CN104619346A - Stabilised amorphous form of agomelatine, a process for its preparation and pharmaceutical compositions containing it. - Google Patents
Stabilised amorphous form of agomelatine, a process for its preparation and pharmaceutical compositions containing it. Download PDFInfo
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Abstract
Stabilised amorphous form of the compound of formula (I): Medicaments.
Description
The present invention relates to the stable amorphous form of N-[2-(7-methoxy-1-naphthyl) ethyl] acetamide of agomelatine or formula (I):
Its preparation method and containing its pharmaceutical composition.
Agomelatine or N-[2-(7-methoxy-1-naphthyl) ethyl] acetamide have valuable pharmacological property.
In fact, it has double grading, and it is the agonist of melatonin energy system receptor on the one hand, and on the other hand, it is 5-HT
2Cthe antagonist of receptor.These character make it in central nervous system, have activity, have activity in the insomnia more especially caused in treatment Serious depression, seasonal affective disorder, sleep disorder, cardiovascular disease, digestive system disease, the time difference and tired out, dysorexia and obesity.
Agomelatine, its crystal form, its complex, its eutectic, the addition salts of itself and pharmaceutically acceptable acid or alkali, its preparation method and purposes in the treatment thereof have been described in following patent application: EP0447285, WO2005/077887, WO2007/015003, WO2007/015002, WO2007/015004, WO2010/097052, WO2010/102554, CN101955440, WO2011/050742, CN102050756, WO2011/006387, WO2011/075943, CN101774937, WO2011/006387, CN101870662 and CN102030673.
And agomelatine a kind ofly has extremely low bioavailability and therefore have the active component of the shortcoming of large interindividual variation.The dissolubility of this low bioavailability partly with agomelatine in water is relevant, and described dissolubility is for be less than 0.15mg/mL at 25 DEG C.
Consider that medical value and the bioavailability thereof of this compound are poor, amorphous form display is a kind of possible strategy, since it is known the amorphous form of solid chemical compound has the Dissolution behaviours better than its corresponding crystal form.
The applicant has been found that now: agomelatine has amorphous state, determines its glass transition temperature at-6 DEG C of places by scanning amount thermal analyses or DSC (" differential scanning calorimetry ").During higher than temperature, this active component carries out the transformation to crystal form.Therefore, it is impossible for keeping agomelatine to be amorphous state at ambient temperature.
Therefore, the technical problem proposed is the amorphous form making it possible to the agomelatine obtained in the formulation, and this is consistent with its application in pharmaceuticals industry, particularly with regard to stability with regard to storing under normal conditions.
Solution well known by persons skilled in the art comprises the dispersion of formation active component in solid matrix, and described solid matrix surrounds molecule and also prevents their from forming lattice.Active component is rarer in the substrate, and unbodied formation is more.Consequently: the size of the tablet containing amorphous active component rolls up due to substrate, this constitutes a major defect for their patient of must swallowing.Therefore, other challenge be to make the amount in order to the interests of active component substrate used minimum, still prevent formation lattice simultaneously.
Use agomelatine to test in cyclodextrin or trehalose (they are generally used for being formed the complex of " Host-guest " type), but never may obtain sought complex type in the mode that overtime is stable.
The applicant has been found that now: be possible can reappear the stabilization formulations obtaining the agomelatine of amorphous form with industrial feasible mode.This new stable form is allowed for pharmaceuticals industry.And it allows high active component content, create and taken the final preparation size conformed to completely by patient.
Therefore, the present invention relates to the stable amorphous form of agomelatine." stablize " and be interpreted as that the amorphous form of agomelatine is when standing to be kept when temperature and humidity degeneration condition of storage reaches at least one week.Temperature and humidity Denaturing of the present invention will be average, such as 40 DEG C/75%RH (relative humidity), 30 DEG C/65%RH, 50 DEG C, 70 DEG C etc.
More particularly, the present invention includes the solid dispersion of agomelatine in organic polymer, be appreciated that agomelatine accounts at least 30% of dispersion weight.The percentage by weight increasing agomelatine according to selected organic polymer is possible.Wherein the percentage by weight of agomelatine is the solid dispersion of 30% to 50%, more preferably 30% to 40% is preferred.Surprisingly, even if under the active component content that those are high, the amorphous form of agomelatine is also kept---in the mode that overtime is stable.And, except the improvement of the dissolution rate be usually contemplated to except adopting the amorphization of active component, the agomelatine dissolubility obtained also greatly increases, sufficiently exceed the dissolubility that crystallization agomelatine is measured, it is at least three times, in some cases for being multiplied by the factor 8.This result is completely beat all, because although a large amount of publication describes the biopharmaceutics performance (dissolubility, dissolution rate) being improved active component by the solid dispersion of design stability in this area, but this is (the people such as Lin being less than the active component of 20% for load, International Journal of Pharmaceutics, 1996
127, 261-272).
Surprisingly, the dissolubility increase of active component maintains at least 4 hours.
Polymer used in the present invention relates more specifically to methacrylic acid complex or vinyl or cellulosic polymer.
More particularly, the polymer used according to the present invention relates to polymethacrylates or methacrylic acid copolymer, and methacrylic acid copolymer is equivalent to the complete polymerized copolymers of methacrylic acid and acrylate or methacrylate.These polymethacrylates are commonly referred to
can be powder or particle form.In commercially available difference
in product, those preferably use in content of the present invention are
l product, more especially
l100 and L100-55 or
ePO.These polymer are particularly suitable for the agomelatine load (the % weight of agomelatine) of all scopes.
Polyvinyl of the present invention relates more specifically to polyvinyl ester, such as polyvinyl acetate phthalate; Based on homopolymer or the copolymer of polyvinylpyrrolidone, such as polyvidone (
k30,
s630), Kollidon VA64 or also have
polyvidone is less than the agomelatine of 50% weight by being used for load.
In the cellulosic cpd used according to the present invention, that can mention has cellulose ether or ester as HPMC, more especially HPMC acetyl group succinate.
The invention still further relates to the method for the stabilization formulations of the amorphous form for obtaining the agomelatine in polymer with high-load.According to method of the present invention, to be obtained by any means and with any crystal form, complex, eutectic or mix in one or more solvents with selected polymer with formula (I) compound that the addition salts of pharmaceutically acceptable acid or alkali exists, component is dissolved completely, then under reduced pressure steams completely and desolventize.
The solvent used according to the present invention to dissolve those of agomelatine and selected polymer; Preferred polar protic or aprotic solvent, such as acetone, alcohol and the mixture of more particularly methanol and ethanol, water, dichloromethane, ethyl acetate or those solvents.Dissolving stir at ambient temperature or by heating blends until component is dissolved completely carries out.The steaming of solvent is except at ambient temperature under reduced pressure or by heating until solvent evaporation is carried out completely.
The Favourable implementations being prepared in polymer the method for the stabilization formulations of the amorphous form of the agomelatine with high-load comprise will be obtained by any means and using any crystal form, complex, eutectic or formula (I) compound existed with the addition salts of pharmaceutically acceptable acid or alkali and selected polymer mixed or admix in advance, then this mixture is incorporated into extruder that its spiral shell square and temperature select as the function of mixture viscosity in obtain extrudate, then extrudate is cut into the size of expection, then optionally grinds.
Preferably, the rotation of screw rod will be carried out between 50 to 200rpm, be more in particular between 75 to 150rpm and carry out.
Selected extrusion temperature will be the function of viscosity of obtained component mixture, and comprise 90 DEG C of end value to 200 DEG C by being.
In the method for stable amorphous form obtaining agomelatine of the present invention, can use and to be obtained by any means and with any crystal form, complex, eutectic or formula (I) compound that exists with the addition salts of pharmaceutically acceptable acid or alkali.
In the method for the invention, the load of agomelatine is more than or equal to 30% weight, more particularly in 30 to 50% weight, preferably changes between 30% to 40%.
The stable amorphous form obtained thus has value in treatment melatonin energy systemic disease, and demonstrate central nervous system and microcirculatory important activity, make it possible to establish it and treating the serviceability in following disease: stress, sleep disorder, anxiety, Serious depression, seasonal affective disorder, bipolar disorder, generalized anxiety disorder, cardiovascular disease, digestive system disease, the insomnia caused due to the time difference and fatigue, schizophrenia, panic attack, melancholia, appetite disorder, obesity, insomnia, pain, mental disorder, epilepsy, diabetes, parkinson disease, senile dementia, with normal or that pathological seaility is relevant various disorders, migraine, the loss of memory, Alzheimer and in addition cerebral circulation diseases.Show in another active field: the amorphous form of agomelatine can be used for sexual dysfunction in the treatment, it has ovulation and suppresses and immuno-modulating properties, and it may be used for Therapeutic cancer potentially.
The stable amorphous form of agomelatine will be preferred for treating Serious depression, seasonal affective disorder, bipolar disorder, generalized anxiety disorder, sleep disorder, cardiovascular disease, digestive system disease, the insomnia caused due to the time difference and fatigue, appetite disorder and obesity.
The stable amorphous form obtaining agomelatine has pharmaceutical preparation preparation being had unanimously and can reappear composition becomes possible advantage, and it has the excellent stability of overtime.
Therefore, according to the present invention, it is possible for obtaining the solid composite medicament with the amorphous form of the agomelatine of high-load, and it is especially used by mouth, cheek, Sublingual, eye, rectum, vagina or parenteral routes.
These pharmaceutical compositions can be made up of the solid dispersion of agomelatine in polymer, and other process operation any not except packaging.But if desired, described pharmaceutical composition can by grinding or being undertaken processing for being filled in capsule or for suppressing or can carrying out coating by granulation.
Pharmaceutical composition of the present invention optionally can also comprise pharmacologically acceptable excipient, and described excipients is as being selected from binding agent, disintegrate material, disintegrating agent, lubricant, diluent, antioxidant, aromatic, coloring agent, antiseptic, sweeting agent and antitack agent.
In pharmaceutical composition of the present invention, particularly can mention tablet or sugar-coat agent, granule, sublingual tablet, capsule, lozenge, suppository, ointment, ointment, skin gel agent, injectable formulation, drinkable suspensoid and Chewing gum.
Preferably, pharmaceutical composition of the present invention contains the agomelatine of at least 25% weight for total formulation weight amount.
Useful dosage can according to the character of disease and seriousness, use by way of and age of patient and body weight and change.Dosage be every day 0.1mg to 1g agomelatine not etc., one or many is used.
Accompanying drawing is sketched
Fig. 1: plurality of stable condition (under 40 DEG C/75%RH 1 week, under 40 DEG C/75%RH 1 week, then at 50 DEG C 1 week, at 70 DEG C 1 week) under the x-ray diffraction pattern of embodiment 10 of record.
Fig. 2: plurality of stable condition (under 40 DEG C/75%RH 1 week, under 40 DEG C/75%RH 1 week, then at 50 DEG C 1 week, at 70 DEG C 1 week) under the x-ray diffraction pattern of embodiment 11 of record.
Fig. 3: plurality of stable condition (under 40 DEG C/75%RH 1 week, under 40 DEG C/75%RH 1 week, then at 50 DEG C 1 week, at 70 DEG C 1 week) under the x-ray diffraction pattern of embodiment 12 of record.
Fig. 4: plurality of stable condition (under 40 DEG C/75%RH 1 week, under 40 DEG C/75%RH 1 week, then at 50 DEG C 1 week, at 70 DEG C 1 week) under the x-ray diffraction pattern of embodiment 19 of record.
Fig. 5: plurality of stable condition (under 40 DEG C/75%RH 1 week, under 40 DEG C/75%RH 1 week, then at 50 DEG C 1 week, at 70 DEG C 1 week) under the x-ray diffraction pattern of embodiment 28 of record.
Fig. 6: embodiment 39 under plurality of stable condition (in uncovered or flask of remaining silent 25 DEG C/60%RH, 30 DEG C/65%RH in uncovered or flask of remaining silent, in uncovered flask 50 DEG C) 3 the end of month record x-ray diffraction pattern.
Fig. 7: embodiment 40 under plurality of stable condition (in uncovered or flask of remaining silent 25 DEG C/60%RH, 30 DEG C/65%RH in uncovered or flask of remaining silent, in uncovered flask 50 DEG C) 3 the end of month record x-ray diffraction pattern.
Following embodiment explains clear the present invention, but does not limit the present invention in any way.
A. by dissolving-evaporating the universal method of the stable amorphous form obtaining agomelatine
Agomelatine and selected polymer are placed in the 10-ml bottle containing 3ml solvent.This mixture is stirred 30 minutes until dissolve completely in 40 DEG C, obtains uniform solution.Under reduced pressure desolventize 30 minutes in 40 DEG C of steamings.Finally, by gained residue dried overnight (12 hours) in a vacuum under ambient temperature (20 DEG C), the stable amorphous form of agomelatine is obtained.For each test, under the Denaturing under 40 DEG C and 75%RH, under 40 DEG C and 75%RH, afterwards at 50 DEG C and at 70 DEG C, test the stability of this amorphous form.
The result that following table lists prepared each embodiment and obtains:
Such as, Fig. 1, Fig. 2, Fig. 3, Fig. 4 and Fig. 5 sets forth plurality of stable condition (under 40 DEG C/75%RH 1 week, under 40 DEG C/75%RH 1 week, then at 50 DEG C 1 week, at 70 DEG C 1 week) under the x-ray diffraction pattern of embodiment 10,11,12,19 and 28 of record.
B. by extruding the universal method of the stable amorphous form obtaining agomelatine
Agomelatine and polymer are admixed 10 minutes in advance in Turbula type agitator.Gained mixture is manually positioned in the conical rotor extruder (diameter 5/14mm) of HAAKE Minilab II Microcompounder type (ThermoFisher).Extruded velocity is 100rpm.
At various temperature and relative humidities, have rated the stability of gained amorphous form: in uncovered or flask of remaining silent 25 DEG C/60%RH, in uncovered or flask of remaining silent 30 DEG C/65%RH, in uncovered flask 50 DEG C.
All embodiments that following table provides all have the stability of being longer than at least 6 week.
Such as, Fig. 6 and Fig. 7 list respectively plurality of stable condition (in uncovered or flask of remaining silent 25 DEG C/60%RH, in uncovered or flask of remaining silent 30 DEG C/65%RH, in uncovered flask 50 DEG C) under 3 the end of month record the x-ray diffraction pattern of embodiment 39 and 40.
C. dissolubility
At 25 DEG C, adopt
type device goes through the stability study that 4 hours have carried out gained preparation in pH6.8 buffer solution, and mixing speed is 700rpm.Test various concentration, monitor the existence of insoluble granule by Turbidity measurement.As a reference, agomelatine dissolubility is under those circumstances 0.14mg/mL.
Following table lists acquired results, and it lists: i) viewed maxima solubility and observe time of this maxima solubility, ii) dissolubility observed at 4 hours.
| Embodiment | The maxima solubility (mg/mL) observed at t minute | At the dissolubility of 4 hours (mg/mL) |
| 14 | At 5 minutes, > 0.9 | >0.59 |
| 20 | At 6 minutes, > 0.9 | >0.42 |
| 31 | At 5 minutes, > 1.5 | >1.20 |
| 32 | At 45 minutes, > 1.2 | >0.46 |
| 33 | At 10 minutes, > 1.1 | >0.52 |
| 34 | At 5 minutes, > 0.67 | >0.24 |
| 35 | At 5 minutes, > 0.9 | >0.40 |
| 36 | At 10 minutes, > 0.76 | >0.33 |
| 37 | At 5 minutes, > 0.79 | >0.32 |
| 38 | At 5 minutes, > 0.34 | >0.34 |
| 39 | At 5 minutes, > 0.64 | >0.43 |
| 40 | At 5 minutes, > 0.53 | >0.29 |
| 41 | At 5 minutes, > 0.73 | >0.37 |
Acquired results display maxima solubility significantly increases.Emphasis is that this dissolubility passes in time was continue to increase: at 4 hours, and result shows its factor for being at least multiplied by 1.7 to 8.5, and this makes active component be absorbed if having time before precipitation again.
D. pharmaceutical composition
embodiment 42
Prepare the formula of 1000 capsules, every capsules contains 25mg agomelatine:
Agomelatine ... 25g
Eudragit L 100-55……………………………………………………..25g
Prepare extrudate according to embodiment 36, be then cut into small substrate, introduced in No. 1 capsule.
embodiment 43
Prepare the formula of 1000 capsules, every capsules contains 25mg agomelatine:
Agomelatine ... 25g
Plasdone S630…..……………………………………………………..58g
Prepare extrudate according to embodiment 38, be then cut into small substrate, introduced in No. 1 capsule.
embodiment 44
The formula of preparation 1000 tablets of tablets, every sheet contains 25mg agomelatine:
Extrudate embodiment 36 ... 50g
Corn starch ... .10g
Lactose ... ..20g
Magnesium stearate ... ..0.5g
Silicon dioxide ... .0.25g
Hydroxypropyl cellulose ... ..2.25g
Claims (26)
1. the stable amorphous form of the agomelatine of formula (I):
2. the stable amorphous form of agomelatine according to claim 1, is characterized in that agomelatine is dispersed in Medium Culture.
3. the stable amorphous form of agomelatine according to claim 2, is characterized in that substrate used is organic polymer.
4., according to the stable amorphous form of the agomelatine of Claims 2 or 3, it is characterized in that substrate used is methacrylic acid complex or vinyl or cellulosic polymer.
5. the stable amorphous form of agomelatine according to claim 4, is characterized in that substrate used is Eudragit L100.
6. the stable amorphous form of agomelatine according to claim 4, is characterized in that substrate used is Eudragit L100-55.
7., according to the stable amorphous form of the agomelatine of Claims 2 or 3, it is characterized in that substrate used is polyvinyl.
8. the stable amorphous form of agomelatine according to claim 7, is characterized in that substrate used is Kollidon VA64 or Soluplus.
9. the stable amorphous form of agomelatine according to claim 7, is characterized in that substrate used is polyvinyl acetate phthalate.
10. the stable amorphous form of agomelatine according to claim 7, is characterized in that substrate used is Plasdone S630.
11., according to the stable amorphous form of the agomelatine of Claims 2 or 3, is characterized in that substrate used is cellulosic polymer.
The stable amorphous form of 12. agomelatines according to claim 11, is characterized in that substrate used is HPMC acetyl group succinate.
13., according to the stable amorphous form of the agomelatine of claim 2-12, is characterized in that the percentage by weight of agomelatine used is for being more than or equal to 30%.
14., according to the stable amorphous form of the agomelatine of claim 2-12, is characterized in that the percentage by weight of agomelatine used is 30% to 50%.
15., according to the stable amorphous form of the agomelatine of claim 2-12, is characterized in that the percentage by weight of agomelatine used is 30% to 40%.
16. for obtaining the method for the stable amorphous form of the agomelatine of any one of claim 1-15, it is characterized in that to be obtained by any means and with any crystal form, complex, eutectic or mix in one or more solvents with selected polymer with formula (I) compound that the addition salts of pharmaceutically acceptable acid or alkali exists, component is dissolved completely, then under reduced pressure steams completely and desolventize.
17. for obtaining the method for the stable amorphous form of the agomelatine of any one of claim 1-15, it is characterized in that to be obtained by any means and using any crystal form, complex, eutectic or formula (I) compound existed with the addition salts of pharmaceutically acceptable acid or alkali and selected polymer mixed and admix in advance, be then incorporated into extruder that its spiral shell square and temperature select as the function of mixture viscosity in obtain extrudate, then extrudate is cut into the size of expection, then optionally grinds.
18., according to the method for the stable amorphous form for obtaining agomelatine of claim 16 or 17, is characterized in that the percentage by weight of agomelatine is for being more than or equal to 30%.
19., according to the method for the stable amorphous form for obtaining agomelatine of claim 16 or 17, is characterized in that the percentage by weight of agomelatine is 30% to 50%.
20., according to the method for the stable amorphous form for obtaining agomelatine of claim 16 or 17, is characterized in that the percentage by weight of agomelatine is 30% to 40%.
21. pharmaceutical compositions, comprise the agomelatine of one of the claim 1-15 as active component stable amorphous form self or with its one or more inert non-toxic and the combination of pharmaceutically useful carrier.
22. pharmaceutical compositions according to claim 21, is characterized in that the percentage by weight of agomelatine for total formulation weight amount for being more than or equal to 25%.
23. according to the pharmaceutical composition of claim 21 or 22, for the preparation of the medicine for the treatment of melatonin energy systemic disease.
24. according to the pharmaceutical composition of claim 21 or 22, for the preparation for the treatment of sleep disorder, stress, anxiety, seasonal affective disorder or Serious depression, cardiovascular disease, digestive system disease, the insomnia caused due to the time difference and fatigue, schizophrenia, panic attack, melancholia, appetite disorder, obesity, insomnia, pain, mental disorder, epilepsy, diabetes, parkinson disease, senile dementia, with normal or that pathological seaility is relevant various disorders, migraine, the loss of memory, Alzheimer, cerebral circulation diseases and sexual dysfunction and the medicine as antiovulatory and immunomodulator and Therapeutic cancer.
25., according to the stable amorphous form of the agomelatine of one of claim 1-15, are used for the treatment of melatonin energy systemic disease.
26. according to the stable amorphous form of the agomelatine of one of claim 1-15, be used for the treatment of sleep disorder, stress, anxiety, seasonal affective disorder or Serious depression, cardiovascular disease, digestive system disease, the insomnia caused due to the time difference and fatigue, schizophrenia, panic attack, melancholia, appetite disorder, obesity, insomnia, pain, mental disorder, epilepsy, diabetes, parkinson disease, senile dementia, with normal or that pathological seaility is relevant various disorders, migraine, the loss of memory, Alzheimer, cerebral circulation diseases and sexual dysfunction and as antiovulatory and immunomodulator and Therapeutic cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910934869.6A CN110639021A (en) | 2012-09-11 | 2013-09-11 | Stable amorphous form of agomelatine, process for its preparation and pharmaceutical compositions containing it |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNPCT/CN2012/081250 | 2012-09-11 | ||
| FR1259064A FR2995896B1 (en) | 2012-09-26 | 2012-09-26 | STABILIZED AMORPHOUS FORM OF AGOMELATIN, PREPARATION METHOD THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME. |
| FR12/59064 | 2012-09-26 | ||
| PCT/EP2013/068792 WO2014041015A1 (en) | 2012-09-11 | 2013-09-11 | Stabilised amorphous form of agomelatine, a process for its preparation and pharmaceutical compositions containing it. |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201910934869.6A Division CN110639021A (en) | 2012-09-11 | 2013-09-11 | Stable amorphous form of agomelatine, process for its preparation and pharmaceutical compositions containing it |
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| CN104619346A true CN104619346A (en) | 2015-05-13 |
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| CN201380046980.2A Pending CN104619346A (en) | 2012-09-11 | 2013-09-11 | Stabilised amorphous form of agomelatine, a process for its preparation and pharmaceutical compositions containing it. |
| CN201910934869.6A Pending CN110639021A (en) | 2012-09-11 | 2013-09-11 | Stable amorphous form of agomelatine, process for its preparation and pharmaceutical compositions containing it |
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| CN201910934869.6A Pending CN110639021A (en) | 2012-09-11 | 2013-09-11 | Stable amorphous form of agomelatine, process for its preparation and pharmaceutical compositions containing it |
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| FR (1) | FR2995896B1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107556209A (en) * | 2016-06-30 | 2018-01-09 | 陕西合成药业股份有限公司 | A kind of new melatonin class compound and preparation method thereof and application medically |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008137461A1 (en) * | 2007-05-01 | 2008-11-13 | Concert Pharmaceuticals Inc. | Naphthyl(ethyl) acetamides |
| CN101836966A (en) * | 2010-05-27 | 2010-09-22 | 北京万全阳光医药科技有限公司 | Agomelatine-containing orally disintegrating tablet |
| WO2012093402A1 (en) * | 2011-01-04 | 2012-07-12 | Symed Labs Limited | Processes for the preparation of n-[2-(7-methoxy-1-naphthyl)ethyl]acetamide |
| CN102716493A (en) * | 2011-03-31 | 2012-10-10 | 天津药物研究院 | Copolymer containing amorphous agomelatine, and preparation method, pharmaceutical composition and application thereof |
-
2012
- 2012-09-26 FR FR1259064A patent/FR2995896B1/en not_active Expired - Fee Related
-
2013
- 2013-09-11 CN CN201380046980.2A patent/CN104619346A/en active Pending
- 2013-09-11 CN CN201910934869.6A patent/CN110639021A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008137461A1 (en) * | 2007-05-01 | 2008-11-13 | Concert Pharmaceuticals Inc. | Naphthyl(ethyl) acetamides |
| CN101836966A (en) * | 2010-05-27 | 2010-09-22 | 北京万全阳光医药科技有限公司 | Agomelatine-containing orally disintegrating tablet |
| WO2012093402A1 (en) * | 2011-01-04 | 2012-07-12 | Symed Labs Limited | Processes for the preparation of n-[2-(7-methoxy-1-naphthyl)ethyl]acetamide |
| CN102716493A (en) * | 2011-03-31 | 2012-10-10 | 天津药物研究院 | Copolymer containing amorphous agomelatine, and preparation method, pharmaceutical composition and application thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107556209A (en) * | 2016-06-30 | 2018-01-09 | 陕西合成药业股份有限公司 | A kind of new melatonin class compound and preparation method thereof and application medically |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2995896A1 (en) | 2014-03-28 |
| CN110639021A (en) | 2020-01-03 |
| FR2995896B1 (en) | 2014-11-21 |
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