CN105924412A - Pharmaceutical composition of dirithromycin and medical application of pharmaceutical composition - Google Patents
Pharmaceutical composition of dirithromycin and medical application of pharmaceutical composition Download PDFInfo
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- CN105924412A CN105924412A CN201610492873.8A CN201610492873A CN105924412A CN 105924412 A CN105924412 A CN 105924412A CN 201610492873 A CN201610492873 A CN 201610492873A CN 105924412 A CN105924412 A CN 105924412A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/38—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D303/40—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals by ester radicals
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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
- A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/32—Separation; Purification
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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)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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Abstract
The invention discloses a pharmaceutical composition of dirithromycin and a medical application of the pharmaceutical composition. The pharmaceutical composition of dirithromycin, provided by the invention, contains dirithromycin and a natural product compound (I) with a novel structure; when dirithromycin and the compound (I) independently act, treatment effect on rat constipation is achieved; when the dirithromycin and the compound (I) act jointly, the treatment effect on rat constipation is further improved, so that a drug for treating constipation can be developed; and compared with the prior art, the pharmaceutical composition has outstanding substantive features and remarkable progress.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of dirithromycin, be specifically related to the drug regimen of a kind of dirithromycin
Thing and medical usage thereof.
Background technology
Dirithromycin is macrolide antibiotics, for the prodrug of erythromycylamine, its mechanism of action be by with sensitive microbial
50S ribosomal subunit combine, thus suppress bacterioprotein to synthesize.The metabolism in liver of dirithromycin part.Macrolide
Class antibiotic all passes through Cytochrome P450 microsomal enzyme system and produces demethylation effect.
Up to now, there is not yet the dependency report of dirithromycin and pharmaceutical composition thereof and treatment constipation.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of dirithromycin, containing dirithromycin and in this pharmaceutical composition
Planting natural product, dirithromycin and this natural product can be with Synergistic treatment constipation.
The above-mentioned purpose of the present invention is achieved by techniques below scheme:
A kind of compound (I) with following structural formula,
The pharmaceutical composition of a kind of dirithromycin, including dirithromycin, compound as claimed in claim 1 (I) and pharmacy
Upper acceptable carrier, is prepared as the dosage form needed.
Further, pharmaceutically acceptable carrier includes diluent, excipient, filler, binding agent, wetting agent, collapses
Solve 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: Rhizoma Belamcandae is pulverized by (a), with 75~85% 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 extraction in (b) step (a)
Take thing macroporous resin remove impurity, first with 8 column volumes of 10% ethanol elution, then with 10 column volumes of 70% ethanol elution, receive
Collecting 70% eluent, concentrating under reduced pressure obtains 70% ethanol elution concentrate;C in () step (b), 70% 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 60:1,30:1,15:1 and 5:1 successively
Component;D in () step (c), component 4 separates further by purification on normal-phase silica gel, be 8:1,4:1 and 2:1 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 75%, collects 10~15 column volume eluents, washes
De-liquid is concentrated under reduced pressure to give compound (I).
Further, in the preparation method of compound (I), described macroporous resin is D101 type macroporous adsorbent resin.
The above-claimed cpd (I) application in the medicine of preparation treatment constipation.
The application in the medicine of preparation treatment constipation of the pharmaceutical composition of above-mentioned dirithromycin.
Advantages of the present invention:
Containing dirithromycin and the natural product of a kind of novel structure in the pharmaceutical composition of the dirithromycin that the present invention provides, ground is red
When mycin, compound (I) independent role, rat constipation had therapeutical effect;Dirithromycin and compound (I) associating
During effect, the therapeutic effect of rat constipation is improved further, can be developed into the medicine for the treatment of constipation.
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.To the greatest extent
The present invention is explained in detail by pipe with reference to preferred embodiment, it will be understood by those within the art that, can be to the present invention
Technical scheme modify or equivalent, 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 chemistry
Reagent company limited, methanol, analytical pure, purchased from Jiangsu Han Bang chemical reagent company limited.
Separation method: Rhizoma Belamcandae (2kg) is pulverized by (a), extracts (15L × 3 time) with 80% alcohol heat reflux, and merging carries
Take liquid, be concentrated into without alcohol taste (3L), successively with petroleum ether (3L × 3 time), ethyl acetate (3L × 3 time) and water saturation
N-butyl alcohol (3L × 3 time) extraction, 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 70%
10 column volumes of ethanol elution, collect 70% eluent, and concentrating under reduced pressure obtains 70% ethanol elution concentrate;(c) step (b)
In 70% ethanol elution concentrate purification on normal-phase silica gel separate, be 60:1 (10 column volumes), 30:1 (8 by volume ratio successively
Column volume), the methylene chloride-methanol gradient elution of 15:1 (10 column volumes) and 5:1 (8 column volumes) obtain 4 components;
D in () step (c), component 4 separates further by purification on normal-phase silica gel, be 8:1 (10 column volumes), 4:1 by volume ratio successively
The methylene chloride-methanol gradient elution of (8 column volumes) and 2:1 (6 column volumes) obtains 3 components;(e) step (d)
The reverse phase silica gel that middle component 2 is bonded by octadecylsilane separates, and washes with the methanol aqueous solution that concentration expressed in percentage by volume is 75% is isocratic
De-, collect 10~15 column volume eluents, eluent is concentrated under reduced pressure to give compound (I), and (HPLC normalization purity is big
In 98%).
Structural identification: HR-ESI-MS shows [M+H]+For m/z 309.1289, can obtain molecular formula in conjunction with nuclear-magnetism feature is
C16H20O6, degree of unsaturation is 8.Hydrogen nuclear magnetic resonance modal data δH(ppm, CDCl3, 500MHz): H-1 (4.03, s),
H-3 (3.31, s), H-5 (2.58, s), H-7 (2.73, dd, J=12.9,3.6Hz), H-8 α (1.72, m),
H-8 β (1.81, m), H-9 α (1.56, m), H-9 β (1.63, m), H-13 (5.76, d, J=3.3Hz), H-13
(6.29, d, J=3.3Hz), and H-14 (1.02, s), H-15 (1.47, s), 12-OMe (3.77, s);Nuclear magnetic resonance, NMR
Carbon modal data δC(ppm, CDCl3, 125MHz): 78.4 (CH, 1-C), 203.4 (C, 2-C), 62.3 (CH,
3-C), 59.1 (C, 4-C), 58.7 (CH, 5-C), 208.6 (C, 6-C), 51.7 (CH, 7-C), 20.3 (CH2,
8-C), 33.5 (CH2, 9-C), 34.3 (C, 10-C), 144.6 (C, 11-C), 167.3 (C, 12-C), 124.9
(CH2, 13-C), 19.2 (CH3, 14-C), 21.6 (CH3, 15-C), 52.7 (CH3, 12-OMe).13C-NMR、
DEPT and hsqc spectrum show 16 carbon signals, including three methyl (one even oxygen carbon), three methylene (
Alkene carbon), four methines (two company's oxygen carbon), and six quaternary carbons (an alkene carbon, three carbonyl carbon and companies
Oxygen quaternary carbon).In conjunction with insatiable hunger sum, function above structure shows that this compound is tricyclic structure.1H-NMR spectrum combines HSQC
Spectrum three methyl proton signal δ of displayH1.02 (3H, s), 1.47 (3H, s) with 3.77 (3H, s), pair of end alkene matter
Subsignal δH6.29 (1H, d, J=3.3Hz) and 5.76 (1H, d, J=3.3Hz), two company oxygen methine proton signal δH
4.03 (1H, s), 3.31 (1H, s).H NMR spectroscopy data δH3.77 (3H, s) and δCThis compound knowable to 52.7 is deposited
In methoxyl group, HMBC spectrum, the coherent signal of methoxyl group proton signal and C-12 indicates methoxyl group and is connected to C-12 position.Root
According to H NMR spectroscopy data δH3.31 (1H, s) and δC62.3,59.1 an existence epoxy construction in this compound is understood.Pass through1H-1H
H-1 Yu C-2, C-3 and C-11 of display, H-3 in H-7/H-8/H-9 coherent signal in COSY spectrum, and HMBC spectrum
With C-1, C-2, C-4 and C-5, H-5 Yu C-6 and C-10, H-7 and C-6, C-8 and C-11, H-13 and C-7, C-11
And C-12, H-14 and C-10 coherent signal, the connected mode of this compound can be built, and above-mentioned spectral data shows this
Compound is eudesmane.C-1, C-3, C-4, C-5, C-7 and C-10 in this compound is chiral carbon, passes through
NOESY test confirms relative configuration with H-H coupling constant.NOESY spectrum in H-1/H-9 β, H-1/H-14, H-3/H-14,
H-3/H-15, H-5/H-7, H-7/H-13, H-8 β/H-13, H-8 β/H-14 and H-14/H-15 this compound of coherent signal table
C-1, C-3, C-4, C-5, C-7 and C-10 are configured as 1R, 3R, 4S, 5S, 7S and 10R.Comprehensive hydrogen is composed, carbon is composed,
HMBC spectrum and NOESY compose, 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 chemical formula and carbon atoms numbered are as follows:
Embodiment 2: pharmacological action
The present embodiment uses morphine hydrochloride to prepare rat Constipation Model, inquires into medicine in constipation rat model serum and colon
Malonaldehyde (MDA), glutathion (GSH), nitric oxide (NO), superoxide dismutase (SOD) level
Impact.
1, materials and methods
1.1 animal
7 week old SD rats 60, SPF level, male and female half and half, purchased from Beijing Experimental Animal Center.Rearing conditions: male and female are divided
Open raising, 6, every cage, room temperature (20 ± 2) DEG C, relative humidity (60 ± 10) %.All rat ad libs are intake.
1.2 reagent and sample
Dirithromycin is purchased from Nat'l Pharmaceutical & Biological Products Control Institute.Compound (I) is made by oneself, and preparation method is shown in embodiment 1.NO、
SOD, MDA, GSH test kit is purchased from Rong Sheng institute of biological products, Shanghai, and morphine hydrochloride is purchased from northeast pharmaceutical Co. Ltd,
Powdered Activated Carbon is purchased from Tianjin pharmaceutcal corporation, Ltd.
Prepared by 1.3 rat packets and model
Rat is randomly divided into 6 groups, often group 10, respectively Normal group, model control group, dirithromycin group (80mg kg-1)、
Compound (I) group (80mg kg-1), dirithromycin and compound (I) compositions group [40mg kg-1Dirithromycin+40mg kg-1
Compound (I)].After adaptability feeds 7d, in addition to normal group subcutaneous injection every day 3.0mg/kg distilled water, remaining group is every
It subcutaneous injection morphine hydrochloride 3.0mg/kg, injects 40d continuously, 1 time/d, makes rat Constipation Model.After modeling success, just
Often group, model group distilled water 10mL/kg gavage, dirithromycin group, compound (I) group, dirithromycin and compound (I)
Compositions group presses above-mentioned dosage gastric infusion.
1.4 serum NO level, MDA, SOD, GSH horizontal detection
Rat oral gavage 4 weeks, fasting can't help water 12h, etherization, and glass capillary is taken a blood sample from eyeground vein clump, separates serum,
4 DEG C of preservations.According to test kit description method, NO, MDA, SOD, GSH level in rat blood serum is measured.
1.5 colon's NO, MDA, SOD, GSH horizontal detection
After putting to death rat, anatomical isolation goes out large intestine, and normal saline flushing is clean, weighs colon 0.3g, grinds with normal saline
Wear into the homogenate of 10%.Supernatant ,-20 DEG C of preservations are extracted after Li Xin.According to the method in test kit description to rat colon
In tissue homogenate, NO, MDA, SOD, GSH level is measured.
1.6 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 Constipation Model rat blood serum NO, MDA, SOD, GSH level
Compared with normal group, model group rats serum NO, MDA level all rise, and SOD, GSH level all declines (P
< 0.05), show rat Constipation Model modeling success.Compared with model group, dirithromycin group and compound (I) group NO,
MDA level reduces, and SOD, GSH level raises (P < 0.05), dirithromycin and compound (I) compositions group NO,
MDA level significantly reduces (P < 0.01), and SOD, GSH level significantly raises (P < 0.01).The results are shown in Table 1.
Table 1 is respectively organized rat blood serum NO, MDA, SOD, GSH level and is compared (μm ol/L)
Group | NO | SOD | MDA | GSH |
Normal group | 12.67±3.94 | 4.12±0.98 | 2.66±0.75 | 12.69±2.15 |
Model control group | 20.69±5.97 | 2.69±0.84 | 4.49±0.85 | 5.67±1.06 |
Dirithromycin group | 16.68±7.61 | 3.16±0.75 | 3.07±0.87 | 9.68±2.11 |
Compound (I) group | 16.34±5.81 | 3.64±0.84 | 2.95±0.99 | 9.96±2.10 |
Dirithromycin and compound (I) compositions group | 13.36±7.51 | 4.18±0.94 | 2.56±0.78 | 12.04±3.01 |
2.2 impacts on Constipation Model rat colon tissue NO, MDA, SOD, GSH level
Compared with normal group, model group serum NO, MDA level rise, and SOD, GSH level declines (P < 0.05).
Compared with model group, dirithromycin group and compound (I) group NO, MDA level reduce, and SOD, GSH level raises (P
< 0.05), dirithromycin significantly reduces with compound (I) compositions group NO, MDA level, and SOD, GSH level shows
Write and raise (P < 0.01).The results are shown in Table 2.
The table 2 impact (μm ol/L) on Constipation Model rat colon tissue NO, MDA, SOD, GSH level
Group | NO | SOD | MDA | GSH |
Normal group | 3.18±0.84 | 2.17±0.41 | 1.68±0.51 | 10.65±1.67 |
Model control group | 5.63±0.74 | 0.89±0.15 | 3.03±0.78 | 5.92±1.06 |
Dirithromycin group | 4.04±0.88 | 1.48±0.43 | 2.65±0.47 | 7.96±2.67 |
Compound (I) group | 3.96±0.71 | 1.62±0.27 | 2.06±0.59 | 7.63±1.61 |
Dirithromycin and compound (I) compositions group | 2.77±0.46 | 2.23±0.41 | 1.58±0.48 | 10.81±2.68 |
The common chronic digestible of one that constipation is is main performance with defecation frequency minimizing, difficult defecation, hard excrement etc. clinically
Road symptom.Due to prolonged stay and the stimulation of hard excrement, colonic mucosa often has inflammatory in various degree to change, thus causes a series of
Oxygen free radical reaction and lipid peroxidation;The inflammatory reaction that constipation causes can produce substantial amounts of oxygen-derived free radicals, thus causes
Increasing the weight of of cell membrane unsaturated fatty acid ester matter extent of peroxidation.
NO is a kind of novel signal molecule discharged by vascular endothelial cell, has the effect of strong expandable blood vessel, thus extensively joins
Regulation with organism physiology pathology function.Too high NO level can make intestinal tube smooth muscle loosening, large intestine delayed conduction, thus draws
Play the exception of intestinal movement, cause constipation.NO creates substantial amounts of oxygen-derived free radicals when generating, and these free radicals make lipid oxygen
Change, and affect Mitochondrial electron transmission function, cause tissue cell insult.Regulation NO concentration in vivo thus recover large intestine
Physiological function and conduction function, the treatment to anal and intestinal disease has important clinical meaning.NO can be analyzed to hydroxyl freely in vivo
Base and NO2-Free radical.Both free radicals have the strongest oxidisability, can aggravate the molecular structure damage of SOD, GSH,
Promote its synthesis and regeneration to reduce, be obviously reduced the antioxidases such as SOD, GSH and removed the ability of free radical, thus to body
Produce bigger cytotoxicity.
The oxygen-derived free radicals that SOD, GSH can produce in scavenger cell metabolic process effectively, terminates free radical chain reactions.SOD
Activity reduces along with the aging of body, thus measure this enzymatic activity can as detection antioxidant ability of organism and old and feeble one quantitatively
Index.In body, the another kind of enzyme system with scavenging activated oxygen anti-aging effects is GSH, and it is to preventing oxygen-derived free radicals in body
Cause lipid peroxidation particular importance.The enzymes such as SOD, GSH play synergism in tying up to body, have and alleviate and block
Lipid peroxidation, protection body from effects such as the infringement of all kinds of oxygen-derived free radicals, slow down aging, be evaluate cell damage with
No important indicator.So, measuring the enzyme systems such as SOD, GSH is one of important method weighing antioxidation of drug.This reality
Testing Constipation Model group rat blood serum with NO, MDA level in colon higher than normal group, SOD, GSH level is less than normal
Group, shows that peroxidization is one of important mechanisms of constipation generation.
Result shows, when dirithromycin, compound (I) independent role, rat constipation is had therapeutical effect;Dirithromycin
During with compound (I) synergy, the therapeutic effect of rat constipation is improved further, can be developed into the medicine for the treatment of constipation.
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. the pharmaceutical composition of a dirithromycin, it is characterised in that: include dirithromycin, chemical combination as claimed in claim 1
Thing (I) and pharmaceutically acceptable carrier, be prepared as the dosage form needed.
The pharmaceutical composition of dirithromycin the most according to claim 2, it is characterised in that: pharmaceutically acceptable carrier
Including diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption
Carrier or lubricant.
The pharmaceutical composition of dirithromycin the most according to claim 2, it is characterised in that: described dosage form includes tablet, glue
Wafer, 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)
By Rhizoma Belamcandae pulverize, with 75~85% alcohol heat reflux extract, united extraction liquid, be concentrated into without alcohol taste, successively use petroleum ether, second
Acetoacetic 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 10% ethanol elution, then with 70%
10 column volumes of ethanol elution, collect 70% eluent, and concentrating under reduced pressure obtains 70% ethanol elution concentrate;(c) step (b)
In 70% ethanol elution concentrate purification on normal-phase silica gel separate, be the dichloromethane of 60:1,30:1,15:1 and 5:1 by volume ratio successively
Alkane-methanol elution gradient obtains 4 components;D in () step (c), component 4 separates further by purification on normal-phase silica gel, use body successively
The methylene chloride-methanol gradient elution that long-pending ratio is 8:1,4:1 and 2:1 obtains 3 components;E in () step (d), component 2 is used
The reverse phase silica gel of octadecylsilane bonding separates, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 75%, collects
10~15 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 D101
Type macroporous adsorbent resin.
7. the application in the medicine of preparation treatment constipation of the compound (I) described in claim 1.
8. the pharmaceutical composition of the arbitrary described dirithromycin of claim 2~4 application in the medicine of preparation treatment constipation.
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Application publication date: 20160907 |