CN106083802A - The pharmaceutical composition of dihydrocodeine bitartrate and the application in biological medicine thereof - Google Patents
The pharmaceutical composition of dihydrocodeine bitartrate and the application in biological medicine thereof Download PDFInfo
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- CN106083802A CN106083802A CN201610489322.6A CN201610489322A CN106083802A CN 106083802 A CN106083802 A CN 106083802A CN 201610489322 A CN201610489322 A CN 201610489322A CN 106083802 A CN106083802 A CN 106083802A
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- compound
- dihydrocodeine bitartrate
- pharmaceutical composition
- dihydrocodeine
- bitartrate
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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
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/76—Benzo[c]pyrans
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
The invention discloses the pharmaceutical composition of dihydrocodeine bitartrate and the application in biological medicine thereof, containing dihydrocodeine bitartrate and the natural product compound (I) of a kind of novel structure in the pharmaceutical composition of the dihydrocodeine bitartrate that the present invention provides, when dihydrocodeine bitartrate, compound (I) independent role, acute gouty arthritis had therapeutical effect；When dihydrocodeine bitartrate and compound (I) synergy, the therapeutic effect of acute gouty arthritis is improved further, the medicine for the treatment of acute gouty arthritis can be developed into, compared with prior art there is prominent substantive distinguishing features and significantly progress.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of dihydrocodeine bitartrate, be specifically related to tartaric acid double
The pharmaceutical composition of hydrogen codeine and the application in biological medicine thereof.
Background technology
The same codeine of dihydrocodeine bitartrate pharmacological action, clinical practice is similar with codeine.
Up to now, there is not yet dihydrocodeine bitartrate and pharmaceutical composition thereof relevant to acute gouty arthritis
Property report.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of dihydrocodeine bitartrate, this pharmaceutical composition contains
Dihydrocodeine bitartrate and the natural product of a kind of novel structure, dihydrocodeine bitartrate and this natural product is had to assist
With treating acute gouty arthritis.
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 pharmaceutical composition of dihydrocodeine bitartrate, including dihydrocodeine bitartrate, as claimed in claim 1
Compound (I) and pharmaceutically acceptable carrier, be prepared as the dosage form needed.
Further, pharmaceutically acceptable carrier include diluent, excipient, filler, binding agent, wetting agent,
Disintegrating agent, absorption enhancer, surfactant, absorption carrier or lubricant.
Further, described dosage form include tablet, capsule, oral liquid, suck 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), comprises following operating procedure: Flos Bombacis Malabarici is pulverized by (a), with 65～85% second
Alcohol circumfluence distillation, united extraction liquid, it is concentrated into without alcohol taste, successively by petroleum ether, ethyl acetate and water saturated n-butyl alcohol extraction
Take, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；N-butyl alcohol extract in (b) step (a)
Use macroporous resin remove impurity, first with 8 column volumes of 6% ethanol elution, then with 8 column volumes of 70% ethanol elution, collect 70% and wash
De-liquid, concentrating under reduced pressure obtains 70% ethanol elution concentrate；C in () step (b), 70% ethanol elution concentrate purification on normal-phase silica gel is divided
From, obtain 4 components with the methylene chloride-methanol gradient elution that volume ratio is 50:1,25:1,15:1 and 5:1 successively；(d) step
Suddenly in (c), component 4 separates further by purification on normal-phase silica gel, successively with the methylene chloride-methanol ladder that volume ratio is 10:1,5:1 and 2:1
Degree affords 3 components；E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, with volume hundred
Point concentration is the methanol aqueous solution isocratic elution of 75%, collects 8～14 column volume eluents, being concentrated under reduced pressure to give of eluent
Compound (I).
Further, in the preparation method of compound (I), described macroporous resin is AB-8 type macroporous adsorbent resin.
The above-claimed cpd (I) application in the medicine of preparation treatment acute gouty arthritis.
The pharmaceutical composition of above-mentioned dihydrocodeine bitartrate is in the medicine of preparation treatment acute gouty arthritis
Application.
Advantages of the present invention:
Containing dihydrocodeine bitartrate and one in the pharmaceutical composition of the dihydrocodeine bitartrate that the present invention provides
The natural product of novel structure, when dihydrocodeine bitartrate, compound (I) independent role, has acute gouty arthritis
There is therapeutical effect；When dihydrocodeine bitartrate and compound (I) synergy, the therapeutic effect to acute gouty arthritis
Improve further, the medicine for the treatment of acute gouty arthritis can be developed into.
Detailed description of the invention
Further illustrate the essentiality content of the present invention below in conjunction with embodiment, but do not limit the present invention with this and protect model
Enclose.
Embodiment 1: compound (I) separates preparation and structural identification
Separation method: Flos Bombacis Malabarici (3kg) is pulverized by (a), extracts (20L × 3 time) with 75% alcohol heat reflux, united extraction
Liquid, is concentrated into without alcohol taste (4L), successively with petroleum ether (4L × 3 time), ethyl acetate (4L × 3 time) and water saturated n-butyl alcohol
(4L × 3 time) extract, and respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；In (b) step (a)
N-butyl alcohol extract AB-8 type macroporous resin remove impurity, first with 8 column volumes of 6% ethanol elution, then with 70% ethanol elution 8
Column volume, collects 70% eluent, and concentrating under reduced pressure obtains 70% ethanol elution concentrate；C in () step (b), 70% ethanol elution is dense
Contracting thing with purification on normal-phase silica gel separate, successively with volume ratio be 50:1 (8 column volumes), 25:1 (8 column volumes), 15:1 (8 cylinders
Long-pending) and the methylene chloride-methanol gradient elution of 5:1 (10 column volumes) obtain 4 components；D in () step (c), component 4 is with just
Phase silica gel separates further, successively with volume ratio be 10:1 (8 column volumes), 5:1 (10 column volumes) and 2:1 (5 cylinders
Long-pending) methylene chloride-methanol gradient elution obtain 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 75%, collects 8～14 column volume eluents,
Eluent is concentrated under reduced pressure to give compound (I) (purity is more than 98%).
Structural identification: HR-ESI-MS shows [M+H]+For m/z 423.2498, can obtain molecular formula in conjunction with nuclear-magnetism feature is
C27H34O4, degree of unsaturation is 11.Hydrogen nuclear magnetic resonance modal data δH(ppm, CD3OD, 500MHz): H-1 (6.76, br, s), H-4
(5.96, s), H-5 (5.78, s), H-9 (2.12, s), H-10 (2.67, d, J=11.4Hz), H-11 (1.99, m), H-12
(1.72, dd, J=12.7,3.6Hz), H-12 (2.09, dd, J=12.7,8.3Hz), H-13 (6.69, dd, J=12.7,
5.4Hz), H-14 (6.17, d, J=12.7Hz), H-16 (1.02, d, J=6.7Hz), H-18 (2.81, m), H-18 (3.27,
Dd, J=17.1,1.9Hz), and H-20 (2.64, m), H-21 (1.34, m), H-21 (1.67, m), H-22 (1.20, m), H-22
(1.26, m), H-23 (1.24, m, 2H), H-24 (1.24, m, 2H), H-25 (1.25, m, 2H), H-26 (0.88, t, J=
7.2Hz), H-27 (1.21, d, J=7.2Hz)；Carbon-13 nmr spectra data δC(ppm, CD3OD, 125MHz): 146.5 (CH, 1-
C), 169.6 (C, 3-C), 115.8 (CH, 4-C), 147.2 (C, 4a-C), 108.1 (CH, 5-C), 189.8 (C, 6-C), 122.4
(C, 7-C), 153.5 (C, 8-C), 112.3 (C, 8a-C), 16.2 (CH3, 9-C), 62.1 (CH, 10-C), 21.1 (CH, 11-C),
33.2(CH2, 12-C), 143.5 (CH, 13-C), 132.3 (CH, 14-C), 197.5 (C, 15-C), 19.5 (CH3, 16-C), 41.1
(CH2, 18-C), 209.3 (C, 19-C), 46.3 (CH, 20-C), 32.7 (CH2, 21-C), 27.6 (CH2, 22-C), 29.0 (CH2,
23-C), 31.3 (CH2, 24-C), 22.2 (CH2, 25-C), 14.2 (CH3, 26-C), 16.6 (CH3, 27-C).In infrared spectrum
1710cm-1224nm absorption band during absorption band is composed with UV shows that this compound contains alpha, beta-unsaturated carbonyl structure.13C-NMR、
DEPT and hsqc spectrum show 27 carbon signals, including four methyl, seven methylene, eight methine (five alkene
Carbon), and eight quaternary carbons (three carbonyl carbon and five alkene carbon), function above structure shows this chemical combination in conjunction with insatiable hunger sum
Thing is tricyclic structure.1H-NMR spectrum combines hsqc spectrum and shows four methyl proton signal δH2.12 (3H, s), 1.02 (3H, d, J=
6.7Hz), 0.88 (3H, t, J=7.2Hz), 1.21 (3H, d, J=7.2Hz), seven groups of methene proton signal δH1.72 (1H,
Dd, J=12.7,3.6Hz) with 2.09 (1H, dd, J=12.7,8.3Hz), 2.81 (1H, m) with 3.27 (1H, dd, J=17.1,
1.9Hz), 1.34 (1H, m) with 1.67 (1H, m), 1.20 (1H, m) with 1.26 (1H, m), 1.24 (2H, m), 1.24 (2H, m),
1.25 (2H, m), five olefinic methine proton signal δH6.76 (1H, br, s), 5.96 (1H, s), 5.78 (1H, s), 6.69
(1H, dd, J=12.7,5.4Hz), 6.17 (1H, d, J=12.7Hz), three methine proton signal δH2.67 (1H, d, J=
11.4Hz), 1.99 (1H, m) 2.64 (1H, m).1H-1There is H-10/H-11/H in H COSY spectrum2-12/H-13/H-14、H3-
27/H-20/H2-21/H2-22/H2-23/H2-24/H2-25/H3-26 coherent signals, H-1 and C-of display in composing in conjunction with HMBC
4a, C-8a and C-8, H-4 Yu C-3, C-4a and C-8a, H-5 and C-4, C-4a and C-6, H-10 and C-3, C-11, C-15 and C-
16, H2-12 with C-11, C-13, C-14 and C-16, H-14 Yu C-12, C-13 and C-15, H2-18 with C-8 and C-19, H-20 and C-
19 coherent signals, can build the connected mode of this compound by the relevant information in above-mentioned H NMR spectroscopy, and according to above-mentioned ripple
Modal data confirms that this chemical combination is Cohaerin derivant.Comprehensive hydrogen spectrum, carbon spectrum, HMBC spectrum and ROESY spectrum, and document is about phase
Closing types of nuclear magnetic data, can substantially determine that this compound is as follows, spatial configuration is determined by ECD test further, theoretical
It is worth basically identical with experiment value.This compound chemical formula and carbon atoms numbered are as follows:
Embodiment 2: pharmacological action
This example uses Monosodium urate to prepare acute gouty arthritis rat model, observes tested joint before and after Drug therapy
Prostaglandin E in Zhou Jing, articular cavity tissue2(PGE), tumor necrosis factor-alpha (TNF-α) content and arthroedema leukocyte
Number.
1, materials and methods
1.1 animal
SD rat, male, cleaning grade, body weight 200～250g, by Guangdong Medical College Experimental Animal Center provide (.In experiment
Room supplies examination after normally raising 3d.
1.2 reagent and sample
Dihydrocodeine bitartrate is purchased from Nat'l Pharmaceutical & Biological Products Control Institute.Compound (I) is made by oneself, and preparation method is shown in reality
Execute example 1.Monosodium urate (offer of Sigma company), prostaglandin E2(PGE2) radioimmunoassay kits (grind by Beijing East immunological technique
Study carefully and provided), tumor necrosis factor-alpha (TNF-α) test kit (Military Medical Science Institute's institute provides).
Prepared by 1.3 rat packets and model
Rat is randomly divided into 5 groups, often group 12, respectively Normal group (not modeling), model control group and tartaric acid
Dihydrocodeine group (80mg kg-1), compound (I) group (80mg kg-1), dihydrocodeine bitartrate and compound (I) group
Compound group [40mg kg-1Dihydrocodeine bitartrate+40mg kg-1Compound (I)].Modeling method: exist with No. 6 entry needles
On the right side of tested rat, ankle joint dorsal part inserts inside tibia tendon with 45° angle, is only injected by 0.2mL/ by 10% Monosodium urate solution
Ankle joint intracavity.
Modeling second day, administration group is according to above-mentioned dosage gastric infusion, once a day, for three days on end；Normal group and mould
The normal saline of type matched group gavage equivalent.
1.4 rat articular swelling determination experiments
Each group rat before modeling, after modeling 3h (before administration) and last be administered after 3d, respectively at tested ankle joint
Same area measures its girth with nonelastic tape, before observing modeling and the change of rat ankle joint girth before and after treatment.
PGE in 1.5 articular cavity2, TNF-α, determination of white cells experiment
Sacrificed by decapitation after each group rat drug treatment 72h the last time, opens tested articular cavity and takes hydrarthrosis, be coated with
Sheet, carries out numeration of leukocyte；Take off articular cavity surrounding soft tissue, use in radioimmunoassay method tissue after homogenate
PGE2, TNF-α, by test kit description operate.
1.6 statistical method
Application 18.0 editions statistical softwares of SPSS carry out one factor analysis of variance and t inspection, have system with P ＜ 0.05 for difference
Meter meaning.
2, experimental result
2.1 impacts on gouty arthritis ankle swelling in rat
Comparing with Normal group, model control group ankle swelling in rat degree substantially increases (P ＜ 0.01).With model pair
Comparing according to group, dihydrocodeine bitartrate group, compound (I) group rat articular swelling degree is obviously reduced (P ＜ 0.05), winestone
Acid dihydrocodeine reduces (P0.01) with compound (I) compositions group arthroncus degree.The results are shown in Table 1.
PGE in 2.2 pairs of gouty arthritis rat articular cavity tissues2, TNF-α level and the impact of numeration of leukocyte
With Normal group ratio, PGE in model group rats articular cavity tissue2, TNF-α content significantly raise (P ＜ 0.01)；
Compare with model control group, PGE in dihydrocodeine bitartrate group, compound (I) group rat articular cavity tissue2, TNF-α content
Reduce (P ＜ 0.05)；Compare with model control group, dihydrocodeine bitartrate and compound (I) compositions group articular cavity tissue
Middle PGE2, TNF-α content significantly reduce (P ＜ 0.01).Compared with Normal group, in model control group rat joint cavity hydrops
Quantity of leucocyte significantly raised (P ＜ 0.01)；With model control group ratio, dihydrocodeine bitartrate group, compound (I) group rat
In arthroedema, quantity of leucocyte reduces (P ＜ 0.05), and dihydrocodeine bitartrate significantly drops with compound (I) compositions group
Low (P ＜ 0.01).The results are shown in Table 2.
The comparison (mm) of Articular swelling change respectively organized by table 1
| Group | Before modeling | Before administration | After administration |
| Normal group | 27.17±2.58 | 27.17±2.53 | 27.16±2.55 |
| Model control group | 27.13±2.63 | 38.74±1.82 | 36.53±2.05 |
| Dihydrocodeine bitartrate group | 27.21±2.53 | 39.05±2.54 | 30.85±1.74 |
| Compound (I) group | 27.06±1.99 | 37.11±2.61 | 30.17±2.47 |
| Dihydrocodeine bitartrate and compound (I) compositions group | 27.24±2.23 | 38.46±1.33 | 27.14±1.67 |
PGE in rat articular cavity tissue respectively organized by table 22, TNF-α content and numeration of leukocyte
Gout is heritability and (or) the acquired underexcretion caused and (or) disorders of purine metabolism, acute gout
The arthritic basic cause of disease of property is hyperuricemia and the precipitation of local joint sodium urate crystals caused thereof.Application Monosodium urate office
Portion's joint injection causes the modeling method that gouty arthritis model is considered as the gouty arthritis of classics, can be used for evaluating
The curative effect of gout arthritis drug.
When Monosodium urate deposits to around articular cavity, lure into monocytes/macrophages phagocytosis crystal, mastocyte, polymorphonuclear addicted to
Neutrophil accumulation is to about, and discharges that cause is scorching, algogenic substance, such as histamine, prostaglandin (PG), leukotriene
The inflammatory mediator such as B4, TNF-α, produces the strongest inflammatory effector and induced pain effect.PG is as the weight that third messenger is inflammatory reaction
Wanting mediator, the generation development of inflammation has substantial connection with local PG content.It is generally believed that in arthritic pathogenic process,
PGE2Effect the strongest.TNF-α as Chemokines and activity factor gouty arthritis generation, developed
Journey also plays an important role.Analyze PGE in tested articular cavity tissue2, quantity of leucocyte is favourable in TNF-α content and hydrarthrosis
In clinical diagnosis and the treatment of instructing gout.
The above results shows, when dihydrocodeine bitartrate, compound (I) independent role, to acute gouty arthritis
There is therapeutical effect；When dihydrocodeine bitartrate and compound (I) synergy, the treatment to acute gouty arthritis is imitated
Fruit is improved further, can develop into the medicine for the treatment of acute gouty arthritis.
The effect of above-described embodiment indicates that the essentiality content of the present invention, but does not limit the protection of the present invention with this
Scope.It will be understood by those within the art that, technical scheme can be modified or equivalent,
Essence and protection domain without deviating from technical solution of the present invention.
Claims (8)
1. a compound (I) with following structural formula,
2. the pharmaceutical composition of a dihydrocodeine bitartrate, it is characterised in that: include dihydrocodeine bitartrate, such as right
Require compound (I) described in 1 and pharmaceutically acceptable carrier, be prepared as the dosage form of needs.
The pharmaceutical composition of dihydrocodeine bitartrate the most according to claim 2, it is characterised in that: pharmaceutically can connect
The carrier being subject to include diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant,
Absorption carrier or lubricant.
The pharmaceutical composition of dihydrocodeine bitartrate the most according to claim 2, it is characterised in that: described dosage form includes
Tablet, capsule, oral liquid, suck 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 characterised in that comprise following operating procedure: (a) is by wood
Cotton Gossypii pulverize, with 65～85% alcohol heat reflux extract, united extraction liquid, be concentrated into without alcohol taste, successively use petroleum ether, acetic acid second
Ester 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 6% ethanol elution, then uses 70% ethanol elution
8 column volumes, collect 70% eluent, and concentrating under reduced pressure obtains 70% ethanol elution concentrate；C in () step (b), 70% ethanol is washed
De-concentrate purification on normal-phase silica gel separates, and washes by the methylene chloride-methanol gradient that volume ratio is 50:1,25:1,15:1 and 5:1 successively
Take off and obtain 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, successively with volume ratio be 10:1,5:1 and
The methylene chloride-methanol gradient elution of 2:1 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 75%, collects 8～14 column volume eluents,
Eluent is concentrated under reduced pressure to give compound (I).
The preparation method of compound the most according to claim 5 (I), it is characterised in that: described macroporous resin is AB-8 type
Macroporous adsorbent resin.
7. the application in the medicine of preparation treatment acute gouty arthritis of the compound (I) described in claim 1.
8. the pharmaceutical composition of the arbitrary described dihydrocodeine bitartrate of claim 2～4 is at preparation treatment acute gout
Application in arthritic medicine.
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| CN105906647A (en) * | 2016-05-19 | 2016-08-31 | 江苏神龙药业有限公司 | Pharmaceutical composition of pramipexole dihydrochloride and application of pharmaceutical composition in biomedicine |
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2016
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105906647A (en) * | 2016-05-19 | 2016-08-31 | 江苏神龙药业有限公司 | Pharmaceutical composition of pramipexole dihydrochloride and application of pharmaceutical composition in biomedicine |
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