CN102218050A - Pharmaceutical composition for treating depression - Google Patents
Pharmaceutical composition for treating depression Download PDFInfo
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- CN102218050A CN102218050A CN2011101716458A CN201110171645A CN102218050A CN 102218050 A CN102218050 A CN 102218050A CN 2011101716458 A CN2011101716458 A CN 2011101716458A CN 201110171645 A CN201110171645 A CN 201110171645A CN 102218050 A CN102218050 A CN 102218050A
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Abstract
The invention belongs to the technical field of medicines, and discloses a pharmaceutical composition for treating depression. The pharmaceutical composition is composed of a raw material agomelatine and auxiliary materials, wherein the raw material agomelatine is micronized agomelatine. Based on a deep research of the physical and chemical properties of agomelatine, the scientific researchers of the company accidentally find that agomelatine can be micronized for obtaining agomelatine with a certain particle size to produce a preparation, the invention has the advantages of uniform quality and good dissolution rate.
Description
Technical field
The invention belongs to medical technical field, to be specifically related to a kind of raw material be micronized agomelatine, have the pharmaceutical composition of treatment depression.
Micronization of the present invention is meant and includes but not limited to that mechanical lapping reaches method below the 75 μ m with raw material particle size.Raw material particle size of the present invention is meant that 50%(is more than or equal to 50% and less than 100% at least) particle diameter is smaller or equal to 75 μ m.
Background technology
Depression (depression) is a kind of common mental sickness, clinical mainly show as depressed, interest goes down but not forfeiture, pessimism, retardation of thinking, lack initiative, the self-accusation from the crime, diet, the sleep poor, worry oneself to suffer from various diseases, feel whole body many places discomfort, suicidal thought and behavior can appear in severe patient.Depression is the highest disease of psychiatric department homicide rate.
According to World Health Organization's statistics, global rate of depression is about 3.1%, and about developed country was near 6%, global patients with depression reached 1.2 hundred million, had become the fourth-largest disease that threatens human health.Along with rhythm of life accelerate day by day, compete increasingly sharpen and the shortage in the road that pressure is releived, the depression sickness rate improves just year by year.In 20 years old adult population, patients with depression increases with annual 11.3% speed, and World Health Organization (WHO) expects the year two thousand twenty, and depression will jump to world's second largest disease, be only second to ischemic heart desease.Among almost per 7 adults 1 patients with depression is just arranged, so it is called as the flu in the psychiatry.China's depression prevalence reaches 3%-5%, patient Yue Da 2,600 ten thousand people at present.
Agomelatine, N-[2-(7-methoxyl group-1-naphthyl) ethyl] acetamide is melatonin receptors (MT1 and MT2) agonist, 5-HT2C receptor antagonist.Agomelatine obtained European Union's approval listing by former the grinding of French Servier company in 2009.Clinical research shows that agomelatine is particularly effective to utmost point major depressive disorder, has anxiety concurrently, adjusts sleep rhythm and regulates the effect of biological clock, untoward reaction simultaneously is few, sexual function is had no adverse effects, also do not see withdrawal reaction, (MDD) provides new method for the clinical treatment major depressive disorder.As the newtype drug of treatment major depressive disorder, agomelatine has the wide development prospect.
Agomelatine is easily molten in oxolane, ethanol, acetic anhydride and methanol, in glacial acetic acid, acetonitrile, ethyl acetate and acetone, dissolve, slightly soluble in dichloromethane, soluble,very slightly in toluene, almost insoluble in 0.1mol/L hydrochloric acid solution, 1mol/L hydrochloric acid solution, 1mol/L sodium hydroxide, water and phosphate buffer (pH6.8).The method that increases the medicine stripping has a lot (solid dispersions technique, nanotechnology, adjuvant add surface activity agent method, superfine powder technology, micronization technology or the like), therefore, select suitable method to prepare the qualified preparation of dissolution, need the scientific research personnel by creationary research.
China CN1287780C, CN101919800A, CN101836966A disclose and have comprised agomelatine oral cavity disintegration tablet or dispersible tablet, above-mentioned patent documentation is that the prescription according to oral cavity disintegration tablet or dispersible tablet is prepared preparation, but depression does not belong to emergency case, does not need to adopt this dosage form that involves great expense of oral cavity disintegration tablet or dispersible tablet.Chinese patent CN101048791A discloses agomelatine pharmaceutical composition and technology thereof, be mixed with into oral formulations with pharmaceutic adjuvant after in this patent agomelatine being crossed 100 mesh sieves, research by related substance and dissolution in the description, determine preparation prescription, but do not disclose the detection method of dissolution, this dissolution is the result remain to be discussed.
Therefore, the scientific research personnel need carry out deep research at preparation and could obtain ideal medicine according to the physicochemical properties of agomelatine.
Summary of the invention
For these reasons, on the basis that the scientific research personnel of our company furthers investigate the agomelatine physicochemical properties, the unexpected discovery, with the agomelatine micronization, after obtaining the agomelatine of certain particle diameter, be prepared into preparation, have quality homogeneous, advantage that dissolution is good.
The present invention is achieved through the following technical solutions.
A kind of pharmaceutical composition for the treatment of depression, this pharmaceutical composition is made up of raw material agomelatine and adjuvant, and the raw material agomelatine is micronized agomelatine.
Micronization of the present invention is meant and includes but not limited to that mechanical lapping reaches method below the 75 μ m with raw material particle size.Raw material particle size of the present invention is meant that 50%(is more than or equal to 50% and less than 100% at least) particle diameter is smaller or equal to 75 μ m.Preferably at least 80% particle diameter is smaller or equal to 75 μ m.Further preferably at least 90% particle diameter smaller or equal to 75 μ m.
Agomelatine of the present invention is meant: acetamide ethyl N-(2-(7-methoxyl group-1-naphthyl)).Its structural formula is:
Molecular formula: C
15H
17NO
2
Molecular weight: 243.30.
Wherein preferred micronized agomelatine particle diameter is 1-40 μ m; At least 50%(is more than or equal to 50% and less than 100%) particle diameter is smaller or equal to 40 μ m.
Wherein preferred micronized agomelatine particle diameter is 1-20 μ m; At least 50%(is more than or equal to 50% and less than 100%) particle diameter is smaller or equal to 20 μ m.
Wherein preferred micronized agomelatine particle diameter is 1-10 μ m; At least 50%(is more than or equal to 50% and less than 100%) particle diameter is smaller or equal to 10 μ m.
Wherein preferred method of micronization is fluid energy mill, colloid mill, comminution by gas stream or ultrasonic grinding.
Above-mentioned pharmaceutic adjuvant is several in filler, binding agent, disintegrating agent and the lubricant.
The wherein tablet of preparation of pharmaceutical compositions or capsule.
Micronized agomelatine 1 weight portion in the above-mentioned described tablet, filler 8-12 weight portion, binding agent 1-5 weight portion, disintegrating agent 0.2-0.8 weight portion, lubricant 0.04-0.08 weight portion.
Above-mentioned described filler is one or more in lactose, microcrystalline Cellulose, corn starch, pregelatinized Starch, mannitol, sorbitol, calcium hydrogen phosphate, the calcium sulfate; Binding agent be in hydroxypropyl cellulose, 30 POVIDONE K 30 BP/USP-30, hypromellose, the polyvinylpyrrolidone one or more; In disintegrating agent low-substituted hydroxypropyl cellulose, hyprolose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, the microcrystalline Cellulose one or more; Lubricant is one or more in magnesium stearate, Pulvis Talci, micropowder silica gel, the Polyethylene Glycol.
1, dissolution determination method
Sample thief, according to dissolution method (two appendix X of Chinese Pharmacopoeia version in 2005 C, second method), be dissolution medium with water 900ml, rotating speed is that per minute 50 changes, operation in accordance with the law, in the time of 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, it is an amount of to get dissolution fluid, filters, precision is measured subsequent filtrate 2ml and is placed the 25ml measuring bottle, thin up shakes up to scale, according to ultraviolet visible spectrophotometry (two appendix of Chinese Pharmacopoeia version in 2005
A), measure absorbance at the wavelength place of 230nm; Other gets the about 20mg of agomelatine reference substance, and accurate the title decides, and places the 100ml measuring bottle, adds methanol 1ml and makes dissolving and thin up to scale, shakes up, and precision is measured 1ml and placed the 100ml measuring bottle, and thin up shakes up to scale, measures with method, calculates stripping quantity.
2, to the research of agomelatine particle diameter
Table 1 preparation prescription
| Supplementary material | Recipe quantity (g) |
| Agomelatine | 2.50g |
| Lactose | 25.85g |
| Polyvinylpolypyrrolidone | 1.20g |
| 6% polyvidone (PVP) K-30 aqueous solution | 5.00g |
| Magnesium stearate | 0.15g |
Test 1: agomelatine is crossed 120 mesh sieves, behind lactose, polyvinylpolypyrrolidone mix homogeneously, add 6% polyvidone (PVP) K-30 aqueous solution, granulate, add magnesium stearate lubricant, tabletting, obtain 100 in tablet, and the dissolution index of sample is detected.
Result of the test: see Table 2.
Table 2 dissolution determination result
Above-mentioned result of the test shows that raw material does not have complete stripping in the 60min.We intend reducing the granularity of raw material to increase the dissolution of raw material.
Test 2: it is identical with table 1 to write out a prescription, and agomelatine is crossed 180 mesh sieves, behind lactose, polyvinylpolypyrrolidone mix homogeneously, add 6% polyvidone (PVP) K-30 aqueous solution, granulate, add magnesium stearate lubricant, tabletting obtains 100 in tablet, and the dissolution index of sample is detected.
Result of the test: see Table 3.
Table 3 dissolution determination result
Above-mentioned result of the test shows that behind the adjustment formulation and technology, though dissolution has raising in the 60min, stripping is still defective in the time of 60 minutes.We intend reducing the granularity of raw material to increase the dissolution of raw material.
Test 3: prescription is identical with table 1 prescription, with agomelatine with comminution by gas stream to 40 μ m(50% particle diameter smaller or equal to 40 μ m), behind lactose, polyvinylpolypyrrolidone mix homogeneously, add 6% polyvidone (PVP) K-30 aqueous solution, granulate, add magnesium stearate lubricant, tabletting, obtain 100 in tablet, and the dissolution index of sample is detected.
Result of the test: see Table 4.
Table 4 dissolution determination result
Above-mentioned result of the test shows that behind the adjusting process prescription, dissolution meets the requirements substantially in the 60min, but still also needs to improve the quality of product.
Test 4: prescription is identical with table 1 prescription, with agomelatine with comminution by gas stream to 20 μ m(50% particle diameter smaller or equal to 20 μ m), behind lactose, polyvinylpolypyrrolidone mix homogeneously, add 6% polyvidone (PVP) K-30 aqueous solution, granulate, add magnesium stearate lubricant, tabletting, obtain 100 in tablet, and the dissolution index of sample is detected.
Result of the test: see Table 5.
Table 5 dissolution determination result
Above-mentioned result of the test shows that behind the adjusting process prescription, dissolution meets the requirements in the 60min.
Test 5: prescription is identical with table 1 prescription, with agomelatine with comminution by gas stream to 9 μ m(50% particle diameter smaller or equal to 9 μ m), behind lactose, polyvinylpolypyrrolidone mix homogeneously, add 6% polyvidone (PVP) K-30 aqueous solution, granulate, add magnesium stearate lubricant, tabletting, obtain 100 in tablet, and the dissolution index of sample is detected.
Result of the test: see Table 6.
Table 6 dissolution determination result
Above-mentioned result of the test shows that behind the adjusting process prescription, dissolution meets the requirements in the 60min.
Conclusion (of pressure testing): above-mentioned test shows that behind the agomelatine micronization, the dissolution of preparation meets the requirements, and when micronization particle diameter during less than 20 μ m, result of extraction is better; When the micronization particle diameter less than 10 μ m, result of extraction is better.
Annotate: above-mentioned test is on the test of many times basis, the concluding test of carrying out.
3, demonstration test
Table 7 demonstration test prescription
| Supplementary material | Recipe quantity (g) |
| Agomelatine | 50 |
| Starch | 128 |
| Lactose | 386 |
| The plain aqueous solution of 10% hydroxy propyl cellulose water | 100 |
| Magnesium stearate | 3 |
Preparation method 1: with agomelatine 50g with comminution by gas stream to 9 μ m(50% particle diameter smaller or equal to 9 μ m), behind lactose, starch mix homogeneously, add the plain aqueous solution of 10% hydroxy propyl cellulose water, granulate, add magnesium stearate lubricant, tabletting obtains 2000 in tablet, and the dissolution index of sample is detected.
Preparation method 2:, behind lactose, starch mix homogeneously, add the plain aqueous solution of 10% hydroxy propyl cellulose water with agomelatine 50g 180 mesh sieves, granulate, add magnesium stearate lubricant, tabletting, obtain 2000 in tablet, and the dissolution index of sample is detected.
Result of the test: see Table 8.
Table 8 dissolution determination result
Conclusion (of pressure testing): above-mentioned test shows that behind the agomelatine micronization, adjuvant changes in the prescription, and dissolution still meets the requirements, and proves absolutely the importance of agomelatine micronization in preparation process thereof.
Preparation embodiment
Embodiment 1
A kind of pharmaceutical composition for the treatment of depression, this pharmaceutical composition by the raw material agomelatine with comminution by gas stream to 20 μ m(50% particle diameter smaller or equal to 20 μ m), mix with pharmaceutic adjuvant, be prepared into tablet or capsule.
Embodiment 2
A kind of pharmaceutical composition for the treatment of depression, this pharmaceutical composition by the raw material agomelatine with fluid energy mill to 14 μ m(50% particle diameter smaller or equal to 14 μ m), mix with pharmaceutic adjuvant, be prepared into tablet or capsule.
Embodiment 3
A kind of pharmaceutical composition for the treatment of depression, this pharmaceutical composition by the raw material agomelatine with colloid mill to 8 μ m(50% particle diameter smaller or equal to 8 μ m), mix with pharmaceutic adjuvant, be prepared into tablet or capsule.
Embodiment 4
A kind of pharmaceutical composition for the treatment of depression, this pharmaceutical composition by the raw material agomelatine with ultrasonic grinding to 5 μ m(50% particle diameter smaller or equal to 5 μ m), mix with pharmaceutic adjuvant, be prepared into tablet or capsule.
Embodiment 5
A kind of pharmaceutical composition for the treatment of depression, this pharmaceutical composition by the raw material agomelatine with comminution by gas stream to 20 μ m(50% particle diameter smaller or equal to 20 μ m), mix with pharmaceutic adjuvant, be prepared into tablet or capsule.Its prescription is:
Tablet formulation is:
Agomelatine 1g, filler 8g, binding agent 1.5g, disintegrating agent 0.3g, lubricant 0.04g.Wherein filler is a microcrystalline Cellulose; Binding agent is 10% hydroxy propyl cellulose aqueous solution; The disintegrating agent hyprolose; Lubricant is Pulvis Talci, Polyethylene Glycol.
The capsule prescription is: agomelatine 1g, filler 9g, binding agent 1.5g, disintegrating agent 0.3g.Wherein filler is pregelatinized Starch, calcium hydrogen phosphate, calcium sulfate; Binding agent is 10% hydroxy propyl cellulose aqueous solution; The disintegrating agent hyprolose.
Embodiment 6
A kind of pharmaceutical composition for the treatment of depression, this pharmaceutical composition by the raw material agomelatine with fluid energy mill to 14 μ m(80% particle diameter smaller or equal to 14 μ m), mix with pharmaceutic adjuvant, be prepared into tablet or capsule.
Tablet formulation is: agomelatine 1g, filler 12g, binding agent 2g, disintegrating agent 0.6g, lubricant 0.06g.Wherein filler is lactose, starch; Binding agent is 10% hydroxy propyl cellulose aqueous solution; The disintegrating agent low-substituted hydroxypropyl cellulose; Lubricant is a magnesium stearate.
The capsule prescription is: agomelatine 1g, filler 11.5g, binding agent 2g, disintegrating agent 0.6g.Wherein filler is lactose, dextrin, Icing Sugar; Binding agent is 10% hydroxypropyl cellulose aqueous solution; Disintegrating agent low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, microcrystalline Cellulose.
Embodiment 7
A kind of pharmaceutical composition for the treatment of depression, this pharmaceutical composition by the raw material agomelatine with colloid mill to 8 μ m(50% particle diameter smaller or equal to 8 μ m), mix with pharmaceutic adjuvant, be prepared into tablet or capsule.
Tablet formulation: agomelatine 1g, filler 9.5g, binding agent 4.8g, disintegrating agent 0.4g, lubricant 0.08g.Wherein filler is microcrystalline Cellulose, calcium hydrogen phosphate, calcium sulfate; Binding agent is the aqueous solution of 3% hydroxypropyl cellulose aqueous solution, 2% 30 POVIDONE K 30 BP/USP-30 aqueous solution, 1% hypromellose; In disintegrating agent low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, microcrystalline Cellulose, the chitin; Lubricant is micropowder silica gel, Polyethylene Glycol.
The capsule prescription is: agomelatine 1g in the tablet, filler 8.8g, binding agent 5g, disintegrating agent 0.75g.Wherein filler is lactose, calcium hydrogen phosphate, calcium sulfate; Binding agent is the aqueous solution of 4% 30 POVIDONE K 30 BP/USP-30 aqueous solution, 5% hypromellose; Disintegrating agent low-substituted hydroxypropyl cellulose, chitin.
Embodiment 8
A kind of pharmaceutical composition for the treatment of depression, this pharmaceutical composition by the raw material agomelatine with ultrasonic grinding to 7 μ m(50% particle diameter smaller or equal to 7 μ m), mix with pharmaceutic adjuvant, be prepared into tablet or capsule.
Tablet formulation is: agomelatine 1g, filler 11.5g, binding agent 4.8g, disintegrating agent 0.6g, lubricant 0.07g.Wherein filler is a lactose; Binding agent is 6% 30 POVIDONE K 30 BP/USP-30 aqueous solution; The disintegrating agent polyvinylpolypyrrolidone; Lubricant is a magnesium stearate.
The capsule prescription is: agomelatine 1g, filler 9g, binding agent 1.5g, disintegrating agent 0.6g.Wherein filler is starch, mannitol, calcium hydrogen phosphate, calcium sulfate; Binding agent is 6% 30 POVIDONE K 30 BP/USP-30 aqueous solution; Disintegrating agent low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose.
Embodiment 9
A kind of pharmaceutical composition for the treatment of depression, this pharmaceutical composition by the raw material agomelatine with ultrasonic grinding to 9 μ m(50% particle diameter smaller or equal to 9 μ m), mix with pharmaceutic adjuvant, be prepared into tablet or capsule.
Tablet formulation is: agomelatine 1g, filler 10g, binding agent 2g, disintegrating agent 0.48g, lubricant 0.06g.Wherein filler is a lactose; Binding agent is 6% polyvidone (PVP) K-30 aqueous solution; The disintegrating agent polyvinylpolypyrrolidone; Lubricant is a magnesium stearate.
The capsule prescription is: agomelatine 1g, filler 10.5g, binding agent 1.9g, disintegrating agent 0.55g.Wherein filler is starch, mannitol, calcium hydrogen phosphate, calcium sulfate; Binding agent is 6% 30 POVIDONE K 30 BP/USP-30 aqueous solution; Disintegrating agent low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose.
Described embodiment includes but not limited to above-mentioned.
Claims (8)
1. pharmaceutical composition for the treatment of depression, this pharmaceutical composition is made up of raw material agomelatine and adjuvant, it is characterized in that the raw material agomelatine is micronized agomelatine.
2. a kind of pharmaceutical composition for the treatment of depression according to claim 1, wherein micronized agomelatine particle diameter are 1-20 μ m.
3. a kind of pharmaceutical composition for the treatment of depression according to claim 1, wherein micronized minodronic acid particle diameter are 1-10 μ m.
4. according to each described a kind of pharmaceutical composition for the treatment of depression of claim 1-3, wherein method of micronization is fluid energy mill, colloid mill, comminution by gas stream or ultrasonic grinding.
5. a kind of pharmaceutical composition for the treatment of depression according to claim 1, wherein pharmaceutic adjuvant is several in filler, binding agent, disintegrating agent and the lubricant.
6. according to claim 1-3,5 each described a kind of pharmaceutical composition for the treatment of depression, the wherein tablet of preparation of pharmaceutical compositions or capsules.
7. a kind of pharmaceutical composition for the treatment of depression according to claim 6, agomelatine 1 weight portion in the tablet wherein, filler 8-12 weight portion, binding agent 1-5 weight portion, disintegrating agent 0.2-0.8 weight portion, lubricant 0.04-0.08 weight portion.
8. according to claim 5 or 7 described a kind of pharmaceutical compositions for the treatment of depression, wherein filler is one or more in lactose, microcrystalline Cellulose, corn starch, pregelatinized Starch, mannitol, sorbitol, calcium hydrogen phosphate, the calcium sulfate; Binding agent be in hydroxypropyl cellulose, 30 POVIDONE K 30 BP/USP-30, hypromellose, the polyvinylpyrrolidone aqueous solution one or more; In disintegrating agent low-substituted hydroxypropyl cellulose, hyprolose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, the microcrystalline Cellulose one or more; Lubricant is one or more in magnesium stearate, Pulvis Talci, micropowder silica gel, the Polyethylene Glycol.
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| CN102552211A (en) * | 2012-02-16 | 2012-07-11 | 福建广生堂药业股份有限公司 | Preparation composite of agomelatine and preparation method thereof |
| CN102579415A (en) * | 2011-01-14 | 2012-07-18 | 成都康弘药业集团股份有限公司 | Agomelatine-containing medicinal composition for oral mucosa or sublingual administration |
| CN102670514A (en) * | 2012-04-29 | 2012-09-19 | 浙江华海药业股份有限公司 | Agomelatine solid preparation |
| CN103251567A (en) * | 2013-06-05 | 2013-08-21 | 重庆华森制药有限公司 | Agomelatine troche and preparation method thereof |
| WO2014048380A1 (en) | 2012-09-28 | 2014-04-03 | 浙江华海药业股份有限公司 | Preparation method of agomelatine solid preparation |
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| CN106727375A (en) * | 2016-12-21 | 2017-05-31 | 江苏豪森药业集团有限公司 | Agomelatine tablet and preparation method thereof |
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| CN102078309A (en) * | 2011-01-22 | 2011-06-01 | 王定豪 | Dispersible tablet containing antipsychotic medicines and application thereof |
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| CN102078309A (en) * | 2011-01-22 | 2011-06-01 | 王定豪 | Dispersible tablet containing antipsychotic medicines and application thereof |
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| CN102552211A (en) * | 2012-02-16 | 2012-07-11 | 福建广生堂药业股份有限公司 | Preparation composite of agomelatine and preparation method thereof |
| CN102670514B (en) * | 2012-04-29 | 2017-05-10 | 浙江华海药业股份有限公司 | Agomelatine solid preparation |
| CN102670514A (en) * | 2012-04-29 | 2012-09-19 | 浙江华海药业股份有限公司 | Agomelatine solid preparation |
| WO2014048380A1 (en) | 2012-09-28 | 2014-04-03 | 浙江华海药业股份有限公司 | Preparation method of agomelatine solid preparation |
| CN103251567A (en) * | 2013-06-05 | 2013-08-21 | 重庆华森制药有限公司 | Agomelatine troche and preparation method thereof |
| CN103251567B (en) * | 2013-06-05 | 2014-03-12 | 重庆华森制药有限公司 | Agomelatine troche and preparation method thereof |
| JP2016531944A (en) * | 2013-12-23 | 2016-10-13 | 天津泰普葯品科技▲発▼展有限公司 | Stable crystalline form I agomelatin tablet and method for its preparation |
| JP2016536351A (en) * | 2013-12-23 | 2016-11-24 | 天津泰普葯品科技▲発▼展有限公司 | Stable crystalline X-form agomelatine tablet and preparation method thereof |
| CN106727375A (en) * | 2016-12-21 | 2017-05-31 | 江苏豪森药业集团有限公司 | Agomelatine tablet and preparation method thereof |
| CN110151735A (en) * | 2019-06-06 | 2019-08-23 | 深圳市泛谷药业股份有限公司 | A kind of agomelatine transdermal patch and preparation method thereof |
| CN110151735B (en) * | 2019-06-06 | 2021-07-06 | 深圳市泛谷药业股份有限公司 | Agomelatine transdermal patch and preparation method thereof |
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