CN102206864B - Agomelatine monocrystal with agomelatine VI crystal form, agomelatine mixed crystal with the agomelatine VI crystal form and preparation methods - Google Patents
Agomelatine monocrystal with agomelatine VI crystal form, agomelatine mixed crystal with the agomelatine VI crystal form and preparation methods Download PDFInfo
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Abstract
The invention discloses an agomelatine monocrystal with an agomelatine VI crystal form and a preparation method thereof, wherein the agomelatine VI crystal form is a novel crystal form of agomelatine. The invention also provides an agomelatine mixed crystal with the agomelatine VI crystal form and a preparation method thereof. The agomelatine mixed crystal has good effects of treating depression and anxiety. The invention further provided an application of the agomelatine mixed crystal with the agomelatine VI crystal form and an agomelatine II crystal form for preparations of medicines for treating cancers. The beneficial effects of the invention comprise providing an agomelatine monocrystal with agomelatine VI crystal form, an agomelatine mixed crystal with the agomelatine VI crystal form and an agomelatine II crystal form, and their preparation methods, wherein the agomelatine mixed crystal is superior to the agomelatine monocrystal in terms of dissolution rate and bioavailability. In addition, the agomelatine mixed crystal has a long-time stability and is suitable for storage without especial equipment, thus the agomelatine mixed crystal has an important superiority in a pharmacy industry.
Description
Technical field
The present invention relates to the crystal formation preparation of agomelatine; The mono-crystalline structures of agomelatine VI crystal formation especially is provided; The mix crystal formation of agomelatine VI crystal formation with agomelatine II crystal formation also disclosed simultaneously; And their method for preparing and the content assaying method of mixed crystal are provided, have belonged to the chemicals preparing technical field.
Background technology
Agomelatine that the present invention relates to (agomelatine) or N-[2-(7-methoxyl group-1-naphthyl) ethyl] acetamide; Has good pharmacological property; Execute new class antidepressants and the antianxiety drugs that only refined (Servier) company develops by France, its structure is as follows:
Discover that agomelatine has dual characteristic, it is the agonist of melatonin ability system receptor, is again 5-HT
2cThe antagonist of receptor.Just because of this double grading; Make it in the central nervous system, have good activity; Of particular concern is it at serious symptom depression, seasonal affective disorder, sleep disorder, cardiovascular disease, digestive system disease, the activity in the insomnia that jet lag causes and fatigue, dysorexia and the bariatrician.
European patent EP 0447285 discloses the Preparation method and use of agomelatine.
In view of the medical value of this chemical compound, the form that obtains splendid purity and favorable reproducibility is very important, and this form all demonstrates valuable characteristic at aspects such as stripping and preparations, and temperature, humidity or oxygen etc. are not had specific (special) requirements.
Of equal importance is to obtain having well-defined crystal formation, the agomelatine that reproducibility is good, filtration and easy formation aspect have valuable characteristic.
As everyone knows, most compounds can two or more crystalline states exist, and this is the instinct of material.The molecule that structure is identical crystallizes into different solid forms, is called the polymorphism material.Crystals with different has different lattice energies, and it shows the physical property of the good and favorable reproducibility of purity when solid-state thus.
At present, agomelatine II crystal formation has had bibliographical information, but the mixed crystal of the monocrystalline of agomelatine VI crystal formation and agomelatine II crystal formation and VI crystal formation is not also seen bibliographical information.
Summary of the invention
The present invention provides a kind of agomelatine VI crystal formation monocrystalline and method for preparing, is the new crystal formation of a kind of agomelatine.
What the present invention also provided agomelatine VI crystal formation and agomelatine VI crystal formation mixes crystal formation and method for preparing, has the depressed and anti-burnt disease of treatment and well acts on.
The present invention further provides the purposes of mix-crystal in preparation treatment cancer drug of agomelatine VI crystal formation and agomelatine II crystal formation.
, the present invention provides a kind of agomelatine VI crystal formation monocrystalline,Structure chart is as follows:
It is characterized in that characterizing as follows:
-orthorhombic lattice;
-lattice parameter: a=31.4306, b=9.4936, c=17.7282, α=β=γ=90.000 °;
-space group: Pca2 (1);
Molecular number in the-elementary cell: 16;
-elementary cell volume: V
Elementary cell=5289.91
3
-density: d=1.222g/cm
3
,The method for preparing of the VI crystal formation monocrystalline of agomelatine of the present invention is characterized in that:
The agomelatine powder dissolution of 0.02mmol in the 0.07mol diisopropyl ether, is positioned in the bottle, and bottleneck is with sealing film phonograph seal; An aperture is opened in the centre; Room temperature is placed, the crystal of several needle point sizes of 2 weeks back bottle end appearance, and this crystal is the VI crystal formation monocrystalline of agomelatine.
,The II crystal formation of agomelatine of the present invention and the mixed crystal type of VI crystal formation is characterized in that percentage by weight is:
The II crystal formation 93%-99% of agomelatine, the VI crystal formation 7%-1% of agomelatine.
,The mixed crystal type of above-mentioned II crystal formation and VI crystal formation, preferred weight percent is:
The VI crystalline form of 5 % of the II crystal formation 95% of agomelatine, agomelatine.
Be characterized by:
1) infrared spectrum characterization: 3249cm
-1, 3068 cm
-1, 1640 cm
-1, 1624 cm
-1, 1509 cm
-1, 1432 cm
-1, 1252 cm
-1, 1212 cm
-1, 1028 cm
-1, 827 cm
-1, 834 cm
-1, 759 cm
-1, 700 cm
-1, 609 cm
-1
2) the X-ray powder diffraction characterizes (2 θ value): 9.355,17.288,18.673,19.868,22.210,24.312,25.506.
3) fusing point: 99.83,110.83.
,The method for preparing of the mixed crystal type of agomelatine II crystal formation according to the invention and VI crystal formation:
The II crystal formation of 93%-99% agomelatine is mixed with the VI crystal formation of 7%-1% agomelatine, and 20～80 ℃ of rotation 1h that reduce pressure down make its uniform mixing.
The advantage that obtains mixed crystal is that it allows preparation to have the pharmaceutical preparation of consistent and reproducible compositions, and it has fabulous stability as time goes by.
Below test shows pharmacotoxicological effect of the present invention
Test Example 1
Pharmacokinetics is measured
Human volunteer is carried out random packet; Per 5 volunteers take the tablet of case 6-8, every volunteer are carried out agomelatine in 0,2,4,6,8,10,12,14,16,18,20,22,24 hour and detect taking the back, write down the maximum plasma concentration (Cmax of this active component; Ng/ml); And blood drug level (AUC, ng.h/ml), Cmax and AUC value of each group see the following form to the TG-AUC of time.
Above result shows that the technical scheme of claim 3 of the present invention or 4 has and the corresponding to bioequivalence of disclosed case study on implementation; And when the ratio of mixed crystal is the II crystal formation 95% of an agomelatine best results during with VI crystalline form of 5 %; Satisfied the requirement of preparation process; Solved the dissolution problem of agomelatine different crystal forms simultaneously, produced a desired effect.
Test Example 2
Biological activity test
Adopt HL-60 human leukemia cell line and the strain of Hela human cervical carcinoma cell, go down to posterity, in the animal cell culture case, cultivate with the RPMI-1640 culture medium (every milliliter contains 100 microgram streptomycins and 100 microgram penicillins respectively) of 10% hyclone.
A. JEG-3: HL-60 human leukemia
Method of testing: tetramethyl azo azoles salt (MTT) method
Test drug: embodiment 3 mixed crystal
Drug level: 2.5 μ g, 5 μ g
Result: cell proliferation inhibition rate 72%, 82%.
B. JEG-3: Hela human cervical carcinoma
Method of testing: srb assay
Test drug: embodiment 3 mixed crystal
Drug level: 2.5 μ g, 5 μ g
Result: cell proliferation inhibition rate 62%, 78%.
The result shows that this mixed crystal has inhibitory action to the growth of cancerous cell, and its raw material is easy to get, and technology is simple, and is safe, can prepare the medicine of treating cancer.
Mixed crystal form to acquisition like this; Pharmaceutical research has shown that it has significant activity in the central nervous system microcirculqtory system of unifying, thus the mixed crystal that can affirm agomelatine can be used for treating blind and fatigue that anxiety, sleep disorder, anxiety neurosis, severe depression, seasonal affective disorder, cardiovascular disease, digestive system disease, the time difference cause, schizophrenia, phobia, melancholia, appetite disorder, obesity, blind disease, mental disorder, epilepsy, diabetes, parkinsonism, senile dementia, with normally or pathologic relevant various diseases, migraine, amnesia, Alzheimer, the brain circulatory diseases that wear out.
The mixed crystal of agomelatine is preferred for treating insomnia and fatigue, appetite disorder and obesity that severe depression, seasonal affective disorder, sleep disorder, cardiovascular disease, the time difference cause.
The invention still further relates to pharmaceutical composition, 95% the II crystal formation and 5% the VI crystal formation that comprise agomelatine also comprise two or more inertia, the excipient of safety simultaneously as active component.In pharmaceutical composition of the present invention, use be more suitable oral, without digestive tract injection or tablet or coated tablet, granule, Sublingual tablet, capsule, suppository, Emulsion, ointment through intranasal administration, be coated with skin glue, ejection preparation, oral liquid.
Mixed crystal type with agomelatine II crystal formation provided by the present invention and VI crystal formation is used for pharmaceutical compositions, is made up of following composition and percentage by weight:
20% agomelatine II crystal formation, 1.05% agomelatine VI crystal formation, 51.95% lactose, 20% starch slurry, 6% cross-linked carboxymethyl cellulose sodium, 1% magnesium stearate.
Good effect of the present invention is: the mixed crystal and the method for preparing of monocrystalline, agomelatine II crystal formation and the VI crystal formation of agomelatine VI crystal formation are provided, and said mixed crystal is demonstrating aspect stripping and the bioavailability than the better characteristic of single crystal form.In addition, this mixed crystal has the stability of highly significant as time goes by, allows its optimum storage and need not special equipment, and this occupies important advantage in pharmaceuticals industry.
Description of drawings:
Fig. 1 is agomelatine II crystal formation 95% and VI crystalline form of 5 % mixed crystal X-ray powder diffraction;
Fig. 2 is agomelatine II crystal formation 95% and VI crystalline form of 5 % mixed crystal infrared spectrum;
Fig. 3 is agomelatine II crystal formation 95% and VI crystalline form of 5 % mixed crystal DSC collection of illustrative plates;
Fig. 4 is an agomelatine mixed crystal content standard curve chart;
Fig. 5 is that agomelatine mixed crystal peak area ratio (A6/2) is to the percentage by weight curve chart.
The practical implementation case
Following examples are only with helping understand the present invention, and are not to be used for also should not being interpreted as the restriction of by any way listed claim being invented.
Embodiment 1:
The mixed crystal of II crystal formation of agomelatine (the crystal formation percentage by weight is 99%) and VI crystal formation (the crystal formation percentage by weight is 1%):
Take by weighing the II crystal formation of 0.1g agomelatine VI crystal formation and 9.9g agomelatine, its mixing is placed in the round-bottomed bottle of 100ml, 20～80 ℃ of rotation 1h that reduce pressure down make its uniform mixing.
The X-ray powder diffraction characterizes (2 θ value): 9.323,17.268,18.671,19.868,22.211,24.314,25.506.
Infrared spectrum: 3246cm
-1, 30628 cm
-1, 1638 cm
-1, 1623 cm
-1, 1509 cm
-1, 1432 cm
-1, 1252 cm
-1, 1211 cm
-1, 1024 cm
-1, 827 cm
-1, 833 cm
-1, 755 cm
-1, 700 cm
-1, 605 cm
-1
Fusing point: 99.81 ℃, 110.69 ℃.
Embodiment 2:
The mixed crystal of II crystal formation of agomelatine (the crystal formation percentage by weight is 97%) and VI crystal formation (the crystal formation percentage by weight is 3%):
Take by weighing the II crystal formation of 0.3g agomelatine VI crystal formation and 9.7g agomelatine, its mixing is placed in the round-bottomed bottle of 100ml, 20～80 ℃ of rotation 1h that reduce pressure down make its uniform mixing.
The X-ray powder diffraction characterizes (2 θ value): 9.353,17.268,18.683,19.863,22.110,24.310,25.505.
Infrared spectrum: 3247cm
-1, 3063 cm
-1, 1640 cm
-1, 1624 cm
-1, 1509 cm
-1, 1432 cm
-1, 1252 cm
-1, 1212 cm
-1, 1022 cm
-1, 827 cm
-1, 835 cm
-1, 759 cm
-1, 700 cm
-1, 608 cm
-1
Fusing point: 99.73 ℃, 110.03 ℃.
Embodiment 3:
The mixed crystal of II crystal formation of agomelatine (the crystal formation percentage by weight is 95%) and VI crystal formation (the crystal formation percentage by weight is 5%):
Take by weighing the II crystal formation of 0.5g agomelatine VI crystal formation and 9.5g agomelatine, its mixing is placed in the round-bottomed bottle of 100ml, 20～80 ℃ of rotation 1h that reduce pressure down make its uniform mixing.
The X-ray powder diffraction characterizes (2 θ value): 9.355,17.288,18.673,19.868,22.210,24.312,25.506.(see figure 1)
Infrared spectrum: 3249cm
-1, 3068 cm
-1, 1640 cm
-1, 1624 cm
-1, 1509 cm
-1, 1432 cm
-1, 1252 cm
-1, 1212 cm
-1, 1028 cm
-1, 827 cm
-1, 834 cm
-1, 759 cm
-1, 700 cm
-1, 609 cm
-1(see figure 2)
Fusing point: 99.83 ℃, 110.83 ℃.(see figure 3)
Embodiment 4:
The mixed crystal of II crystal formation of agomelatine (the crystal formation percentage by weight is 93%) and VI crystal formation (the crystal formation percentage by weight is 7%):
Take by weighing the II crystal formation of 0.7g agomelatine VI crystal formation and 9.3g agomelatine, its mixing is placed in the round-bottomed bottle of 100ml, 20～80 ℃ of rotation 1h that reduce pressure down make its uniform mixing.
The X-ray powder diffraction characterizes (2 θ value): 9.345,17.298,18.672,19.768,22.211,24.3132,25.516.
Infrared spectrum: 3239cm
-1, 3068 cm
-1, 1641 cm
-1, 1642 cm
-1, 1509 cm
-1, 1432 cm
-1, 1252 cm
-1, 1212 cm
-1, 1028 cm
-1, 827 cm
-1, 834 cm
-1, 759 cm
-1, 710 cm
-1, 608 cm
-1
Fusing point: 99.77 ℃, 110.53 ℃.
Embodiment 5:
Pharmaceutical composition: with 21.05g agomelatine II crystal formation and 51.95g lactose, 20g starch slurry, 3g cross-linked carboxymethyl cellulose sodium mix homogeneously that progressively increases, the system soft material is granulated; Drying, granulate adds 3g cross-linked carboxymethyl cellulose sodium and 1g magnesium stearate; Tabletting gets 842, the 25mg/ sheet.
Embodiment 6:
Pharmaceutical composition: with 21.05g agomelatine VI crystal formation and 51.95g lactose, 20g starch slurry, 3g cross-linked carboxymethyl cellulose sodium mix homogeneously that progressively increases, the system soft material is granulated; Drying, granulate adds 3g cross-linked carboxymethyl cellulose sodium and 1g magnesium stearate; Tabletting gets 842, the 25mg/ sheet.
Embodiment 7:
Pharmaceutical composition: with 10g embodiment 1 gained mixed crystal and 24.68g lactose, 9.5g starch slurry, 1.42g cross-linked carboxymethyl cellulose sodium mix homogeneously that progressively increases, the system soft material is granulated; Drying, granulate adds 1.43g cross-linked carboxymethyl cellulose sodium and 0.48g magnesium stearate; Tabletting gets 400, the 25mg/ sheet.
Embodiment 8:
Pharmaceutical composition: with 10g embodiment 2 gained mixed crystal and 24.68g lactose, 9.5g starch slurry, 1.42g cross-linked carboxymethyl cellulose sodium mix homogeneously that progressively increases, the system soft material is granulated; Drying, granulate adds 1.43g cross-linked carboxymethyl cellulose sodium and 0.48g magnesium stearate; Tabletting gets 400, the 25mg/ sheet.
Embodiment 9:
Pharmaceutical composition: with 10g embodiment 3 gained mixed crystal and 24.68g lactose, 9.5g starch slurry, 1.42g cross-linked carboxymethyl cellulose sodium mix homogeneously that progressively increases, the system soft material is granulated; Drying, granulate adds 1.43g cross-linked carboxymethyl cellulose sodium and 0.48g magnesium stearate; Tabletting gets 400, the 25mg/ sheet.
Embodiment 10:
Pharmaceutical composition: with 10g embodiment 4 gained mixed crystal and 24.68g lactose, 9.5g starch slurry, 1.42g cross-linked carboxymethyl cellulose sodium mix homogeneously that progressively increases, the system soft material is granulated; Drying, granulate adds 1.43g cross-linked carboxymethyl cellulose sodium and 0.48g magnesium stearate; Tabletting gets 400, the 25mg/ sheet.
Embodiment 11:
The case study on implementation of being announced with patent CA2558782 is embodiment as a comparison
With 19.23g agomelatine II crystal formation and 47.62g lactose, the 23.04g cellulose hydroxyl ethyl ester sodium mix homogeneously that progressively increases, be 30 POVIDONE K 30 BP/USP 30 solution that solvent is prepared 50% concentration with water, as binding agent, the system soft material, drying, granulate adds 0.23gSiO
2, 2.00g stearic acid and 1.00g magnesium stearate, tabletting gets 769, the 25mg/ sheet.
Embodiment 12:
Mixed crystal content standard (xrd method)
Select 25.496 place's characteristic peaks of VI crystal formation and 22.225 place's characteristic peaks of II crystal formation for use, two peak angle values differ bigger, and the symmetry at peak is good, and angle value meets and chooses requirement near 20-25.
With two peak intensities ratio is abscissa, and percentage composition is a vertical coordinate, is figure according to principle of least square method and sees Fig. 4.
Case study on implementation 13:
Mixed crystal content standard (DSC method)
II crystal formation and VI crystal formation fusing point differ bigger, and the fusing point of II crystal formation is 109 ~ 111 ℃, and the fusing point of VI crystal formation is 99-101 ℃, and fusing point is different, and the heat that is absorbed during heat fused is also different, thereby causes the area of absworption peak not wait.Accurately take by weighing the mixed crystal of the different proportionings of equivalent (1% ~ 5%), calculate the peak area ratio of each ratio,, to percentage by weight (X6/2) mapping, see Fig. 5 with peak area ratio (A6/2) according to principle of least square method:
Claims (1)
1. the mixed crystal of the II crystal formation of an agomelatine and VI crystal formation is characterized in that percentage by weight is:
The II crystal formation 93%-99% of agomelatine, the VI crystal formation 7%-1% of agomelatine;
The VI crystal formation monocrystalline of described agomelatine characterizes as follows:
-orthorhombic lattice;
-lattice parameter: a=31.4306, b=9.4936, c=17.7282, α=β=γ=90.000 °;
-space group: Pca2 (1);
Molecular number in the-elementary cell: 16;
-elementary cell volume: V
Elementary cell=5289.91
3
-density: d=1.222g/cm
3
2, the mixed crystal of said II crystal formation of claim 1 and VI crystal formation is characterised in that percentage by weight is:
The VI crystalline form of 5 % of the II crystal formation 95% of agomelatine, agomelatine;
1) infrared spectrum characterization: 3249cm
-1, 3068 cm
-1, 1640 cm
-1, 1624 cm
-1, 1509 cm
-1, 1432 cm
-1, 1252 cm
-1, 1212 cm
-1, 1028 cm
-1, 827 cm
-1, 834 cm
-1, 759 cm
-1, 700 cm
-1, 609 cm
-1
2) the X-ray powder diffraction of 2 θ values characterizes: 9.355,17.288,18.673,19.868,22.210,24.312,25.506;
3) fusing point: 99.83 ℃, 110.83 ℃.
3, the method for preparing of the mixed crystal of claim 1 or 2 said agomelatine II crystal formations and VI crystal formation:
The II crystal formation of agomelatine is mixed with the VI crystal formation of agomelatine, and 20～80 ℃ of rotation 1h that reduce pressure down promptly get its uniform mixing.
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| FR2978916B1 (en) | 2011-08-10 | 2013-07-26 | Servier Lab | SOLID PHARMACEUTICAL COMPOSITION FOR BUCCAL ADMINISTRATION OF AGOMELATIN |
| CN102503886B (en) * | 2011-10-11 | 2013-09-11 | 中山大学 | Agomelatine-isonicotine eutectic crystal and compound and preparation method thereof |
| FR3001894A1 (en) | 2013-02-08 | 2014-08-15 | Servier Lab | SOLID PHARMACEUTICAL COMPOSITION FOR BUCCAL ADMINISTRATION OF AGOMELATIN |
| CN105777572A (en) * | 2014-12-26 | 2016-07-20 | 辽宁药联制药有限公司 | Preparation method of agomelatine mixed crystal and application thereof in tablets |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5225442A (en) * | 1990-02-27 | 1993-07-06 | Adir Et Compagnie | Compounds having a naphthalene structure |
| CN101429134A (en) * | 2007-11-09 | 2009-05-13 | 瑟维尔实验室 | New crystalline form VI of agomelatine, method of preparation and pharmaceutical compositions thereof |
-
2011
- 2011-04-13 CN CN201110091682A patent/CN102206864B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5225442A (en) * | 1990-02-27 | 1993-07-06 | Adir Et Compagnie | Compounds having a naphthalene structure |
| CN101429134A (en) * | 2007-11-09 | 2009-05-13 | 瑟维尔实验室 | New crystalline form VI of agomelatine, method of preparation and pharmaceutical compositions thereof |
Non-Patent Citations (1)
| Title |
|---|
| S.Yous et al.Novel naphthalenic ligands with high affinity for the melatonin receptor.《J.Med.Chem.》.1992,第35卷 * |
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