CN105708837A - Pharmaceutical composition of etodolac and medical application thereof - Google Patents
Pharmaceutical composition of etodolac and medical application thereof Download PDFInfo
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- CN105708837A CN105708837A CN201610279138.9A CN201610279138A CN105708837A CN 105708837 A CN105708837 A CN 105708837A CN 201610279138 A CN201610279138 A CN 201610279138A CN 105708837 A CN105708837 A CN 105708837A
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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
- A61K31/11—Aldehydes
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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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
- C07C45/79—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
- C07C47/38—Unsaturated compounds having —CHO groups bound to carbon atoms of rings other than six—membered aromatic rings
- C07C47/44—Unsaturated compounds having —CHO groups bound to carbon atoms of rings other than six—membered aromatic rings polycyclic
- C07C47/445—Unsaturated compounds having —CHO groups bound to carbon atoms of rings other than six—membered aromatic rings polycyclic containing a condensed ring system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/898—Orchidaceae (Orchid family)
- A61K36/8984—Dendrobium
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- General Health & Medical Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a pharmaceutical composition of etodolac and a medical application thereof. The pharmaceutical composition of etodolac comprises etodolac and a novel-structure natural product compound (I). When the etodolac and the compound (I) are separately used, a treatment effect on acute pharyngitis is realized; and when the etodolac and the compound (I) are combined, the treatment effect on acute pharyngitis is further improved. The pharmaceutical composition of etodolac can be developed into a medicine for treating acute pharyngitis and has outstanding substantive characteristics and remarkable progress in comparison with the prior art.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of etodolac, be specifically related to the pharmaceutical composition of etodolac and the application in acute pharyngitis thereof.
Background technology
Etodolac is NSAID (non-steroidal anti-inflammatory drug), it is possible to relief from osteoarthritis (degenerated joint pathological changes), the sings and symptoms of rheumatoid arthritis.Alleviating pain symptom.Rheumatoid arthritis, including this sick distinctive Cranial defect (erosion), arthrostenosis, osteoarthritis (degenerative joint disease) and mild to moderate pain.
Up to now, there is not yet the dependency of etodolac and pharmaceutical composition thereof and acute pharyngitis report.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of etodolac, containing etodolac and a kind of natural product in this pharmaceutical composition, etodolac and this natural product can Synergistic treatment acute pharyngitises.
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 etodolac, including etodolac, 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: Herba Dendrobii is pulverized by (a), extract with 70～80% 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 6 column volumes of 15% 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 80:1,30:1,15:1 and 5:1 methylene chloride-methanol gradient elution obtain 4 components；D in () step (c), component 3 separates further by purification on normal-phase silica gel, successively with volume ratio be 25:1,15:1 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 72%, collecting 8～14 column volume eluents, eluent concentrating under reduced pressure obtains pure compound (I).
Further, in the preparation method of compound (I), step (a) is extracted with 75% 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 acute pharyngitis.
The application in the medicine of preparation treatment acute pharyngitis of the pharmaceutical composition of above-mentioned etodolac.
Advantages of the present invention:
The pharmaceutical composition of etodolac provided by the invention contains the natural product of etodolac and a kind of novel structure, when etodolac and this natural product independent role, acute pharyngitis is had therapeutical effect；During the two synergy, the therapeutic effect of acute pharyngitis is improved further, it is possible to develop into the medicine for the treatment of acute pharyngitis.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: Herba Dendrobii (2kg) is pulverized by (a), (20L × 3 time) are extracted with 75% alcohol heat reflux, united extraction liquid, it is concentrated into without alcohol taste (4L), extract with petroleum ether (4L × 3 time), ethyl acetate (4L × 3 time) and water saturated n-butyl alcohol (4L × 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 6 column volumes of 15% 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 80:1 (8 column volumes), 30:1 (8 column volumes), 15:1 (8 column volumes) and 5:1 (10 column volumes) successively；D in () step (c), component 3 separates further by purification on normal-phase silica gel, obtain 3 components with the methylene chloride-methanol gradient elution that volume ratio is 25:1 (8 column volumes), 15:1 (10 column volumes) and 2:1 (5 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 72%, collecting 8～14 column volume eluents, eluent concentrating under reduced pressure obtains compound (I) (HPLC normalization purity is more than 98%).
Structural identification: white powder, HR-ESIMS shows [M+H]+For m/z285.2171, can obtain molecular formula in conjunction with nuclear-magnetism feature is C20H28O, degree of unsaturation is 7.Hydrogen nuclear magnetic resonance modal data δH(ppm, CDCl3, 500MHz): H-2 (1.65, m), H-3 (1.59, m), H-3 (2.21, m), H-4 (1.92, dd, J=7.1, 17.3Hz), H-4 (2.31, m), H-7 (2.21, m), H-7 (2.26, m), H-8 (2.01, d, J=13.2Hz), H-8 (2.57, dt, J=4.6, 13.2Hz), H-10 (5.06, d, J=7.8Hz), H-11 (6.13, dd, J=7.8, 13.1Hz), H-12 (5.94, d, J=13.1Hz), H-14 (6.70, dd, J=2.4, 12.2Hz), H-15 (1.97, d, J=15.6Hz), H-15 (2.82, ddd, J=6.6, 12.2, 15.6Hz), H-16 (0.87, s), H-17 (0.97, s), H-18 (1.73, s), H-19 (10.43, s), H-20 (1.63, s)；Carbon-13 nmr spectra data δC(ppm, CDCl3, 125MHz): 37.8 (C, 1-C), 42.5 (CH, 2-C), 27.2 (CH2, 3-C), 31.6 (CH2, 4-C), 127.5 (C, 5-C), 136.4 (C, 6-C), 26.5 (CH2, 7-C), 38.4 (CH2, 8-C), 136.6 (C, 9-C), 130.4 (CH, 10-C), 126.8 (CH, 11-C), 129.5 (CH, 12-C), (134.6 C, 13-C), 165.3 (CH, 14-C), 33.7 (CH2, 15-C), 24.6 (CH3, 16-C), 33.1 (CH3, 17-C), 22.2 (CH3, 18-C), 192.8 (CH2, 19-C), 18.9 (CH3, 20-C).Infrared spectrum shows that this compound contains aldehyde radical (1645cm-1) and alkene key (1609cm-1)。13C-NMR, DEPT and hsqc spectrum show 20 carbon signals, including four methyl δC24.6,33.1,22.2,18.9；Five methylene δC27.2,31.6,26.5,38.4,33.7；Six methine (four alkene carbon) δC42.5,130.4,126.8,129.5,165.3,192.8；And five quaternary carbon (four alkene carbon) δC37.8,127.5,136.4,136.6,134.6.H in HMBC spectrum2-7 and C-6, H-10 and C-9 and C-11, H-11 and C-10 and C-12, H-12 and C-11 and C-13, H-14 and C-12 and C-13, H3-16 with C-1, C-2, C-6 and C-17, H3-17 with C-1, C-2, C-6 and C-16, H3-18 with C-4, C-5 and C-6, H-19 and C-13 and C-14, H3-20 with the dependency of C-8, C-9 and C-10 and1H-1H-14/H in HCOSY spectrum2-15/H-2/H2-3/H2-4、H2-7/H2-8, the coherent signal of H-10/H-11/H-12 shows that this compound is to be connected, with cyclodoecatriene, the endocyclic compound formed by cyclohexene by C-1, C-2 and C-6 position.Comprehensive hydrogen spectrum, carbon spectrum, HMBC spectrum and NOESY 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
The present embodiment adopts ammonia continuous 3d that the pharyngeal nebulization of rat is set up acute pharyngitis animal model, measure the expression of interleukin-1 ' beta ' (IL-1 β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in Polymorphonuclear Leukocyte quantity, serum, observe the medicine therapeutical effect to acute pharyngitis.
1, materials and methods
1.1 animals
Wistar rat, body weight (250 ± 20) g, male and female half and half, Shanghai Slac Experimental Animal Co., Ltd. provide.
1.2 reagent and sample
Etodolac is purchased from Nat'l Pharmaceutical & Biological Products Control Institute.Compound (I) is made by oneself, and preparation method is shown in embodiment 1.Dexamethasone acetate tablets (Shanghai Sine Pharmaceutical Co., Ltd.).Interleukin-1 ' beta ' (IL-1 β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) enzyme linked immunological kit (being all purchased from Mei Lian bio tech ltd, Shanghai).
1.3 instruments
7080 type automatic clinical chemistry analyzers (FDAC), BX53 type binocular biological microscope (Japan Olympus), in good KDC-1042 type low speed centrifuge (in China section).
Prepared by 1.4 rat packets and model
60 rats are randomly divided into 6 groups, often group 10, respectively blank group, model control group, positive controls (dexamethasone, 5mg kg-1) and etodolac group (80mg kg-1), compound (I) group (80mg kg-1), etodolac and compound (I) compositions group [40mg kg-1Etodolac+40mg kg-1Compound (I)].Except blank group, all the other 5 groups the 1st～3 in the sky, afternoon respectively with pharyngeal 1 time of 15% ammonia spray rat, every time with aerosol apparatus spray 3 times, being equivalent to 6 μ L15% ammonia, to stay rat pharyngeal.The pharyngeal spray distilled water of blank group.Respectively the aspects such as the general symptom occurred after animal model, sign and pharyngeal pathomorphology are investigated, whether successful to evaluate animal model.After modeling success, carry out Drug therapy.Administering mode is positive controls ig5mg kg-1Dexamethasone, every day 1 time, continuous 5d；Blank group and model group ig every day distilled water 10mL kg-1.The medicine of the above-mentioned dosage of medicine group gavage, every day 1 time, successive administration 5d.
1.5 Polymorphonuclear Leukocyte countings
Each group rat 24h after last is administered, takes blood from rat aorta and puts to death animal, and blood sample is saved in vacuum respectively and takes in blood vessel and disposable EP pipe, is respectively used to neutrophil count and inflammatory factor detection.
1.6 rat blood serum preparation and mensuration
Take rat aorta blood 2mL, after injection EP pipe is to be solidified, 4 DEG C of 3000r min-1Centrifugal 10min, separates serum.To-70 DEG C of Refrigerator stores.Sample is made to melt (avoiding multigelation) again in room temperature before mensuration, again in 4 DEG C of 3000r min-1Centrifugal 5min, takes serum, measures IL-1 β, IL-6 and TNF-α level in serum by enzyme linked immunosorbent assay (ELISA), and operation illustrates to carry out according to test kit.
1.7 statistical methods
This experiment adopts SPSS18.0 statistical software analytical data, and P < 0.05 has statistical significance for difference.
2, experimental result
2.1 impacts on acute pharyngitis rat model neutrophilic granulocyte number
With blank group ratio, model control group Polymorphonuclear Leukocyte quantity significantly reduces (P < 0.01), and modeling success is described；Compared with model control group, positive controls Polymorphonuclear Leukocyte substantially increases (P < 0.01)；With model control group ratio, etodolac group, compound (I) group Polymorphonuclear Leukocyte quantity substantially increases (P < 0.01)；Compared with model control group, etodolac and compound (I) compositions group Polymorphonuclear Leukocyte substantially increase (P < 0.01).Result is in Table 1.
IL-1 β in 2.2 pairs of acute pharyngitis rat model serum, IL-6, the impact of TNF-α content
With blank group ratio, IL-1 β in model control group rat blood serum, IL-6, TNF-α content all substantially increases (P < 0.01), and modeling success is described；Compared with model control group, IL-1 β in positive controls rat blood serum, IL-6, TNF-α content all substantially reduces (P < 0.01)；With model control group ratio, IL-1 β, IL-6 in etodolac group, compound (I) group rat blood serum, TNF-α content all decreases (P < 0.05)；Compared with model control group, IL-1 β, IL-6 in etodolac and compound (I) compositions group rat blood serum, TNF-α content all substantially reduces (P < 0.01).Result is in Table 1.
Table 1 is to IL-1 β, IL-6, the impact of TNF-α content in acute pharyngitis rat model neutrophilic granulocyte quantity and serum
Acute pharyngitis is a kind of common clinical, frequently-occurring disease, at modern medicine great majority employing antibiotics and antiviral treatment acute pharyngitis, but less effective, the state of an illness is easily repeatedly.Cause model group rats immune system damage to make model group Neutrophilic granulocytopenia owing to ammonia stimulates, and dexamethasone makes neutrophilic granulocyte raise, but reduce the functions such as its migration, phagocytosis, digestion, thus weaken the infiltration to inflammation district and phagocytosis.In inflammatory reaction, lymphocyte, eosinophilic granulocyte ratio increases, and dexamethasone can reduce whole blood medium-sized lymphocyte and other cell ratio, makes inflammation alleviate.
When etodolac, compound (I) independent role, acute pharyngitis had therapeutical effect；When etodolac and compound (I) synergy, the therapeutic effect of acute pharyngitis is improved further, it is possible to develop into the medicine for the treatment of acute pharyngitis.
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 an etodolac, it is characterised in that: include etodolac, compound as claimed in claim 1 (I) and pharmaceutically acceptable carrier, prepare into the dosage form of needs.
3. the pharmaceutical composition of etodolac 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 etodolac 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: Herba Dendrobii is pulverized by (a), extract with 70～80% 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 6 column volumes of 15% 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 80:1,30:1,15:1 and 5:1 methylene chloride-methanol gradient elution obtain 4 components；D in () step (c), component 3 separates further by purification on normal-phase silica gel, successively with volume ratio be 25:1,15:1 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 72%, collecting 8～14 column volume eluents, eluent concentrating under reduced pressure obtains pure compound (I).
6. the preparation method of compound according to claim 5 (I), it is characterised in that: step (a) is extracted with 75% 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 acute pharyngitis of the compound (I) described in claim 1.
10. the pharmaceutical composition of the arbitrary described etodolac of claim 2～4 application in the medicine of preparation treatment acute pharyngitis.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105859535A (en) * | 2016-05-19 | 2016-08-17 | 江苏神龙药业有限公司 | Pramipexole dihydrochloride medicine composition and medical application thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105859535A (en) * | 2016-05-19 | 2016-08-17 | 江苏神龙药业有限公司 | Pramipexole dihydrochloride medicine composition and medical application thereof |
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Application publication date: 20160629 |