CN102218050B - A kind of pharmaceutical composition of Cure of depression - Google Patents
A kind of pharmaceutical composition of Cure of depression Download PDFInfo
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- CN102218050B CN102218050B CN201110171645.8A CN201110171645A CN102218050B CN 102218050 B CN102218050 B CN 102218050B CN 201110171645 A CN201110171645 A CN 201110171645A CN 102218050 B CN102218050 B CN 102218050B
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- agomelatine
- pharmaceutical composition
- depression
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Abstract
The invention belongs to medical art, the invention discloses a kind of pharmaceutical composition of Cure of depression, this pharmaceutical composition is made up of raw material agomelatine and adjuvant, and its Raw agomelatine is micronized agomelatine.On the basis that the scientific research personnel of our company furthers investigate agomelatine physicochemical properties, find unexpectedly, by agomelatine micronization, after obtaining the agomelatine of certain particle diameter, be prepared into preparation, there is the advantage that quality is homogeneous, dissolution is good.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of raw material and be micronized agomelatine, there is the pharmaceutical composition of Cure of depression.
Micronization of the present invention refers to and includes but not limited to that raw material particle size is reached the method for less than 75 μm by mechanical lapping.Raw material particle size of the present invention refers to that at least 50%(is more than or equal to 50% and is less than 100%) particle diameter is less than or equal to 75 μm.
Background technology
Depression (depression) is a kind of common mental sickness, clinical main manifestations is depressed, interest goes down but does not lose, pessimistic, retardation of thinking, lack initiative, self-accusation from crime, diet, sleep poor, worry oneself to suffer from various disease, feeling that whole body many places are uncomfortable, can there is suicidal thought and behavior in severe patient.Depression is the disease that psychiatric department homicide rate is the highest.
According to World Health Organization's statistics, global rate of depression is about 3.1%, and in developed country close to about 6%, global patients with depression reaches 1.2 hundred million, has become the fourth-largest disease threatening human health.Along with day by day the accelerating of rhythm of life, increasingly sharpening and the shortage in road that pressure is releived of competing, depression rate improves just year by year.In the adult population of 20 years old, patients with depression increases with the speed of annual 11.3%, 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.Almost just have 1 patients with depression in every 7 adults, therefore it is called as the flu in psychiatry.Current China depression prevalence reaches 3%-5%, patient Yue Da 2,600 ten thousand people.
Agomelatine, N-[2-(7-methoxy-1-naphthyl) ethyl] acetamide is melatonin receptors (MT1 and MT2) agonist, 5-HT2C receptor antagonist.Agomelatine grinds by French Servier company is former, in the approval listing of 2009 Nian Huo European Union.Clinical research shows, agomelatine is particularly effective to pole major depressive disorder, has the effect of anxiety, adjustment sleep rhythm and adjustment biological clock concurrently, untoward reaction is simultaneously few, sexual function is had no adverse effects, also has no withdrawal reaction, for clinical treatment major depressive disorder (MDD) provides new method.As the newtype drug for the treatment of major depressive disorder, agomelatine has wide DEVELOPMENT PROSPECT.
Agomelatine is easily molten in oxolane, ethanol, acetic anhydride and methanol, dissolve in glacial acetic acid, acetonitrile, ethyl acetate and acetone, 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 increasing drug-eluting has a lot (solid dispersions technique, nanotechnology, adjuvant add surface activity agent method, ultrastructurepower technology, micronization technology etc.), therefore, select suitable method to prepare the qualified preparation of dissolution, need scientific research personnel by creationary research.
China CN1287780C, CN101919800A, CN101836966A disclose and comprise agomelatine oral cavity disintegration tablet or dispersible tablet, above-mentioned patent documentation is prepared preparation according to the prescription of oral cavity disintegration tablet or dispersible tablet, but depression does not belong to emergency case, do not need to adopt oral cavity disintegration tablet or this dosage form involved great expense of dispersible tablet.Chinese patent CN101048791A discloses agomelatine medicinal composition and technique thereof, oral formulations is mixed with into pharmaceutic adjuvant after agomelatine being crossed 100 mesh sieves in this patent, by the research of related substance and dissolution in description, determine preparation prescription, but do not disclose the detection method of dissolution, this dissolution results remains to be discussed.
Therefore, scientific research personnel needs the physicochemical properties according to agomelatine, carries out deep research could obtain desirable medicine for preparation.
Summary of the invention
For these reasons, on the basis that the scientific research personnel of our company furthers investigate agomelatine physicochemical properties, find unexpectedly, by agomelatine micronization, after obtaining the agomelatine of certain particle diameter, be prepared into preparation, there is the advantage that quality is homogeneous, dissolution is good.
The present invention is achieved through the following technical solutions.
A pharmaceutical composition for Cure of depression, this pharmaceutical composition is made up of raw material agomelatine and adjuvant, and raw material agomelatine is micronized agomelatine.
Micronization of the present invention refers to and includes but not limited to that raw material particle size is reached the method for less than 75 μm by mechanical lapping.Raw material particle size of the present invention refers to that at least 50%(is more than or equal to 50% and is less than 100%) particle diameter is less than or equal to 75 μm.Preferably at least 80% particle diameter is less than or equal to 75 μm.Preferably at least 90% particle diameter is less than or equal to 75 μm further.
Agomelatine of the present invention refers to: N-(2-(7-methoxy-1-naphthyl) ethyl) acetamide.Its structural formula is:
Molecular formula: C
15h
17nO
2.
Molecular weight: 243.30.
Wherein preferred micronized agomelatine particle diameter is 1-40 μm; At least 50%(is more than or equal to 50% and is less than 100%) particle diameter is less than or equal to 40 μm.
Wherein preferred micronized agomelatine particle diameter is 1-20 μm; At least 50%(is more than or equal to 50% and is less than 100%) particle diameter is less than or equal to 20 μm.
Wherein preferred micronized agomelatine particle diameter is 1-10 μm; At least 50%(is more than or equal to 50% and is less than 100%) particle diameter is less than or equal to 10 μm.
Wherein preferably 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 lubricant.
The wherein tablet prepared of pharmaceutical composition or capsule.
Micronized agomelatine 1 weight portion in tablet described above, 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.
Filler described above is one or more in lactose, microcrystalline Cellulose, corn starch, pregelatinized Starch, mannitol, sorbitol, calcium hydrogen phosphate, calcium sulfate; Binding agent is one or more in hydroxypropyl cellulose, PVP K-30, hypromellose, polyvinylpyrrolidone; One or more in disintegrating agent low-substituted hydroxypropyl cellulose, hyprolose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, microcrystalline Cellulose; Lubricant is one or more in magnesium stearate, Pulvis Talci, micropowder silica gel, Polyethylene Glycol.
1, dissolution determination method
Sample thief, according to dissolution method (China's coastal port two annex Ⅹ C second methods), with water 900ml for dissolution medium, rotating speed is 50 turns per minute, operate in accordance with the law, through 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes time, get dissolution fluid appropriate, filter, precision measures subsequent filtrate 2ml and is placed in 25ml measuring bottle, be diluted with water to scale, shake up, according to ultraviolet visible spectrophotometry (China's coastal port two annex
a), absorbance is measured at the wavelength place of 230nm; Separately get agomelatine reference substance and be about 20mg, accurately weighed, be placed in 100ml measuring bottle, add methanol 1ml and make dissolving and be diluted with water to scale, shake up, precision measures 1ml and is placed in 100ml measuring bottle, is diluted with water to scale, shakes up, and is measured in the same method, and 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, after mixing homogeneously with lactose, polyvinylpolypyrrolidone, add 6% polyvidone (PVP) K-30 aqueous solution, granulate, add magnesium stearate lubricant, tabletting, obtain 100, tablet, and the dissolution index of sample is detected.
Result of the test: in table 2.
Table 2 dissolution determination result
Above-mentioned result of the test display, in 60min, raw material does not have complete stripping.We intend the granularity of reduction raw material to increase the dissolution of raw material.
Test 2: prescription is identical with table 1, agomelatine is crossed 180 mesh sieves, after mixing homogeneously with lactose, polyvinylpolypyrrolidone, add 6% polyvidone (PVP) K-30 aqueous solution, granulate, add magnesium stearate lubricant, tabletting, obtains 100, tablet, and detects the dissolution index of sample.
Result of the test: in table 3.
Table 3 dissolution determination result
Above-mentioned result of the test display, after adjustment formulation and technology, though dissolution is improved in 60min, 60 minutes time, stripping is still defective.We intend the granularity of reduction raw material to increase the dissolution of raw material.
Test 3: prescription is identical with table 1 prescription, by agomelatine comminution by gas stream to 40 μm (50% particle diameter is less than or equal to 40 μm), after mixing homogeneously with lactose, polyvinylpolypyrrolidone, add 6% polyvidone (PVP) K-30 aqueous solution, granulate, add magnesium stearate lubricant, tabletting, obtain 100, tablet, and the dissolution index of sample is detected.
Result of the test: in table 4.
Table 4 dissolution determination result
Above-mentioned result of the test shows, after adjusting process prescription, in 60min, dissolution meets the requirements substantially, but still also needs the quality improving product.
Test 4: prescription is identical with table 1 prescription, by agomelatine comminution by gas stream to 20 μm (50% particle diameter is less than or equal to 20 μm), after mixing homogeneously with lactose, polyvinylpolypyrrolidone, add 6% polyvidone (PVP) K-30 aqueous solution, granulate, add magnesium stearate lubricant, tabletting, obtain 100, tablet, and the dissolution index of sample is detected.
Result of the test: in table 5.
Table 5 dissolution determination result
Above-mentioned result of the test shows, after adjusting process prescription, in 60min, dissolution meets the requirements.
Test 5: prescription is identical with table 1 prescription, by agomelatine comminution by gas stream to 9 μm (50% particle diameter is less than or equal to 9 μm), after mixing homogeneously with lactose, polyvinylpolypyrrolidone, add 6% polyvidone (PVP) K-30 aqueous solution, granulate, add magnesium stearate lubricant, tabletting, obtain 100, tablet, and the dissolution index of sample is detected.
Result of the test: in table 6.
Table 6 dissolution determination result
Above-mentioned result of the test shows, after adjusting process prescription, in 60min, dissolution meets the requirements.
Conclusion (of pressure testing): above-mentioned test shows, after agomelatine micronization, the dissolution of preparation meets the requirements, and when micronization particle diameter is less than 20 μm, result of extraction is better; When micronization particle diameter is less than 10 μm, result of extraction is better.
Note: above-mentioned test is on test of many times basis, the concluding of carrying out is tested.
3, demonstration test
Table 7 demonstration test prescription
| Supplementary material | Recipe quantity (g) |
| Agomelatine | 50 |
| Starch | 128 |
| Lactose | 386 |
| 10% hydroxy propyl cellulose water element aqueous solution | 100 |
| Magnesium stearate | 3 |
Preparation method 1: by agomelatine 50g comminution by gas stream to 9 μm (50% particle diameter is less than or equal to 9 μm), after mixing homogeneously with lactose, starch, add 10% hydroxy propyl cellulose water element aqueous solution, granulate, add magnesium stearate lubricant, tabletting, obtains 2000, tablet, and detects the dissolution index of sample.
Preparation method 2: by agomelatine 50g 180 mesh sieves, after mixing homogeneously with lactose, starch, adds 10% hydroxy propyl cellulose water element aqueous solution, granulate, add magnesium stearate lubricant, tabletting, obtain 2000, tablet, and the dissolution index of sample is detected.
Result of the test: in table 8.
Table 8 dissolution determination result
Conclusion (of pressure testing): above-mentioned test shows, after agomelatine micronization, in prescription, adjuvant changes, and dissolution still meets the requirements, and absolutely proves the importance of agomelatine micronization in preparation process thereof.
Preparation embodiment
Embodiment 1
A pharmaceutical composition for Cure of depression, this pharmaceutical composition, by raw material agomelatine comminution by gas stream to 20 μm (50% particle diameter is less than or equal to 20 μm), mixes with pharmaceutic adjuvant, is prepared into tablet or capsule.
Embodiment 2
A pharmaceutical composition for Cure of depression, this pharmaceutical composition, by raw material agomelatine fluid energy mill to 14 μm (50% particle diameter is less than or equal to 14 μm), mixes with pharmaceutic adjuvant, is prepared into tablet or capsule.
Embodiment 3
A pharmaceutical composition for Cure of depression, this pharmaceutical composition, by raw material agomelatine colloid mill to 8 μm (50% particle diameter is less than or equal to 8 μm), mixes with pharmaceutic adjuvant, is prepared into tablet or capsule.
Embodiment 4
A pharmaceutical composition for Cure of depression, this pharmaceutical composition, by raw material agomelatine ultrasonic grinding to 5 μm (50% particle diameter is less than or equal to 5 μm), mixes with pharmaceutic adjuvant, is prepared into tablet or capsule.
Embodiment 5
A pharmaceutical composition for Cure of depression, this pharmaceutical composition, by raw material agomelatine comminution by gas stream to 20 μm (50% particle diameter is less than or equal to 20 μm), mixes with pharmaceutic adjuvant, is 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 microcrystalline Cellulose; Binding agent is 10% hydroxy propyl cellulose aqueous solution; Disintegrating agent hyprolose; Lubricant is Pulvis Talci, Polyethylene Glycol.
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; Disintegrating agent hyprolose.
Embodiment 6
A pharmaceutical composition for Cure of depression, this pharmaceutical composition, by raw material agomelatine fluid energy mill to 14 μm (80% particle diameter is less than or equal to 14 μm), mixes with pharmaceutic adjuvant, is 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; Disintegrating agent low-substituted hydroxypropyl cellulose; Lubricant is magnesium stearate.
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 pharmaceutical composition for Cure of depression, this pharmaceutical composition, by raw material agomelatine colloid mill to 8 μm (50% particle diameter is less than or equal to 8 μm), mixes with pharmaceutic adjuvant, is 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% PVP K-30 aqueous solution, 1% hypromellose; In disintegrating agent low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, microcrystalline Cellulose, chitin; Lubricant is micropowder silica gel, Polyethylene Glycol.
Capsule prescription is: agomelatine 1g in 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% PVP K-30 aqueous solution, 5% hypromellose; Disintegrating agent low-substituted hydroxypropyl cellulose, chitin.
Embodiment 8
A pharmaceutical composition for Cure of depression, this pharmaceutical composition, by raw material agomelatine ultrasonic grinding to 7 μm (50% particle diameter is less than or equal to 7 μm), mixes with pharmaceutic adjuvant, is 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 lactose; Binding agent is 6% PVP K-30 aqueous solution; Disintegrating agent polyvinylpolypyrrolidone; Lubricant is magnesium stearate.
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% PVP K-30 aqueous solution; Disintegrating agent low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose.
Embodiment 9
A pharmaceutical composition for Cure of depression, this pharmaceutical composition, by raw material agomelatine ultrasonic grinding to 9 μm (50% particle diameter is less than or equal to 9 μm), mixes with pharmaceutic adjuvant, is 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 lactose; Binding agent is 6% polyvidone (PVP) K-30 aqueous solution; Disintegrating agent polyvinylpolypyrrolidone; Lubricant is magnesium stearate.
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% PVP K-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 (1)
1. a pharmaceutical composition for Cure of depression, this pharmaceutical composition is made up of raw material agomelatine and adjuvant, it is characterized in that: pharmaceutical composition consists of: agomelatine 2.50g, lactose 25.85g, polyvinylpolypyrrolidone 1.20g, 6% PVP K-30 aqueous solution 5g, magnesium stearate 0.15g;
Pharmaceutical composition is prepared into tablet, and its preparation method is: agomelatine comminution by gas stream to 50% particle diameter is less than or equal to 9 μm, after mixing homogeneously with lactose, polyvinylpolypyrrolidone, add 6% PVP K-30 aqueous solution, granulate, add magnesium stearate lubricant, tabletting, obtains 100, tablet.
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Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102579415B (en) * | 2011-01-14 | 2014-11-05 | 成都康弘药业集团股份有限公司 | Agomelatine-containing medicinal composition for oral mucosa or sublingual administration |
| CN102552211B (en) * | 2012-02-16 | 2013-07-17 | 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 |
| CN102988315B (en) | 2012-09-28 | 2017-11-17 | 浙江华海药业股份有限公司 | The preparation method of agomelatine solid preparation |
| CN103251567B (en) * | 2013-06-05 | 2014-03-12 | 重庆华森制药有限公司 | Agomelatine troche and preparation method thereof |
| CN103655499B (en) * | 2013-12-23 | 2015-07-22 | 天津泰普药品科技发展有限公司 | Stable X-crystal-shaped agomelatine tablet and preparation method thereof |
| CN103690499B (en) * | 2013-12-23 | 2015-05-06 | 天津泰普药品科技发展有限公司 | Stable crystalline form I agomelatine tablets and preparation method thereof |
| CN106727375B (en) * | 2016-12-21 | 2020-07-07 | 江苏豪森药业集团有限公司 | Agomelatine tablet 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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| 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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