CN103446066A - Paroxetine liensinine freeze-dried powder and preparation method thereof - Google Patents
Paroxetine liensinine freeze-dried powder and preparation method thereof Download PDFInfo
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- CN103446066A CN103446066A CN2013104203405A CN201310420340A CN103446066A CN 103446066 A CN103446066 A CN 103446066A CN 2013104203405 A CN2013104203405 A CN 2013104203405A CN 201310420340 A CN201310420340 A CN 201310420340A CN 103446066 A CN103446066 A CN 103446066A
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- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 title claims abstract description 46
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 229960002296 paroxetine Drugs 0.000 title claims abstract description 46
- 239000000843 powder Substances 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims description 7
- XCUCMLUTCAKSOZ-FIRIVFDPSA-N Liensinine Chemical compound C([C@@H]1C=2C=C(C(=CC=2CCN1C)OC)OC=1C(O)=CC=C(C=1)C[C@H]1N(C)CCC=2C=C(C(=CC=21)OC)OC)C1=CC=C(O)C=C1 XCUCMLUTCAKSOZ-FIRIVFDPSA-N 0.000 title abstract 2
- XCUCMLUTCAKSOZ-JSOSNVBQSA-N Liensinine Natural products C([C@@H]1C=2C=C(C(=CC=2CCN1C)OC)OC=1C(O)=CC=C(C=1)C[C@@H]1N(C)CCC=2C=C(C(=CC=21)OC)OC)C1=CC=C(O)C=C1 XCUCMLUTCAKSOZ-JSOSNVBQSA-N 0.000 title abstract 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 63
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000008215 water for injection Substances 0.000 claims abstract description 35
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims abstract description 25
- 239000011975 tartaric acid Substances 0.000 claims abstract description 24
- 235000002906 tartaric acid Nutrition 0.000 claims abstract description 24
- 229940085675 polyethylene glycol 800 Drugs 0.000 claims abstract description 16
- 239000002994 raw material Substances 0.000 claims abstract description 3
- 238000003756 stirring Methods 0.000 claims description 43
- 239000000243 solution Substances 0.000 claims description 24
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 claims description 9
- 238000003556 assay Methods 0.000 claims description 9
- 238000005261 decarburization Methods 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 9
- 238000004108 freeze drying Methods 0.000 claims description 9
- 238000005374 membrane filtration Methods 0.000 claims description 9
- 238000012856 packing Methods 0.000 claims description 9
- 238000007689 inspection Methods 0.000 claims description 8
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims 1
- 229940075582 sorbic acid Drugs 0.000 claims 1
- 235000010199 sorbic acid Nutrition 0.000 claims 1
- 239000004334 sorbic acid Substances 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 230000000052 comparative effect Effects 0.000 description 9
- 239000006184 cosolvent Substances 0.000 description 8
- 239000003002 pH adjusting agent Substances 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- SNIXRMIHFOIVBB-UHFFFAOYSA-N N-Hydroxyl-tryptamine Chemical class C1=CC=C2C(CCNO)=CNC2=C1 SNIXRMIHFOIVBB-UHFFFAOYSA-N 0.000 description 1
- 206010029897 Obsessive thoughts Diseases 0.000 description 1
- 206010041250 Social phobia Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 210000000467 autonomic pathway Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960002464 fluoxetine Drugs 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 208000019906 panic disease Diseases 0.000 description 1
- 229940023488 pill Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 1
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 1
- 229960002073 sertraline Drugs 0.000 description 1
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
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- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a paroxetine liensinine freeze-dried powder, which is prepared from the following raw materials: 22 g of paroxetine, 16 g of tartaric acid, 8 g of citric acid, 48 g of polyethylene glycol 800, and 2000 ml of water for injection. The pH is adjusted to the range from 6.6 to 6.8.
Description
Technical field
The present invention relates to paroxetine freeze-dried powder and preparation method thereof.Background technology
Paroxetine (-) 2paroxetine, be that U.S. Glaxo Smith Kline company develops, and in the anti-depression drug of approval listing in 1992, usually used as medicinal application is its hydrochlorate.Paroxetine can make 5-hydroxy tryptamine in synaptic space (5-HT) Enrichment, the performance antidepressant effect, to other Neurotransmitters a little less than, less on the unify impact of cardiovascular system of autonomic nerve system, be selectivity nervus centralis 52 hydroxytryptamines (52HT) reuptake inhibitors (SSRI).Be mainly used in clinically Cure of depression, also can treat the diseases such as obsession, panic disorder or social anxiety disorder.At present, it and fluoxetine, Sertraline be called the large anti-depression drug in the world three.The dosage form of paroxetine is mainly tablet, micropill at present.CN1568987A discloses a kind of paroxetine drop pill, and CN102525966A discloses a kind of paroxetine tablet.
For the needs being more suitable for the patient aspect dosage form, except oral tablet, also need to develop other dosage forms.But the dissolubility of paroxetine in a lot of solvents is low, make the purpose that changes dosage form be difficult to reach.
Summary of the invention
The invention provides a kind of stable paroxetine freeze-dried powder and preparation method thereof, described paroxetine freeze-dried powder adjuvant is less, good stability, and clinical safety in utilization is higher.
Technical scheme provided by the invention is: the paroxetine freeze-dried powder, by following raw material, made: 22g paroxetine, 16g tartaric acid, 8g citric acid, 48g Polyethylene Glycol 800,2000ml water for injection; Adjust pH to 6.6～6.8.
Its mesotartaric acid and citric acid have also played the effect of antioxidant when playing cosolvent.
The present invention also provides the preparation method of above-mentioned paroxetine freeze-dried powder:
1, get tartaric acid and the citric acid of recipe quantity, add the water for injection of 50% amount, be heated to 50～55 ℃, stir it is dissolved, the paroxetine of getting recipe quantity adds in solution, after stirring and dissolving, continues to stir 15 minutes.
2, get the Polyethylene Glycol 800 of recipe quantity, add the water for injection of 40% amount, stir 15 minutes, with hydrochloric acid (the preferably hydrochloric acid of 1mol/L), adjust PH to 3.0～3.5.
3,1,2 solution are merged, with PH regulator (the preferably sodium hydroxide solution of 1mol/L), adjust PH to 6.6～6.8, add to the full amount of water for injection, add 0.15% needle-use activated carbon, stir 25 minutes, filter decarburization, intermediate checks, qualified rear use 0.22 μ m membrane filtration degerming.
4, filtrate is poured in cillin bottle, carry out lyophilization, obtain freeze-dried powder, after the assay was approved, packing.
The inventor finds amazedly, the tartaric acid of use specified quantitative and the combination of citric acid are as cosolvent, and the use Polyethylene Glycol 800 of specified quantitative rather than the Polyethylene Glycol of other molecular weight are as frozen-dried supporting agent, the paroxetine lyophilized injectable powder stability prepared is high, and its related substances is few.And paroxetine freeze-dried powder adjuvant of the present invention is less, good stability, clinical safety in utilization is higher.
The specific embodiment
Below test further illustrates the present invention:
the investigation of cosolvent
The dissolving of paroxetine needs acid cosolvent, and we are investigated several cosolvents.Respectively getting the 1g paroxetine adds in the 200ml water that is 6.6～6.8 left and right with various cosolvents tune pH values respectively in advance.Place 10 days at 60 ℃, investigate the variation of paroxetine content, the results are shown in Table 1:
Table 1
The result of the test surface, place after 10 days for 60 ℃, and the paroxetine content that various cosolvents dissolve has obvious decline, but it is obviously less to do the sample size decline of cosolvent by tartaric acid and citric acid composition.
Further the tartaric acid of our unexpected discovery specified quantitative of research and the quality stability of using improving paroxetine of combining of citric acid and Polyethylene Glycol 800 have played beyond thought remarkable result.
Embodiment 1:
Paroxetine: 22g
Tartaric acid and citric acid: 16g tartaric acid+8g citric acid
Polyethylene Glycol 800:48g
PH regulator: appropriate
Water for injection: 2000ml
Technique:
1, get tartaric acid and the citric acid of recipe quantity, add 50% water for injection, be heated to 50～55 ℃, stir it is dissolved, the paroxetine of getting recipe quantity adds in solution, after stirring and dissolving, continues to stir 15 minutes.
2, get the Polyethylene Glycol 800 of recipe quantity, add 40% water for injection, stir 15 minutes, with hydrochloric acid, adjust pH to 3.0～3.5.
3,1,2 solution are merged, by pH adjusting agent (sodium hydroxide solution), adjust pH to 6.6～6.8, add to the full amount of water for injection, add 0.15% needle-use activated carbon, stir 25 minutes, filter decarburization, the intermediate inspection, qualified rear use 0.22 μ m membrane filtration degerming, filtrate is poured in cillin bottle, carry out lyophilization, obtain freeze-dried powder, after the assay was approved, packing.
Comparative examples 1:
Paroxetine: 22g
Tartaric acid and citric acid: 16g tartaric acid+8g citric acid
PH regulator: appropriate
Water for injection: 2000ml
Technique:
1, get tartaric acid and the citric acid of recipe quantity, add 80% water for injection, be heated to 50～55 ℃, stir it is dissolved, the paroxetine of getting recipe quantity adds in solution, after stirring and dissolving, continues to stir 15 minutes.
2, adjust PH to 6.6～6.8 by pH adjusting agent (sodium hydroxide solution), add to the full amount of water for injection, add 0.15% needle-use activated carbon, stir 25 minutes, filter decarburization, the intermediate inspection, qualified rear use 0.22 μ m membrane filtration degerming, pour into filtrate in cillin bottle, carry out lyophilization, obtain freeze-dried powder, after the assay was approved, packing.
Comparative examples 2:
Paroxetine: 22g
Polyethylene Glycol 800:48g
PH adjusting agent: appropriate
Water for injection: 2000ml
Technique:
1, get the Polyethylene Glycol 800 of recipe quantity, add 80% water for injection, stir 15 minutes, with hydrochloric acid, adjust pH to 3.0～3.5.The paroxetine of getting recipe quantity adds in solution, after stirring and dissolving, continues to stir 15 minutes.
2, adjust PH to 6.6～6.8 by pH adjusting agent (sodium hydroxide solution), add to the full amount of water for injection, add 0.15% needle-use activated carbon, stir 25 minutes, filter decarburization, the intermediate inspection, qualified rear use 0.22 μ m membrane filtration degerming, pour into filtrate in cillin bottle, carry out lyophilization, obtain freeze-dried powder, after the assay was approved, packing.
Comparative examples 3:
Paroxetine: 22g
Tartaric acid and citric acid: 16g tartaric acid+8g citric acid
Polyethylene glycol 6000: 48g
PH regulator: appropriate
Water for injection: 2000ml
Technique:
1, get tartaric acid and the citric acid of recipe quantity, add 50% water for injection, be heated to 50～55 ℃, stir it is dissolved, the paroxetine of getting recipe quantity adds in solution, after stirring and dissolving, continues to stir 15 minutes.
2, get the polyethylene glycol 6000 of recipe quantity, add 40% water for injection, stir 15 minutes, with hydrochloric acid, adjust pH to 3.0～3.5.
3,1,2 solution are merged, by pH adjusting agent (sodium hydroxide solution), adjust pH to 6.6～6.8, add to the full amount of water for injection, add 0.15% needle-use activated carbon, stir 25 minutes, filter decarburization, the intermediate inspection, qualified rear use 0.22 μ m membrane filtration degerming, filtrate is poured in cillin bottle, carry out lyophilization, obtain freeze-dried powder, after the assay was approved, packing.
Comparative examples 4:
Paroxetine: 22g
Tartaric acid: 24g
Polyethylene Glycol 800:48g
PH regulator: appropriate
Water for injection: 2000ml
Technique:
1, get the tartaric acid of recipe quantity, add 50% water for injection, be heated to 50～55 ℃, stir it is dissolved, the paroxetine of getting recipe quantity adds in solution, after stirring and dissolving, continues to stir 15 minutes.
2, get the Polyethylene Glycol 800 of recipe quantity, add 40% water for injection, stir 15 minutes, with hydrochloric acid, adjust pH to 3.0～3.5.
3,1,2 solution are merged, by pH adjusting agent (sodium hydroxide solution), adjust pH to 6.6～6.8, add to the full amount of water for injection, add 0.15% needle-use activated carbon, stir 25 minutes, filter decarburization, the intermediate inspection, qualified rear use 0.22 μ m membrane filtration degerming, filtrate is poured in cillin bottle, carry out lyophilization, obtain freeze-dried powder, after the assay was approved, packing.
Comparative examples 5:
Paroxetine: 22g
Lactic acid: 24g
Polyethylene Glycol 800:48g
PH regulator: appropriate
Water for injection: 2000ml
Technique:
1, get the tartaric acid of recipe quantity, add 50% water for injection, be heated to 50～55 ℃, stir it is dissolved, the paroxetine of getting recipe quantity adds in solution, after stirring and dissolving, continues to stir 15 minutes.
2, get the Polyethylene Glycol 800 of recipe quantity, add 40% water for injection, stir 15 minutes, with hydrochloric acid, adjust pH to 3.0～3.5.
3,1,2 solution are merged, by pH adjusting agent (sodium hydroxide solution), adjust pH to 6.6～6.8, add to the full amount of water for injection, add 0.15% needle-use activated carbon, stir 25 minutes, filter decarburization, the intermediate inspection, qualified rear use 0.22 μ m membrane filtration degerming, filtrate is poured in cillin bottle, carry out lyophilization, obtain freeze-dried powder, after the assay was approved, packing.
Comparative examples 6:
Paroxetine: 15g
Tartaric acid and citric acid: 5g tartaric acid+15g citric acid
Polyethylene Glycol 800:30g
PH regulator: appropriate
Water for injection: 2000ml
Technique:
1, get tartaric acid and the citric acid of recipe quantity, add 50% water for injection, be heated to 50～55 ℃, stir it is dissolved, the paroxetine of getting recipe quantity adds in solution, after stirring and dissolving, continues to stir 15 minutes.
2, get the Polyethylene Glycol 800 of recipe quantity, add 40% water for injection, stir 15 minutes, with hydrochloric acid, adjust pH to 3.0～3.5.
3,1,2 solution are merged, by pH adjusting agent (sodium hydroxide solution), adjust pH to 6.6～6.8, add to the full amount of water for injection, add 0.15% needle-use activated carbon, stir 25 minutes, filter decarburization, the intermediate inspection, qualified rear use 0.22 μ m membrane filtration degerming, filtrate is poured in cillin bottle, carry out lyophilization, obtain freeze-dried powder, after the assay was approved, packing.
The product that above-mentioned 7 embodiment are made is positioned in 60 ℃ of climatic chambers, in sampling calibrating in the 5th, 10 days, and result and comparison in 0 day:
Related substance, content are pressed high effective liquid chromatography for measuring (in Table 2).
Table 2
Result shows: embodiment 1 and comparative examples 1-6 compare, and pH, related substance, stable content have obvious advantage, and obvious advantage is used more separately in the use of combining of the tartaric acid of specified quantitative, citric acid and Polyethylene Glycol 800.
Paroxetine freeze-dried powder and the comparative examples 1-6 of the embodiment of the present invention 1 preparation are carried out to long-time stability investigation (25 ℃ ± 2 ℃, RH 60% ± 10%), the results are shown in Table 5:
Table 5
Result shows: paroxetine freeze-dried powder prepared by the present invention (embodiment 1) is compared with comparative examples 1-7, and quality stability increases significantly.
Claims (3)
1. paroxetine freeze-dried powder, wherein active component is paroxetine.
2. paroxetine freeze-dried powder as claimed in claim 1, it is made by following raw material: 22g paroxetine, 16g tartaric acid, 8g citric acid, 48g Polyethylene Glycol 800,2000ml water for injection; Adjust pH to 6.6～6.8.
3. the preparation method of paroxetine freeze-dried powder as claimed in claim 2:
(1) get tartaric acid and the sorbic acid of recipe quantity, add the water for injection of 50% amount, be heated to 50～55 ℃, stir it is dissolved, the paroxetine of getting recipe quantity adds in solution, after stirring and dissolving, continues to stir 15 minutes;
(2) get the Polyethylene Glycol 800 of recipe quantity, add the water for injection of 40% amount, stir 15 minutes, with hydrochloric acid, adjust PH to 3.0～3.5;
(3) 1,2 solution are merged, with the PH regulator, adjust PH to 6.6～6.8, add to the full amount of water for injection, add 0.15% needle-use activated carbon, stir 25 minutes, filter decarburization, intermediate inspection, qualified rear use 0.22 μ m membrane filtration degerming;
(4) filtrate is poured in cillin bottle, carry out lyophilization, obtain freeze-dried powder, after the assay was approved, packing.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310420340.5A CN103446066B (en) | 2013-09-16 | 2013-09-16 | Paroxetine liensinine freeze-dried powder and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310420340.5A CN103446066B (en) | 2013-09-16 | 2013-09-16 | Paroxetine liensinine freeze-dried powder and preparation method thereof |
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| CN103446066B CN103446066B (en) | 2014-12-24 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1809355A (en) * | 2003-04-17 | 2006-07-26 | 葛兰素集团有限公司 | Combinations comprising paroxetine and 2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoro-2-methyl-phenyl)-ethyl]-methyl amide for treatment of depression and/or a |
| US20090227682A1 (en) * | 2008-03-04 | 2009-09-10 | Pharma Pass Ii Llc | Xetine compositions |
-
2013
- 2013-09-16 CN CN201310420340.5A patent/CN103446066B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1809355A (en) * | 2003-04-17 | 2006-07-26 | 葛兰素集团有限公司 | Combinations comprising paroxetine and 2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoro-2-methyl-phenyl)-ethyl]-methyl amide for treatment of depression and/or a |
| US20090227682A1 (en) * | 2008-03-04 | 2009-09-10 | Pharma Pass Ii Llc | Xetine compositions |
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