CN102596189A - Use of guaifenesin for inhibiting mucin secretion - Google Patents
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Abstract
A method of inhibiting mucus secretion in an individual that includes administering an effective amount of a composition which comprises guaifenesin.
Description
Technical field
The present invention relates to the purposes in the mucous secretion of medical compounds in suppressing individuality.Particularly, the present invention relates to the purposes of the inhibition mucous secretion of guaifenesin.
Background technology
Guaifenesin (guaifenesin), its chemical name are 3-(2-methoxyl group phenoxy group)-1, and the 2-propylene glycol is a kind of expectorant.Expectorant is the medicine that a kind of help is taken mucus and other materials out of from lung, bronchus and trachea.Guaifenesin is considered to through making mucus dilution, making expectorant and bronchial secretion is thinning and respiratory tract through lubricated irriate plays a role.Through dilution mucus, guaifenesin has reduced the viscosity of mucus secretion, and its result has improved from trachea and bronchus and removes the coughre flex of the secretions that gathers and the efficient of ciliary action.The individual effect of being experienced is that become expectorant and frequency of dry cough reduces.
Disclose the method for inhibition of mucin in the prior art.But what these methods were directed against is the treatment of chronic disease such as asthma etc.WO2004/043392 disclose chemical compound that a kind of use has the qualification molecular formula of at least two aromatic rings adjust the synthetic method of mucin and said chemical compound control with as the excessive aborning treatment application of the mucin of chronic obstructive pulmonary disease (COPD) (comprising chronic bronchitis) and inflammatory lung disease, asthma, cystic fibrosis and disease associations such as acute or chronic respiratory infectious disease.
Summary of the invention
The applicant has developed a kind of method that suppresses the mucous secretion in the individuality, and this method comprises the compositions that comprises guaifenesin of using effective dose.
According to a first aspect of the invention, a kind of method that suppresses the mucous secretion in the individuality is provided, this method comprises the compositions that comprises guaifenesin of using effective dose.Said composition can contain the guaifenesin of the 600mg～1200mg that has an appointment.
Guaifenesin can be to use like tablet, powder, capsule, liquid or liquid gel many appropriate formats such as (liquigel).Guaifenesin can be oral.
Mucin can produce at the upper respiratory tract of individuality.
Compositions can contain one or more other activating agents or its combination that is selected from the group that includes but not limited to anti-tussive agents (like dextromethorphan hydrobromide), Decongestant (phenylephrine hydrochloride, pseudoephedrine hydrochloride or ephedrine), hydryllin (like chlorphenamine, brompheniramine maleate, phenindamine tartrate, Pyrilamine, doxylamine succinate, citric acid phenyltoloxamine, diphhydramine hydrochloride, promethazine and clemastine fumarate, fexofenadine).
Compositions can have release portion and lasting release portion immediately, so that the about 12 hours inhibition to mucous secretion when being embodied as in treatment.
Dosage every day of guaifenesin can be 2400mg.
According to a second aspect of the invention; Provide a kind of combination treatment that comprises the guaifenesin described in first aspect of the present invention that uses effective dose to suffer from the method for the individuality of disease or disease, said disease or disease are characterised in that mucin secretion increases.
Be characterised in that the inflammatory disease that disease that mucin secretion increases or disease can be selected from air flue.
Description of drawings
Illustrative embodiments of the present invention is described below with reference to accompanying drawings in more detail.
Fig. 1 is illustrated therapeutic scheme.
Fig. 2 shows the figure of guaifenesin for the effect of MUC5AC mucin secretion: 30 minutes.
Fig. 3 a and 3b show the figure of guaifenesin for the effect of MUC5AC mucin secretion: 6 hours.
Fig. 4 a and 4b show the figure of guaifenesin for the effect of MUC5AC mucin secretion: 24 hours.
Fig. 5 a and 5b show the figure of guaifenesin for the effect of MUC5AC mucin secretion: 48 hours.
Fig. 6 shows the figure of guaifenesin for the effect of mucociliary clearance.
Fig. 7 a and 7b show metabolic figure.
Fig. 8 a, 8b and 8c show the rheol figure of mucus.
Fig. 9 a and 9b be show viscosity and elasticity with respect to the vector of time and dosage and figure.
The specific embodiment
Material and method
Cell:
Being grown in surface area is 1cm
2Or 4.2cm
2Millipore Transwells on EpiAirway cultivate (normal person's bronchiolar epithelium) cell.Said cell is available from MatTek, and before using, cultivates for 2 weeks at liquid-vapor interface (the synthetic and secretion of mucus) or 3 weeks (mucociliary conveying and mucus rheology).
Guaifenesin (GGE) is handled:
For mucociliary clearance; At the guaifenesin stock solution that is prepared in the 2mg/mL in the culture medium morning that carries out each experiment; And make it to keep colder, and be diluted to then in the warm medium, reach the aimed concn of 0.2 μ g/mL, 2 μ g/mL, 20 μ g/mL or 200 μ g/mL.Culture medium in the substrate outside compartment of each culture is contained the medium displacement of GGE, and makes culture be back to 37 ℃, 5%CO
2Incubator in keep the specified time.Repeat three experiments for culture independently.
The employed concentration of experiment is 0.2 μ g/mL～20mg/mL in the body, the clear and definite thus border for the employed clinical dosage of people.
The measurement of mucin secretion:
Prepare guaifenesin solution through before handling cell, being dissolved in immediately among the PBS (phosphate buffered saline (PBS)).(Labvision, Fremont CA) come the MUC5AC mucin is carried out quantitatively through ELISA to use 45M1 antibody.The 1cm that converges that uses 200 μ L PBS to grow at gas/liquid interface from the top surface washing
2The NHBE cell, and use the culture medium of growth fully of the new system that is added into bottom compartment to cultivate.Culture cultivated collected top fluid (pretreatment sample or PT) to add 100 μ L PBS through top surface in 24 hours to culture.Adding PBS is for diluting the sticking thin rete malpighii of lip-deep height.Because insert small-sized, it is infeasible therefore under the situation of not adding PBS, to collect the mucus that is enough to be used in pharmacology and rheol amount.After the mucus sample (PT) of collecting 100 μ L dilution; Culture is divided into 3 groups (6 hours, 24 hours and 48 hours); Every group of 16 inserts; And the guaifenesin (0 μ g/mL, 0.2 μ g/mL, 2 μ g/mL, 20 μ g/mL) that uses variable concentrations is handled each time group, 4 inserts of every dosage use.Thus, 48 inserts (4 insert/dosage * 4 dosage/time point * 3 time points) are altogether used in research for this reason.From all cultures, collected the top fluid, and whether influenced mucinous " secretion " in 30 minutes after drug treating to observe guaifenesin.The top mucus sample was collected with two steps---and at first add 100 μ L PBS (the 1st washing), add the PBS (the 2nd washing) that 100 μ L contain 5mM dithiothreitol, DTT (DTT) then to top surface.Analysis is from the MUC5AC content in the sample of each washing, and two values (the 1st washing washed with the 2nd time) sum is expressed as " MUC5AC of release " of culture.Three different time points (promptly; 6 hours, 24 hours and 48 hours), the washing culture to be collecting top fluid (" mucin of release ") as stated, and uses cracking buffer agent (PBS; PH7.2; 1mM Triton X-100,2mM EDTA, 1mM PSMF and 5mM DTT) (" cell mucin ") carry out cracking.Divided by by the mucinous amount in the PT sample of collecting in the same hole,, thereby compensate the variation in the culture with the mucinous amount in each sample (excretory, release or cell lysate) with acquisition " secretion index ".Processing scheme is depicted among Fig. 1.
The measurement of mucociliary clearance:
Make culture (4.2cm
2) contact 1 hour or 6 hours with basolateral guaifenesin.From the incubation case, take out culture and place it on the dressing table of digital imaging microscope system.The video data that uses 25 * object lens to collect 10 seconds.Transparent template covering and the stopwatch of use on video image, carries out 30～45 times altogether and measures to measure at least 5 granules on each culture the rate travel of video image analysis endogenous cell fragment under every kind of condition.
Mucous collection:
After carrying out, obtain mucus and do not dilute by the top surface of culture to the analysis of removing.
Vigor:
Use the top surface of PBS washing culture then, and use water-soluble tetrazolium salts (WST) to analyze (Boehringer) and measure metabolic activity as the vigor index.
Flow measurement:
Utilize parallel plate geometry, use AR1000 controlled stress flow graph (TA Instruments, New Castle, DE) rheological equationm of state of measurement top mucus secretion (20 μ L).By the strain-responsive of concussion stress is confirmed the behavior of dynamic linear viscoelasticity, and its note made energy storage or elastic modelling quantity (G ') and loss or viscosity (G ") modulus, it is the function of frequencies omega, for example viscosities il '=G "/ω.Rheological data also can use vector symbol to represent, said vector symbol for example as the tangent δ of viscosity and the ratio of elasticity and as the vector of viscosity and elastic mechanical impedance and G* (mechanical impedance).When the stress in use is in the range of linearity came evaluating material, material character did not rely on stress.
For carrying out the frequency scanning of 0.1rad/s～1000rad/s, use the creep test when 0.5Pa keeps 2 minutes to estimate viscoelasticity.Strain-responsive is fit to discontinuous relaxation spectrum, is converted into retardation spectrum, uses the method by the PI exploitation to be converted into energy storage and loss modulus (it is the function of frequency) then.Estimate the linear viscoelasticity when 1rad/s and 100rad/s, and used concussion stress scans and stable shear flow to test the behavior of assessing in the non-linear domain.Through observing G ' and G " stress of intersection, analyzed the concussion scan-data.This point shows that material has shown than the behavior of rebounding (recoil behavior) behavior of viscosity more (irreversible distortion and mobile).
All flow measurements are all undertaken by the technical staff who does not know the processed group situation.
Statistics:
For mucin secretion, assess the difference between matched group and the guaifenesin processed group through relatively using, and think that p＜0.05 has significance to the meansigma methods of the not student t test of paired samples.Only if point out in addition, otherwise all values among the figure is represented the meansigma methods ± SEM (* p＜0.05, * * p＜0.01) of 4 cultures.
For mucociliary clearance, assess the difference between matched group and the guaifenesin processed group through the meansigma methods of relatively using ANOVA, and utilize Bonferroni to examine and determine to assess afterwards with after processing in the difference of matched group of test.P value less than 0.05 is considered to have statistical significance.
For rheological experiment, use StatView
TM5 statistical packages are come analytical data.Whether visual definite raw material is about the meansigma methods normal distribution.ANOVA is used for relatively using the result of processing expectorant of the guaifenesin of variable concentrations.Carry out the protected least significant difference test of Fisher, to confirm the significance of multiple comparison.Only if point out in addition, otherwise data are represented with cell mean ± 1 standard error.By convention, p＜0.05 is considered to have statistical significance.
The result
In Fig. 2, use the guaifenesin of prescribed concentration to handle the EpiAirway culture 30 minutes.Excretory MUC5AC is compared with the preceding value of processing.
During 30 minutes processing, there is not significant difference (p＜0.05) between matched group and the guaifenesin group.
In Fig. 3 a, white box is represented the mucinous amount relevant with cell, and black box is illustrated in the mucinous amount that is discharged in the given treatment period.Therefore, the mucinous total amount that adds and be illustrated in generation in the given period of white box and black box.The statistical discrepancy of the total amount of the MUC5AC between comparative control group (no guaifenesin) and the guaifenesin group.
Use guaifenesin to handle the NHBE cell and do not influence the mucinous amount (Fig. 3 b) that is discharged in 6 hours.Yet the mucinous total amount that when being, produces in 6 hours processing period receives remarkable (p＜0.01) inhibition that guaifenesin (2 μ g/ml and 20 μ g/ml) exists.
Use 2 μ g/mL or 20 μ g/mL 24 hours of guaifenesin to handle to have suppressed significantly mucin release (Fig. 4 b) with mucin generation (Fig. 4 a).
Use guaifenesin (2 μ g/mL and 20 μ g/mL) handle 48 hours significantly (p＜0.01) suppressed mucinous generation (Fig. 5 a).As if yet the mucinous amount that is discharged in the section does not at this moment receive appreciable impact.
Guaifenesin is for the effect of mucociliary clearance:
As if as shown in Figure 6, guaifenesin has improved the animal migration of the lip-deep cell debris of the culture of handling 1 hour, but have few evidence about dose response, in fact, has only the effect of 2 μ g/mg to have statistical significance.But,, have the strong tendency of dose response, and the surfacing of all three kinds of concentration of being tested is mobile obviously rapid than matched group, as shown in Figure 6 at 6 hours these time points.
Use the guaifenesin of specified concentration to handle the EpiAirway culture 1 hour or 6 hours.Rate travel assessment mucociliary clearance property through lip-deep endogenous fragment.* * representes to be different from significantly at one time the culture of contrast, p＜0.005.
Vigor:
Analyze institute like WST and show, do not have detrimental effect about the vigor of cell.In fact, the tendency that in the cell of handling with guaifenesin, as if exists metabolic activity to improve, but this does not reach statistical significance.Data show from one of three same experiments is following.
Shown in Fig. 7 a and 7b, use the guaifenesin of prescribed concentration to handle the EpiAirway culture 1 hour or 6 hours.Use and separately be added into the top of culture or the WST analysis and evaluation metabolic activity of lower surface.
Rheological characteristic:
Analysis is from 96 samples of total of 5 groups of experiments.Receive the mucus from first batch of four experiments at room temperature, the analysis of the rheological characteristic of these samples shows extreme anisotropism, and the rheology scanning curve that is obtained is consistent with degraded.Therefore result displayed comes from 22 samples that are received from the 5th batch among Fig. 7 and 8.All samples all are the non newtonian viscoelastic gels.
The result proved and when with the cilium frequency measurement of 1rad/s roughly, existed sample 1 hour (p＜0.05), particularly the significant guaifenesin dose dependent of viscosity, elasticity and complex modulus (G*) reduces by 6 hours the time, but then not remarkable corresponding to the 100rad/s of cough the time.
The slime flux degeneration.Fig. 3 a:G " viscosity, Fig. 8 b:G ' elasticity, Fig. 8 c G* mechanical impedance (viscosity and elastic vector with).Data presented is meansigma methods and the standard error from the data of combination 1 hour and 6 hours time points.
G*: by time and dosage isolating 1rad/s (Fig. 9 a) and the viscosity during 100rad/sec (Fig. 9 b) and elastic vector with.
In all three processing time sections (6 hours, 24 hours and 48 hours), the guaifenesin of 2 μ g/mL and 20 μ g/mL has suppressed to produce mucin by the NHBE cell of growing on gas/liquid interface.Similarly, use 2 μ g/mL and 20 μ g/mL guaifenesin to handle and showed that remarkable (p＜0.05) that mucin discharges reduced in 24 hours.
For understanding the effect of guaifenesin, measured the mucociliary transfer rate for mucociliary clearance.The purpose of these experiments is to study the potential variation that is exposed to the mucociliary clearance that guaifenesin brings out through the primary human trachea-bronchia epithelial cell that will break up.It is that the fluorescent microsphere of 1 μ m is deposited on the surface of culture with aerosolized diameter that initial plan is to use nebulizer.But owing to it be unclear that, though can on culture, identify microsphere, only considerably less culture shows mobile, although the endogenous cell fragment obviously moves.Convert the video of collecting the endogenous fragment into.
Viscosity (loss modulus) is the energy loss of rheology probe or the stress that applies, therefore is that opposing is mobile.Elasticity (storage modulus) is the resilience energy of passing back to probe.Complex modulus G* is also referred to as mechanical impedance.As the vector of storage modulus and loss modulus with, G* measurements shows for the repellence of being out of shape.Viscoelasticity is the character of non-Newtonian fluid (gel).Dynamic viscoelastic is measured the strain-responsive of mucus for the stress that is applied.Because mucus met with low stress (ciliary beat) and heavily stressed (cough) condition, measured the strain that develops in response to dynamic stress.
These results are consistent with the secretions of taking from as the noble cells of mucus gel.Though the degraded from experiment 1～4 sample has produced the inconsistent result (if needs can provide all baseline results) who shows degraded, last is organized, and result of experiment has also obtained good preservation and these results are very strong.The reduction of the complex modulus parallel with viscosity (loss modulus) reduction and the increase that cilium is carried are consistent.The rheological behavior of these samples shows that having produced viscosity approximates elastic goblet cell, rather than elasticity is usually greater than the submucosal gland body secretions of viscosity.The structure of being reported of these results and EpiAirway culture is consistent.Useful information can be provided with these results with comparing from the result of the human tissue explant that is exposed to guaifenesin.
Guaifenesin with clinical relevant concentration, with the dose dependent mode in vitro inhibition the mucin of the human bronchial epithelial cell of the property converged of on gas/liquid interface, growing produce.The minimizing that mucus produces carries increase and mucous viscoelasticity to reduce relevant with mucociliary.
Can carry out other modifications and improvement, and not depart from scope of the present invention described herein.
Claims (35)
1. method that suppresses the mucous secretion in the individuality, said method comprises the compositions that comprises guaifenesin of using effective dose.
2. the method for claim 1, wherein said compositions comprises about 600mg～1200mg guaifenesin.
3. method as claimed in claim 2, wherein, said compositions comprises about 600mg guaifenesin.
4. method as claimed in claim 2, wherein, said compositions comprises about 1200mg guaifenesin.
5. the method for claim 1, wherein said compositions that comprises guaifenesin of using effective dose comprises to be used said compositions as tablet.
6. the method for claim 1, wherein said compositions that comprises guaifenesin of using effective dose comprises to be used said compositions as powder.
7. the method for claim 1, wherein said compositions that comprises guaifenesin of using effective dose comprises to be used said compositions as capsule.
8. the method for claim 1, wherein said compositions that comprises guaifenesin of using effective dose comprises said compositions as liquid application.
9. the method for claim 1, wherein said compositions that comprises guaifenesin of using effective dose comprises to be used said compositions as liquid gel.
10. the method for claim 1, wherein said mucous secretion produces in the upper respiratory tract of individuality.
11. the method for claim 1, wherein said compositions also comprises one or more activating agents.
12. method as claimed in claim 11, wherein, said one or more activating agents are selected from the group of being made up of anti-tussive agents, Decongestant and hydryllin.
13. method as claimed in claim 12, wherein, said anti-tussive agents comprises dextromethorphan hydrobromide.
14. method as claimed in claim 12, wherein, said Decongestant is selected from the group of being made up of phenylephrine hydrochloride, pseudoephedrine hydrochloride and ephedrine.
15. method as claimed in claim 12; Wherein, said hydryllin is selected from the group of being made up of chlorphenamine, brompheniramine maleate, phenindamine tartrate, Pyrilamine, doxylamine succinate, citric acid phenyltoloxamine, diphhydramine hydrochloride, promethazine, clemastine fumarate and fexofenadine.
16. the method for claim 1, wherein said compositions comprises release portion and lasting release portion immediately, so that about 12 hours inhibition when being embodied as in treatment to said mucous secretion.
17. a combination treatment that comprises guaifenesin that uses effective dose suffers from the method for the individuality of disease or disease, said disease or disease are characterised in that mucin secretion increases.
18. method as claimed in claim 17, wherein, said compositions comprises about 600mg～1200mg guaifenesin.
19. method as claimed in claim 18, wherein, said compositions comprises about 600mg guaifenesin.
20. method as claimed in claim 18, wherein, said compositions comprises about 1200mg guaifenesin.
21. method as claimed in claim 17, wherein, the compositions that comprises guaifenesin of using effective dose comprises to be used said compositions as tablet.
22. method as claimed in claim 17, wherein, the compositions that comprises guaifenesin of using effective dose comprises to be used said compositions as powder.
23. method as claimed in claim 17, wherein, the compositions that comprises guaifenesin of using effective dose comprises to be used said compositions as capsule.
24. method as claimed in claim 17, wherein, the compositions that comprises guaifenesin of using effective dose comprises said compositions as liquid application.
25. method as claimed in claim 17, wherein, the compositions that comprises guaifenesin of using effective dose comprises to be used said compositions as liquid gel.
26. method as claimed in claim 17, wherein, said mucous secretion produces in the upper respiratory tract of individuality.
27. method as claimed in claim 17, wherein, said compositions also comprises one or more activating agents.
28. method as claimed in claim 27, wherein, said one or more activating agents are selected from the group of being made up of anti-tussive agents, Decongestant and hydryllin.
29. method as claimed in claim 28, wherein, said anti-tussive agents comprises dextromethorphan hydrobromide.
30. method as claimed in claim 28, wherein, said Decongestant is selected from the group of being made up of phenylephrine hydrochloride, pseudoephedrine hydrochloride and ephedrine.
31. method as claimed in claim 28; Wherein, said hydryllin is selected from the group of being made up of chlorphenamine, brompheniramine maleate, phenindamine tartrate, Pyrilamine, doxylamine succinate, citric acid phenyltoloxamine, diphhydramine hydrochloride, promethazine, clemastine fumarate and fexofenadine.
32. method as claimed in claim 17, wherein, said compositions comprises release portion and lasting release portion immediately, so that the about 12 hours inhibition to said mucous secretion when being embodied as in treatment.
33. method as claimed in claim 17, wherein, dosage every day of said guaifenesin is 2400mg.
34. method as claimed in claim 17, wherein, said infectious conditions and the inflammatory disease that is characterised in that disease that mucin secretion increases or disease are selected from air flue.
35. the method for claim 1, wherein dosage every day of said guaifenesin is 2400mg.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US12/558,517 | 2009-09-12 | ||
| US12/558,517 US20110065744A1 (en) | 2009-09-12 | 2009-09-12 | Method Of Inhibiting Mucin Secretion |
| GBGB1002039.4A GB201002039D0 (en) | 2010-02-09 | 2010-02-09 | Method of inhibiting mucin secretion |
| GB1002039.4 | 2010-02-09 | ||
| PCT/GB2010/051525 WO2011030163A1 (en) | 2009-09-12 | 2010-09-13 | Use of guaifenesin for inhibiting mucin secretion |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102596189A true CN102596189A (en) | 2012-07-18 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN2010800492171A Pending CN102596189A (en) | 2009-09-12 | 2010-09-13 | Use of guaifenesin for inhibiting mucin secretion |
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| Country | Link |
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| EP (1) | EP2475360A1 (en) |
| JP (1) | JP2013504554A (en) |
| KR (1) | KR20120068889A (en) |
| CN (1) | CN102596189A (en) |
| AU (1) | AU2010294008B2 (en) |
| BR (1) | BR112012005517A2 (en) |
| CA (1) | CA2773611A1 (en) |
| MX (1) | MX2012003042A (en) |
| MY (1) | MY161187A (en) |
| RU (1) | RU2012114323A (en) |
| WO (1) | WO2011030163A1 (en) |
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| CA2869257A1 (en) * | 2012-04-06 | 2013-10-10 | The Uab Research Foundation | Methods for increasing cftr activity |
| KR102211605B1 (en) * | 2018-02-26 | 2021-02-04 | 대한민국 | Methods for Screening Therapeutic Agents for Airway Conduct MucinSecretion Inhibitor Using the Frog Embryo |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| ZA963590B (en) * | 1995-05-10 | 1996-11-19 | Adcock Ingram Ltd | Pharmaceutical composition |
| US6846799B1 (en) * | 1998-08-18 | 2005-01-25 | The Regents Of The University Of California | Preventing airway mucus production by administration of EGF-R antagonists |
| US7985420B2 (en) * | 2000-04-28 | 2011-07-26 | Reckitt Benckiser Inc. | Sustained release of guaifenesin combination drugs |
| WO2003065988A2 (en) * | 2002-02-04 | 2003-08-14 | Pharmacia Corporation | A combination for treating cold and cough |
| CA2530058A1 (en) * | 2003-06-19 | 2004-12-29 | Genaera Corporation | Mucin synthesis inhibitors |
| US20050095288A1 (en) * | 2003-11-03 | 2005-05-05 | Andrx Labs, Llc | Decongestant and expectorant tablets |
| US20050266032A1 (en) * | 2003-12-17 | 2005-12-01 | Sovereign Pharmaceuticals, Ltd. | Dosage form containing multiple drugs |
| US20080014261A1 (en) * | 2006-07-12 | 2008-01-17 | Giordano John A | Non-narcotic biphasic release compositions and methods for treatment of coughing, sneezing, rhinorrhea, and/or nasal obstruction |
| US20090202633A1 (en) * | 2008-01-03 | 2009-08-13 | Siva Ramakrishna Velaga | Extended release formulations of guaifenesin |
-
2010
- 2010-09-13 CA CA2773611A patent/CA2773611A1/en not_active Abandoned
- 2010-09-13 JP JP2012528455A patent/JP2013504554A/en active Pending
- 2010-09-13 MX MX2012003042A patent/MX2012003042A/en unknown
- 2010-09-13 CN CN2010800492171A patent/CN102596189A/en active Pending
- 2010-09-13 BR BR112012005517A patent/BR112012005517A2/en not_active Application Discontinuation
- 2010-09-13 KR KR1020127007996A patent/KR20120068889A/en not_active Application Discontinuation
- 2010-09-13 MY MYPI2012001112A patent/MY161187A/en unknown
- 2010-09-13 AU AU2010294008A patent/AU2010294008B2/en active Active
- 2010-09-13 EP EP10757117A patent/EP2475360A1/en not_active Ceased
- 2010-09-13 WO PCT/GB2010/051525 patent/WO2011030163A1/en active Application Filing
- 2010-09-13 RU RU2012114323/15A patent/RU2012114323A/en unknown
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2012
- 2012-03-13 ZA ZA2012/01822A patent/ZA201201822B/en unknown
Non-Patent Citations (1)
| Title |
|---|
| 徐怀诚: "愈创木酚甘油醚对HIV感染病人鼻和鼻窦炎的治疗作用", 《国际耳鼻咽喉头颈外科杂志》 * |
Also Published As
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|---|---|
| WO2011030163A1 (en) | 2011-03-17 |
| MY161187A (en) | 2017-04-14 |
| AU2010294008B2 (en) | 2014-08-14 |
| MX2012003042A (en) | 2012-05-29 |
| KR20120068889A (en) | 2012-06-27 |
| RU2012114323A (en) | 2013-10-20 |
| CA2773611A1 (en) | 2011-03-17 |
| ZA201201822B (en) | 2013-05-29 |
| BR112012005517A2 (en) | 2016-04-19 |
| JP2013504554A (en) | 2013-02-07 |
| AU2010294008A1 (en) | 2012-04-05 |
| EP2475360A1 (en) | 2012-07-18 |
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