox olamine, including ciclopirox olamine, compound as claimed in claim 1 (I) and pharmaceutically acceptable carrier, prepares into the dosage form of needs.
Further, pharmaceutically acceptable carrier includes diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier or lubricant.
Further, described dosage form includes tablet, capsule, oral liquid, sucks agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, powder, solution, injection, suppository, spray, drop or patch.
The preparation method of above-claimed cpd (I), comprise following operating procedure: Radix Asteris is pulverized by (a), extract with 75～85% alcohol heat reflux, united extraction liquid, it is concentrated into without alcohol taste, successively with 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 n-butyl alcohol extract macroporous resin remove impurity in () step (a), first with 8 column volumes of 10% ethanol elution, then with 10 column volumes of 70% ethanol elution, collects 70% eluent, concentrating under reduced pressure obtains 70% ethanol elution concentrate；In (c) step (b) 70% ethanol elution concentrate with purification on normal-phase silica gel separate, successively with volume ratio be 60:1,30:1,15:1 and 5:1 methylene chloride-methanol gradient elution obtain 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, successively with volume ratio be 8:1,4:1 and 2:1 methylene chloride-methanol gradient elution obtain 3 components；E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 75%, collecting 10～15 column volume eluents, eluent concentrating under reduced pressure obtains compound (I).
Further, in the preparation method of compound (I), step (a) is extracted with 80% 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) replaces ethyl acetate to extract with dichloromethane, obtains dichloromethane extract.
The above-claimed cpd (I) application in the medicine of preparation treatment diabetic nephropathy.
The application in the medicine of preparation treatment diabetic nephropathy of the pharmaceutical composition of above-mentioned ciclopirox olamine.
Advantages of the present invention:
The pharmaceutical composition of ciclopirox olamine provided by the invention contains the natural product of ciclopirox olamine and a kind of novel structure, when ciclopirox olamine and this natural product independent role, there is treatment diabetic nephropathy effect；During the two synergy, treatment diabetic nephropathy effect is higher, it is possible to develop into the medicine for the treatment of diabetic nephropathy.The present invention compared with prior art has prominent substantive distinguishing features and significant progressive.
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.Although the present invention being explained in detail with reference to preferred embodiment, it will be understood by those within the art that, it is possible to technical scheme is modified or equivalent replacement, without deviating from the spirit and scope of technical solution of the present invention.
Embodiment 1: compound (I) separates preparation and structural identification
Reagent source: ethanol, petroleum ether, ethyl acetate, n-butyl alcohol, dichloromethane are analytical pure, purchased from Shanghai Ling Feng chemical reagent company limited, methanol, analytical pure, purchased from Jiangsu Han Bang chemical reagent company limited.
Separation method: Radix Asteris (2kg) is pulverized by (a), (15L × 3 time) are extracted with 80% alcohol heat reflux, united extraction liquid, it is concentrated into without alcohol taste (3L), extract with petroleum ether (3L × 3 time), ethyl acetate (3L × 3 time) and water saturated n-butyl alcohol (3L × 3 time) successively, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；B n-butyl alcohol extract D101 type macroporous resin remove impurity in () step (a), first with 8 column volumes of 10% ethanol elution, then with 10 column volumes of 70% ethanol elution, collects 70% eluent, concentrating under reduced pressure obtains 70% ethanol elution concentrate；C in () step (b), 70% ethanol elution concentrate purification on normal-phase silica gel separates, obtain 4 components with the methylene chloride-methanol gradient elution that volume ratio is 60:1 (10 column volumes), 30:1 (8 column volumes), 15:1 (10 column volumes) and 5:1 (8 column volumes) successively；D in () step (c), component 4 separates further by purification on normal-phase silica gel, obtain 3 components with the methylene chloride-methanol gradient elution that volume ratio is 8:1 (10 column volumes), 4:1 (8 column volumes) and 2:1 (6 column volumes) successively；E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 75%, collecting 10～15 column volume eluents, eluent concentrating under reduced pressure obtains compound (I) (HPLC normalization purity is more than 98%).
Structural identification: HR-ESI-MS shows [M+H]+For m/z537.2774, can obtain molecular formula in conjunction with nuclear-magnetism feature is C32H40O7, degree of unsaturation is 13.Hydrogen nuclear magnetic resonance modal data δH(ppm, pyridine-d5, 500MHz): H-1 (6.94, d, J=12.3Hz), H-2 (6.02, d, J=12.3Hz), H-5 (4.21, s), H-6 (3.52, d, J=6.0Hz), H-7a (2.53, dd, J=2.0, 15.1Hz), H-7b (2.74, m), H-8 (2.00, m), H-11a (1.93, dd, J=8.2, 13.1Hz), H-11b (1.85, dd, J=10.9, 13.1Hz), H-12 (2.74, dd, J=8.2, 10.9Hz), H-15a (1.62, dd, J=3.0, 15.9Hz), H-15b (2.01, m), H-16 (5.63, d, J=3.0Hz), H-18a (5.15, s), H-18b (4.92, s), H-19 (6.26, s), H-20 (2.99, m), H-21 (1.01, d, J=7.2Hz), H-22 (4.46, m), H-23a (2.03, m), H-23b (2.22, m), H-24 (6.34, d, J=6.0Hz), H-27 (1.81, s), H-28 (1.21, s), H-29 (1.48, s), H-30 (1.47, s), 9-OAc (1.97, s)；Carbon-13 nmr spectra data δC(ppm, pyridine-d5, 125MHz): 145.1 (CH, 1-C), 118.2 (CH, 2-C), 166.4 (C, 3-C), 80.7 (C, 4-C), 50.8 (CH, 5-C), 67.8 (CH, 6-C), 32.0 (CH2, 7-C), 50.2 (CH, 8-C), 79.2 (C, 9-C), 140.4 (C, 10-C), 53.2 (CH2, 11-C), 53.6 (CH, 12-C), 148.7 (C, 13-C), 42.4 (C, 14-C), 38.3 (CH2, 15-C), 124.8 (CH, 16-C), 139.4 (C, 17-C), 108.5 (CH2, 18-C), 144.1 (CH, 19-C), 39.9 (CH, 20-C), 15.3 (CH3, 21-C), 81.4 (CH, 22-C), 25.8 (CH2, 23-C), 139.7 (CH, 24-C), 128.5 (C, 25-C), 166.2 (C, 26-C), 16.8 (CH3, 27-C), 27.2 (CH3, 28-C), 29.7 (CH3, 29-C), 26.4 (CH3, 30-C), 21.9 (CH3, COCH 3-C), 171.8 (C,COCH3-C).1695cm in infrared spectrum-1And 1700cm-1Absorption band shows that this compound contains α, β-unsaturated lactone structure.225nm and 276nm absorption band in UV spectrum shows that this compound has several conjugated system.13C-NMR, DEPT and hsqc spectrum show 32 carbon signals, including ten quaternary carbon signals (four olefinic carbon signals, two company's oxygen carbon signals and three carbonyl carbon), six methyl (acetonyl), five methylene (an olefinic methylene), 11 methines (two company's oxygen carbon and five alkene carbon).In conjunction with insatiable hunger sum, above functional group shows that this compound has 5 circuluses.1H-NMR spectrum shows five methyl proton signal δ in conjunction with hsqc spectrumH1.01 (1H, d, J=7.2Hz), 1.81 (1H, s), 1.21 (1H, s), 1.48 (1H, s), 1.47 (1H, s), an acetylmethyl proton signal δH1.97 (3H, s), an outer olefinic methene proton signal δ of ringH5.15 (1H, s) He 4.92 (1H, s), five olefinic proton signals δH6.94 (1H, d, J=12.3Hz), 6.02 (1H, d, J=12.3Hz), 5.63 (1H, d, J=3.0Hz), 6.26 (1H, s), 6.34 (1H, d, J=6.0Hz), two oxygen-containing carbon signal δH(1H, m), comprehensive information above can show that this compound is a triterpenoid compound to 3.52 (1H, d, J=6.0Hz) and 4.46.In HMBC spectrum, the dependency of OH-6 and C-6 illustrates that C-6 position connects a hydroxyl, and to high field displacement, C-9 position carbon signal illustrates that the position of acetyl group is in C-9 position.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 is determined by ECD test further, and theoretical value is basically identical with experiment value.This compound chemistry formula and carbon atoms numbered are as follows:
Embodiment 2: pharmacological action
1, materials and methods
1.1 animals
3～4 months aged Wistar rats 40, male and female half and half, body weight 210g～250g, Jiamusi University's Experimental Animal Center provide.Animal feeding temperature (22 ± 1) DEG C, relative humidity 55%～65%, 12h periodicity of illumination aeration-drying environment in, adopt big mice maintain material 1022 raising.
1.2 reagent and sample
Ciclopirox olamine is purchased from National Institute for Food and Drugs Control.Compound (I) is made by oneself, and preparation method is shown in embodiment 1.Streptozotocin (STZ) purchased from American Sigma company；The test kits such as SOD, Coomassie brilliant blue protein determination all build up Bioengineering Research Institute purchased from Nanjing.Triglyceride Reagent box is purchased from remittance power engineering development center, Changchun.
1.3 instruments
High speed low temperature centrifugal machine (5810R, Eppendorf company of the U.S.), high performance liquid chromatography coulomb electrochemical analysis system (HPLC-ECDCoulchem III, ESA, the U.S.).
Prepared by 1.4 rat packets and model
Wherein 50 being served only for model group, 10 are served only for Normal group.After fasting 8h～16h (freely drinking water), model group rats is through tail vein injection STZ25mg/kg (0.1mol/L citric acid-sodium citrate buffer, pH4.4).After injecting 2 weeks, carry out glucose tolerance test, select impaired glucose tolerance (IGT) totally 40, be randomly divided into model control group, ciclopirox olamine group (60mg kg-1·d-1), compound (I) group (60mg kg-1·d-1), ciclopirox olamine and compound (I) compositions group [30mg kg-1·d-1Ciclopirox olamine+30mg kg-1·d-1Compound (I)], feed with high sugar-high fat diet, normal feedstuff mix with sucrose, refining Adeps Sus domestica, fresh hen egg etc., its total amount of heat 20.08J/g.Rats in normal control group is fed with normal feedstuff (containing protein 20%, carbohydrate 53%, fat 9%, total amount of heat for 15,42J/g).Normal group and diabetic groups gavage normal saline every day, persistently feed and gavage 8 weeks.Experiment terminates the previous day and does glucose tolerance test.
The collection of 1.5 blood samples
Under etherization, angular vein takes blood and is about 6ml, 2000rpm/min centrifugal 15min separation rat limosis, takes serum, surveys blood fat.
The preparation of 1.6 renal tissue homogenate
Take renal cortex, remove surface mucosa, repeatedly swing with pre-cold saline and wash 3 times, filter paper blots, and weighs and is placed in glass homogenizer, and this specimen is made the tissue homogenate of 1:10 with the normal saline of freezing processing, 4000～6000rpm/min is centrifuged 15min, takes supernatant standby.
1.7 statistical methods
Experimental data mean ± standard deviation (x ± s) represents, application SPSS18.0 version statistical software carries out one factor analysis of variance and t inspection, statistically significant for difference with P < 0.05.
2, experimental result
2.1 impacts on type 2 diabetes mellitus rat model blood fat
During medication the 8th week, comparing with Normal group, in model control group rat blood serum, triglyceride, cholesterol level and low density lipoprotein, LDL content increase (P < 0.05), and modeling success is described.Compare with model control group, ciclopirox olamine group, compound (I) group triglyceride, cholesterol, low-density lipoprotein are decreased obviously (P < 0.05), comparing with model control group, ciclopirox olamine and compound (I) compositions group triglyceride, cholesterol, low density lipoprotein, LDL are decreased obviously (P < 0.01).
Result is in Table 1.
2.2 on the impact of superoxide dismutase (SOD) activity in type 2 diabetes mellitus rat model renal tissue
Comparing with Normal group, in model control group rat kidney tissue, superoxide dismutase (SOD) activity reduces (P < 0.05).Comparing with model control group, ciclopirox olamine and compound (I) compositions group SOD significantly improve (P < 0.01)；Comparing with model control group, in ciclopirox olamine group, compound (I) group rat kidney tissue, superoxide dismutase (SOD) activity improves (P < 0.05).Result is in Table 2.
Table 1 triglyceride, cholesterol, low density lipoprotein, LDL content (mmol/L, x ± s)
| Group | Triglyceride | T-CHOL | Low density lipoprotein, LDL |
| Normal group | 0.83±0.13 | 1.73±0.11 | 2.36±0.06 |
| Model control group | 2.62±0.19 | 3.82±0.12 | 4.68±0.13 |
| Ciclopirox olamine group | 1.29±0.08 | 2.13±0.42 | 3.11±0.11 |
| Compound (I) group | 1.24±0.28 | 2.14±0.18 | 3.25±0.27 |
| Ciclopirox olamine and compound (I) compositions group | 0.92±0.11 | 1.82±0.15 | 2.40±0.49 |
Superoxide dismutase (SOD) activity (nmol/mgprot) (x ± s) in table 2 nephridial tissue
| Group | SOD activity |
| Normal group | 92.67±12.34 |
| Model control group | 76.46±13.29 |
| Ciclopirox olamine group | 87.16±11.55 |
| Compound (I) group | 88.69±10.33 |
| Ciclopirox olamine and compound (I) compositions group | 92.16±13.45 |
Superoxide dismutase (SOD) activity can reflect the anti peroxidation of lipid ability of body, is one of the member of internal scavenging activated oxygen Antioxidant Enzyme Systems.The Main Function of SOD is strong peroxidation capacity, is one of the member of internal scavenging activated oxygen Antioxidant Enzyme Systems.The Main Function of SOD is that superoxide anion reaction is generated hydrogen peroxide, the latter is transformed into water under the effect of catalase (CAT) and glutathione peroxidase (GSH-Px), thus reducing oxygen-derived free radicals to accumulate the too much lipid peroxidation aggravation caused, the normal configuration of maintenance organization cell and function in vivo.Diabetes (DM) early stage exists for significantly disorders of lipid metabolism.
There is obvious oxidative stress in DM rat kidney, nephridial tissue peroxide injury is notable.Ciclopirox olamine, compound (I) can protect the activities of antioxidant enzymes of rat, scavenging free radicals, anti-lipid peroxidation to react, and prompting antioxidation is one of mechanism of ciclopirox olamine, compound (I) protection DM rat kidney.After ciclopirox olamine and compound (I) are used in combination; Regulating Blood Lipid Effect and Renoprotective Effect to type 2 diabetes mellitus rat improve further; early stage application can delay generation and the development of diabetes nephropathy effectively, it is possible to develops into the medicine preventing and treating diabetes nephropathy.
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, it is possible to technical scheme is modified or equivalent replacement, without deviating from essence and the protection domain of technical solution of the present invention.
Claims (10)
1. a compound (I) with following structural formula,
2. the pharmaceutical composition of a ciclopirox olamine, it is characterised in that: include ciclopirox olamine, compound as claimed in claim 1 (I) and pharmaceutically acceptable carrier, prepare into the dosage form of needs.
3. the pharmaceutical composition of ciclopirox olamine according to claim 2, it is characterised in that: pharmaceutically acceptable carrier includes diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier or lubricant.
4. the pharmaceutical composition of ciclopirox olamine according to claim 2, it is characterised in that: described dosage form includes tablet, capsule, oral liquid, sucks agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, powder, solution, injection, suppository, spray, drop or patch.
5. the preparation method of the compound (I) described in claim 1, it is characterized in that, comprise following operating procedure: Radix Asteris is pulverized by (a), extract with 75～85% alcohol heat reflux, united extraction liquid, it is concentrated into without alcohol taste, successively with petroleum ether, ethyl acetate and water saturated n-butanol extraction, respectively obtains petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；B n-butyl alcohol extract macroporous resin remove impurity in () step (a), first with 8 column volumes of 10% ethanol elution, then with 10 column volumes of 70% ethanol elution, collects 70% eluent, concentrating under reduced pressure obtains 70% ethanol elution concentrate；In (c) step (b) 70% ethanol elution concentrate with purification on normal-phase silica gel separate, successively with volume ratio be 60:1,30:1,15:1 and 5:1 methylene chloride-methanol gradient elution obtain 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, successively with volume ratio be 8:1,4:1 and 2:1 methylene chloride-methanol gradient elution obtain 3 components；E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 75%, collecting 10～15 column volume eluents, eluent concentrating under reduced pressure obtains compound (I).
6. the preparation method of compound according to claim 5 (I), it is characterised in that: step (a) is extracted with 80% alcohol heat reflux, united extraction liquid.
7. the preparation method of compound according to claim 5 (I), it is characterised in that: described macroporous resin is D101 type macroporous adsorbent resin.
8. the preparation method of compound according to claim 5 (I), it is characterised in that: step (a) replaces ethyl acetate to extract with dichloromethane, obtains dichloromethane extract.
9. the application in the medicine of preparation treatment diabetic nephropathy of the compound (I) described in claim 1.
10. the pharmaceutical composition of the arbitrary described ciclopirox olamine of claim 2～4 application in the medicine of preparation treatment diabetic nephropathy.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105924412A (en) * | 2016-06-24 | 2016-09-07 | 丁俣汀 | Pharmaceutical composition of dirithromycin and medical application of pharmaceutical composition |
| US11026625B2 (en) | 2017-08-08 | 2021-06-08 | Fresenius Medical Care Holdings, Inc. | Systems and methods for treating and estimating progression of chronic kidney disease |
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2016
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105924412A (en) * | 2016-06-24 | 2016-09-07 | 丁俣汀 | Pharmaceutical composition of dirithromycin and medical application of pharmaceutical composition |
| US11026625B2 (en) | 2017-08-08 | 2021-06-08 | Fresenius Medical Care Holdings, Inc. | Systems and methods for treating and estimating progression of chronic kidney disease |
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Application publication date: 20160629 |