CN106478556A - A kind of pharmaceutical composition of Lofexidine Hydrochloride and its medical usage - Google Patents
A kind of pharmaceutical composition of Lofexidine Hydrochloride and its medical usage Download PDFInfo
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- CN106478556A CN106478556A CN201610817652.3A CN201610817652A CN106478556A CN 106478556 A CN106478556 A CN 106478556A CN 201610817652 A CN201610817652 A CN 201610817652A CN 106478556 A CN106478556 A CN 106478556A
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- lofexidine hydrochloride
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
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- 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)
- A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
- A61K36/8969—Polygonatum (Solomon's seal)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of pharmaceutical composition of Lofexidine Hydrochloride and its medical usage, containing the natural products compound (I) that Lofexidine Hydrochloride and a kind of structure are novel in the pharmaceutical composition of the Lofexidine Hydrochloride that the present invention is provided, when Lofexidine Hydrochloride, compound (I) independent role, there is therapeutic action to rat constipation；When Lofexidine Hydrochloride and compound (I) synergy, the therapeutic effect to rat constipation is improved further, can be developed into the medicine for the treatment of constipation, has prominent substantive distinguishing features compared with prior art progressive with significant.
Description
Technical field
The invention belongs to biomedicine field, is related to the new application of Lofexidine Hydrochloride, and in particular to a kind of hydrochloric acid Lip river is non-
Western fixed pharmaceutical composition and its medical usage.
Background technology
Lofexidine Hydrochloride is clinically used for mitigating or releasing the withdrawal syndrome of opioid drug.
Content of the invention
It is an object of the invention to provide a kind of pharmaceutical composition of Lofexidine Hydrochloride, contains salt in the pharmaceutical composition
Sour lofexidine and a kind of natural products, Lofexidine Hydrochloride and the natural products 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,
A kind of pharmaceutical composition of Lofexidine Hydrochloride, including Lofexidine Hydrochloride, compound as claimed in claim 1
(I) and pharmaceutically acceptable carrier, is prepared into the formulation of needs.
Further, pharmaceutically acceptable carrier include diluent, excipient, filler, adhesive, wetting agent,
Disintegrant, sorbefacient, surfactant, absorption carrier or lubricant.
Further, the formulation include tablet, capsule, oral liquid, mouth containing agent, granule, electuary, pill, powder,
Paste, sublimed preparation, supensoid agent, pulvis, solution, injection, suppository, spray, drops or patch.
The preparation method of above-claimed cpd (I), comprising following operating procedure：A radix polygonati officinalis is crushed by (), with 75～85% ethanol
Circumfluence distillation, merges extract, is concentrated into nothing alcohol taste, uses petroleum ether, ethyl acetate and water saturated extracting n-butyl alcohol successively,
Respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；B in () step (a), n-butyl alcohol extract is used
Macroreticular resin removal of impurities, first with 10% ethanol elution, 8 column volumes, then with 70% ethanol elution, 10 column volumes, collects 70% and washes
De- liquid, reduced pressure concentration obtain 70% ethanol elution concentrate；C in () step (b), 70% ethanol elution concentrate is divided with purification on normal-phase silica gel
From it is 60 to use volume ratio successively:1、30:1、15:1 and 5:1 methylene chloride-methanol gradient elution obtains 4 components；(d) step
Suddenly in (c), component 4 is separated further with purification on normal-phase silica gel, and it is 8 to use volume ratio successively:1、4:1 and 2:1 methylene chloride-methanol ladder
Degree affords 3 components；E component 2 is bonded with octadecylsilane in () step (d) reverse phase silica gel is separated, with volume hundred
Point concentration is 75% methanol aqueous solution isocratic elution, collects 10～15 column volume eluents, and eluent is concentrated under reduced pressure to give
Compound (I).
Further, in the preparation method of compound (I), step (a) is extracted with 80% alcohol heat reflux, is merged and is extracted
Liquid.
Further, in the preparation method of compound (I), the macroreticular resin is D101 type macroporous absorbent resin.
Further, in the preparation method of compound (I), in step (a), ethyl acetate is replaced to be extracted with dichloromethane
Take, obtain dichloromethane extract.
Application of the above-claimed cpd (I) in the medicine for preparing treatment constipation.
Application of the pharmaceutical composition of above-mentioned Lofexidine Hydrochloride in the medicine for preparing treatment constipation.
Advantages of the present invention：
Novel containing Lofexidine Hydrochloride and a kind of structure in the pharmaceutical composition of the Lofexidine Hydrochloride that the present invention is provided
Natural products, when Lofexidine Hydrochloride, compound (I) independent role, there is therapeutic action to rat constipation；Hydrochloric acid Luo Feixi
During fixed and compound (I) synergy, the therapeutic effect to rat constipation is improved further, can be developed into the medicine for the treatment of constipation
Thing.
Specific embodiment
The essentiality content of the present invention is further illustrated with reference to embodiment, but the present invention is not limited with this and protected model
Enclose.Although being explained in detail to the present invention with reference to preferred embodiment, it will be understood by those within the art that, can be right
Technical scheme is modified or equivalent, without deviating from the spirit and scope of technical solution of the present invention.
Embodiment 1：Compound (I) is separated and is prepared and structural identification
Reagent source：Ethanol, petroleum ether, ethyl acetate, n-butanol, dichloromethane are pure for analysis, insult peaking purchased from Shanghai
Reagent Co., Ltd is learned, methyl alcohol, analysis are pure, purchased from Jiangsu Han Bang chemical reagent Co., Ltd.
Separation method：A radix polygonati officinalis (2kg) is crushed by (), extract (15L × 3 time) with 80% alcohol heat reflux, merges and extracts
Liquid, is concentrated into nothing alcohol taste (3L), uses petroleum ether (3L × 3 time), ethyl acetate (3L × 3 time) and water saturated n-butanol successively
(3L × 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 D101 type macroreticular resin removal of impurities, first with 10% ethanol elution, 8 column volumes, then with 70% ethanol elution 10
Individual column volume, collects 70% eluent, and reduced pressure concentration obtains 70% ethanol elution concentrate；70% ethanol elution in (c) step (b)
Concentrate is separated with purification on normal-phase silica gel, and it is 60 to use volume ratio successively:1 (10 column volumes), 30:1 (8 column volumes), 15:1 (10
Column volume) and 5:The methylene chloride-methanol gradient elution of 1 (8 column volumes) obtains 4 components；D in () step (c), component 4 is used
Purification on normal-phase silica gel is separated further, and it is 8 to use volume ratio successively:1 (10 column volumes), 4:1 (8 column volumes) and 2:1 (6 cylinders
Product) methylene chloride-methanol gradient elution obtain 3 components；What e in () step (d), component 2 was bonded with octadecylsilane is anti-
Phase silica gel is separated, 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) (purity is more than 98%).
Structural identification：HR-ESI-MS shows [M+H]+For m/z 237.1769, can obtain molecular formula in conjunction with nuclear-magnetism feature is
C15H24O2, degree of unsaturation is 4.Hydrogen nuclear magnetic resonance modal data δH(ppm, CDCl3, 500MHz)：H-2 α (1.79, m), H-2 β
(2.01, m), H-3 α (1.69, m), H-3 α (2.22, m), H-5 (2.24, br, t, J=7.8Hz), H-6 α (2.16, br, d, J=
12.6Hz), H-6 β (2.26, ddd, J=12.6,7.8,1.8Hz), H-8 α (1.89, m), H-8 β (1.76, m), H-9 α (2.03,
Dd, J=7.5,4.6Hz), and H-9 β (2.15, m), H-12 (1.17, s), H-13 (1.24, s), H-14 (1.87, s), H-15
(1.34, s)；Carbon-13 nmr spectra data δC(ppm, CDCl3, 125MHz)：123.6 (C, 1-C), 32.2 (CH2, 2-C), 39.9
(CH2, 3-C), 93.3 (C, 4-C), 55.7 (CH, 5-C), 33.8 (CH2, 6-C), 94.6 (C, 7-C), 29.9 (CH2, 8-C),
34.8(CH2, 9-C), 120.8 (C, 10-C), 74.2 (C, 11-C), 24.1 (CH3, 12-C), 25.2 (CH3, 13-C), 33.7
(CH3, 14-C), 29.8 (CH3, 15-C).Infrared spectrum (3374cm-1) show that the compound contains oh group.Compound
Show that the compound has four unimodal methyl signals (δ in hydrogen spectrumH1.17,1.24,1.87 and 1.34).The carbon spectrum of the compound is aobvious
Show 15 carbon signals, wherein have one group of double bond carbon signal, and three company's oxygen carbon signals.Comprehensive high resolution mass spectrum and nuclear-magnetism number
According to the compound may be a sesquiterpenoids.Consulting literatures can be seen that the compound and 4 α of known compound, 7
α-Epoxyguaiane-10 α, 11-diol have similar structure.Relatively both nuclear magnetic datas find, phase in noval chemical compound
Only difference is that and had more one group of double bond carbon signal compared with 4 α, 7 α-Epoxyguaiane-10 α, 11-diol.In noval chemical compound
HMBC spectrum in, the explanation of the correlation of H-9/C-10, H-9/C-14 and H-14/C-1 is double bond between C-10 and C-1 position.Cause
This, the compound remains the guainane type sequiterpene that C-4, C-7 position forms oxygen bridge.H-5 and H-15 in ROESY spectrum,
The correlation of H-6 β and H-12 shows H-5 and H-15 for beta comfiguration, and the oxygen bridge of C-4 and C-7 is α configuration.Comprehensive hydrogen is composed, carbon is composed,
HMBC spectrum and ROESY spectrum, and document is with regard to correlation type nuclear magnetic data, can determine substantially that the compound is as follows, three-dimensional
By ECD test, configuration determines that theoretical value is basically identical with experiment value further.
The compound chemical formula and carbon atoms numbered as follows：
Embodiment 2：Pharmacological action
The present embodiment prepares rat Constipation Model with morphine hydrochloride, inquires into medicine to constipation rat model serum and colon group
Knit middle MDA (MDA), glutathione (GSH), nitric oxide (NO), the impact of superoxide dismutase (SOD) level.
1st, 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 separate
Raise, per 6, cage, room temperature (20 ± 2) DEG C, relative humidity (60 ± 10) %.All rat ad lib water inlets.
1.2 reagents and sample
Lofexidine Hydrochloride 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 kit is purchased from Rong Sheng institute of biological products, Shanghai, and morphine hydrochloride is purchased from the limited public affairs of northeast pharmacy
Department, Powdered Activated Carbon are purchased from Tianjin pharmaceutcal corporation, Ltd.
Prepared by the packet of 1.3 rats and model
Rat is randomly divided into 6 groups, per group 10, respectively Normal group, model control group, Lofexidine Hydrochloride group
(80mg·kg-1), compound (I) group (80mg kg-1), Lofexidine Hydrochloride and compound (I) composition group【40mg·kg-1
Lofexidine Hydrochloride+40mg kg-1Compound (I)】.After adaptability feeds 7d, except the daily hypodermic injection 3.0mg/kg of normal group
Outside distilled water, the daily hypodermic injection morphine hydrochloride 3.0mg/kg of remaining group, continuously injects 40d, 1 time/d, makes rat constipation mould
Type.After modeling success, normal group, model group distilled water 10mL/kg gavage, Lofexidine Hydrochloride group, compound (I) group, hydrochloric acid
Lofexidine presses above-mentioned dosage gastric infusion with compound (I) composition group.
1.4 serum NO level, MDA, SOD, GSH horizontal detection
Rat oral gavage 4 weeks, fasting can't help water 12h, and etherization, glass capillary are taken a blood sample from eyeground vein clump, separate blood
Clearly, 4 DEG C of preservations.According to kit specification 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, with physiology salt
Water grinds to form 10% homogenate.Supernatant, -20 DEG C of preservations are extracted after centrifugation.According to the method in kit specification to big
In mouse colon homogenate, NO, MDA, SOD, GSH level is measured.
1.6 statistical method
Experimental data represents that with mean ± standard deviation (x ± s) application SPSS18.0 version statistical software carries out single factor test variance
Analysis and t inspection, statistically significant as difference with P ＜ 0.05.
2nd, experimental result
The impact of 2.1 pairs of Constipation Model rat blood serum NO, MDA, SOD, GSH levels
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, Lofexidine Hydrochloride group and compound (I) organize NO, MDA
Level reduces, and SOD, GSH level raises (P ＜ 0.05), and Lofexidine Hydrochloride is shown with compound (I) composition group NO, MDA level
Write and reduce (P ＜ 0.01), SOD, GSH level significantly raises (P ＜ 0.01).It is shown in Table 1.
1 each group rat blood serum NO, MDA, SOD, GSH level of table compares (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 |
| Lofexidine Hydrochloride 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 |
| Lofexidine Hydrochloride and compound (I) composition group | 13.36±7.51 | 4.18±0.94 | 2.56±0.78 | 12.04±3.01 |
2.2 pairs of Constipation Model rat colons organize the impact of NO, MDA, SOD, GSH level
Compared with normal group, model group serum NO, MDA level rise, and SOD, GSH level declines (P ＜ 0.05).With mould
Type group is compared, and Lofexidine Hydrochloride group and compound (I) group NO, MDA level reduce, and SOD, GSH level raises (P ＜ 0.05),
Lofexidine Hydrochloride is significantly reduced with compound (I) composition group NO, MDA level, and SOD, GSH level significantly raises (P ＜
0.01).The results are shown in Table 2.
The impact (μm ol/L) of NO, MDA, SOD, GSH level organized by table 2 to Constipation Model rat colon
| 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 |
| Lofexidine Hydrochloride 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 |
| Lofexidine Hydrochloride and compound (I) composition group | 2.77±0.46 | 2.23±0.41 | 1.58±0.48 | 10.81±2.68 |
Constipation is clinically common slow as one kind of main performance with defecation frequency minimizing, difficult defecation, hard excrement etc.
Property symptom of digestive tract.Due to prolonged stay and the stimulation of hard excrement, colonic mucosa often has different degrees of inflammatory to change, so as to cause
A series of oxygen free radical reaction and peroxidatic reaction of lipid；The inflammatory reaction that constipation causes can produce substantial amounts of oxygen radical,
So as to cause increasing for cell membrane unsaturated fatty acid ester matter extent of peroxidation.
NO is a kind of novel signal molecule discharged by vascular endothelial cell, plays the role of strong expandable blood vessel, so as to wide
The general regulation for participating in organism physiology pathology function.Too high NO level can make intestinal tube smooth muscle relaxation, large intestine delayed conduction, so as to
Cause the exception of intestinal movement, cause constipation.NO generates substantial amounts of oxygen radical when generating, and these free radicals make lipid oxygen
Change, and Mitochondrial electron transmission function is affected, cause tissue cell insult.NO concentration in vivo is adjusted so as to recover large intestine life
Reason function and conduction function, the treatment to anal and intestinal disease have important clinical meaning.NO can be analyzed to hydroxy radical in vivo
And NO2-Free radical.Both free radicals have very strong oxidisability, and the molecular structure that can aggravate SOD, GSH is damaged, and promote its conjunction
Become and regenerate minimizing, the ability that the antioxidases such as SOD, GSH remove free radical has been obviously reduced, bigger so as to produce to body
Cytotoxicity.
The oxygen radical that SOD, GSH effectively can be produced in scavenger-cell metabolic process, terminates free radical chain reactionses.
SOD activity reduces with the aging of body, thus determine the enzymatic activity can be used as detecting the one of antioxidant ability of organism and aging
Individual quantitative target.In body, the another kind of enzyme system with scavenging activated oxygen anti-aging effects is GSH, and it is to preventing oxygen in body
Free radical causes peroxidatic reaction of lipid particular importance.The enzyme systems such as SOD, GSH play synergy in the body, with mitigating and
Blocking peroxidatic reaction of lipid, body is protected from the effect such as the infringement of all kinds of oxygen radicals, anti-aging, be to evaluate cell to receive
The important indicator that whether damages.So, it is to weigh one of important method of antioxidation of drug to determine the enzyme system such as SOD, GSH.This
Experiment Constipation Model group rat blood serum is higher than normal group with NO, MDA level in colon, and SOD, GSH level is less than normal group,
Show that peroxidization is one of important mechanisms that constipation is produced.
As a result show, when Lofexidine Hydrochloride, compound (I) independent role, there is therapeutic action to rat constipation；Hydrochloric acid
When lofexidine and compound (I) synergy, the therapeutic effect to rat constipation is improved further, can be developed into treatment constipation
Medicine.
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 (10)
1. a kind of compound (I) with following structural formula,
2. a kind of pharmaceutical composition of Lofexidine Hydrochloride, it is characterised in that：Including Lofexidine Hydrochloride, as claim 1 institute
The compound (I) stated and pharmaceutically acceptable carrier, are prepared into the formulation of needs.
3. the pharmaceutical composition of Lofexidine Hydrochloride according to claim 2, it is characterised in that：Pharmaceutically acceptable
Carrier includes diluent, excipient, filler, adhesive, wetting agent, disintegrant, sorbefacient, surfactant, absorption
Carrier or lubricant.
4. the pharmaceutical composition of Lofexidine Hydrochloride according to claim 2, it is characterised in that：The formulation includes piece
Agent, capsule, oral liquid, mouth containing agent, granule, electuary, pill, powder, paste, sublimed preparation, supensoid agent, pulvis, solution, note
Penetrate agent, suppository, spray, drops or patch.
5. the preparation method of compound (I) described in claim 1, it is characterised in that comprising following operating procedure：A () is by jade
Bamboo powder is broken, is extracted with 75～85% alcohol heat reflux, merges extract, is concentrated into nothing alcohol taste, uses petroleum ether, ethyl acetate successively
With water saturated extracting n-butyl alcohol, petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract is respectively obtained；(b) step
Suddenly n-butyl alcohol extract macroreticular resin removal of impurities in (a), first with 10% ethanol elution, 8 column volumes, then uses 70% ethanol elution
10 column volumes, collect 70% eluent, and reduced pressure concentration obtains 70% ethanol elution concentrate；C in () step (b), 70% ethanol is washed
De- concentrate is separated with purification on normal-phase silica gel, and it is 60 to use volume ratio successively:1、30:1、15:1 and 5:1 methylene chloride-methanol gradient is washed
Take off and obtain 4 components；D in () step (c), component 4 is separated further with purification on normal-phase silica gel, it is 8 to use volume ratio successively:1、4:1 and 2:
1 methylene chloride-methanol gradient elution obtains 3 components；What e in () step (d), component 2 was bonded with octadecylsilane is anti-phase
Silica gel is separated, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 75%, is collected 10～15 column volume eluents, is washed
De- liquid is concentrated under reduced pressure to give compound (I).
6. preparation method according to claim 5 to compound (I), it is characterised in that：Step (a) is returned with 80% ethanol heat
Stream is extracted, and merges extract.
7. preparation method according to claim 5 to compound (I), it is characterised in that：The macroreticular resin is D101 type
Macroporous absorbent resin.
8. preparation method according to claim 5 to compound (I), it is characterised in that：Dichloromethane generation is used in step (a)
Extracted for ethyl acetate, obtained dichloromethane extract.
9. application of the compound (I) described in claim 1 in the medicine for preparing treatment constipation.
10. the pharmaceutical composition of the arbitrary described Lofexidine Hydrochloride of claim 2～4 is in the medicine for preparing treatment constipation
Application.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105924412A (en) * | 2016-06-24 | 2016-09-07 | 丁俣汀 | Pharmaceutical composition of dirithromycin and medical application of pharmaceutical composition |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105924412A (en) * | 2016-06-24 | 2016-09-07 | 丁俣汀 | Pharmaceutical composition of dirithromycin and medical application of pharmaceutical composition |
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Application publication date: 20170308 |