CN104297366A - Liquid phase analysis method of maleic acid asenapine and impurities thereof - Google Patents
Liquid phase analysis method of maleic acid asenapine and impurities thereof Download PDFInfo
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- CN104297366A CN104297366A CN201410492993.9A CN201410492993A CN104297366A CN 104297366 A CN104297366 A CN 104297366A CN 201410492993 A CN201410492993 A CN 201410492993A CN 104297366 A CN104297366 A CN 104297366A
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- CN
- China
- Prior art keywords
- maleic acid
- separating
- buffer salt
- acid asenapine
- asenapine
- Prior art date
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- VSWBSWWIRNCQIJ-GJZGRUSLSA-N (R,R)-asenapine Chemical compound O1C2=CC=CC=C2[C@@H]2CN(C)C[C@H]2C2=CC(Cl)=CC=C21 VSWBSWWIRNCQIJ-GJZGRUSLSA-N 0.000 title claims abstract description 53
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 title claims abstract description 53
- 229960005245 asenapine Drugs 0.000 title claims abstract description 53
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 title claims abstract description 53
- 239000011976 maleic acid Substances 0.000 title claims abstract description 53
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title claims abstract description 53
- 239000012535 impurity Substances 0.000 title claims abstract description 38
- 239000007791 liquid phase Substances 0.000 title description 5
- 238000004458 analytical method Methods 0.000 title description 3
- 238000000034 method Methods 0.000 claims abstract description 24
- 239000012071 phase Substances 0.000 claims abstract description 19
- 239000000337 buffer salt Substances 0.000 claims abstract description 13
- 239000012074 organic phase Substances 0.000 claims abstract description 7
- 238000004811 liquid chromatography Methods 0.000 claims abstract description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000000945 filler Substances 0.000 claims abstract description 4
- FPLYNRPOIZEADP-UHFFFAOYSA-N octylsilane Chemical group CCCCCCCC[SiH3] FPLYNRPOIZEADP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000000741 silica gel Substances 0.000 claims abstract description 4
- 229910002027 silica gel Inorganic materials 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 9
- 239000000523 sample Substances 0.000 claims description 7
- 239000012488 sample solution Substances 0.000 claims description 7
- 238000000926 separation method Methods 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 238000004090 dissolution Methods 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 5
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- 150000004675 formic acid derivatives Chemical class 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 238000013016 damping Methods 0.000 claims 1
- 239000012530 fluid Substances 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- CUFNKYGDVFVPHO-UHFFFAOYSA-N azulene Chemical compound C1=CC=CC2=CC=CC2=C1 CUFNKYGDVFVPHO-UHFFFAOYSA-N 0.000 description 8
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 8
- 235000019796 monopotassium phosphate Nutrition 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 230000014759 maintenance of location Effects 0.000 description 6
- 238000010828 elution Methods 0.000 description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000008055 phosphate buffer solution Substances 0.000 description 4
- 238000005070 sampling Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000003908 quality control method Methods 0.000 description 3
- YXCPDVDLUQEPKX-UHFFFAOYSA-N 2h-azulen-1-one Chemical compound C1=CC=CC=C2C(=O)CC=C21 YXCPDVDLUQEPKX-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- GMDCDXMAFMEDAG-CHHFXETESA-N (S,S)-asenapine maleate Chemical compound OC(=O)\C=C/C(O)=O.O1C2=CC=CC=C2[C@H]2CN(C)C[C@@H]2C2=CC(Cl)=CC=C21 GMDCDXMAFMEDAG-CHHFXETESA-N 0.000 description 1
- 208000020925 Bipolar disease Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000008451 emotion Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
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- Investigating Or Analysing Biological Materials (AREA)
- Treatment Of Liquids With Adsorbents In General (AREA)
Abstract
The invention belongs to the field of analytical chemistry and discloses a method for separating and determining maleic acid asenapine and impurities thereof by a liquid chromatography. The method adopts a chromatographic column taking octyl silane bonded silica gel as a filler, buffer salt solution-organic phase with certain proportion is used as a moving phase, the contents of the maleic acid asenapine and the impurities thereof can be quantitatively determined, and the quality of the maleic acid asenapine can be effectively controlled. The method has strong specificity, high accuracy and convenience in operation.
Description
Technical field
The invention belongs to analytical chemistry field, be specifically related to the method for liquid chromatography separation determination maleic acid asenapine and impurity thereof.
Background technology
Maleic acid asenapine be used for acute manic disorder or with/without the two-way disturbance of emotion of type of mental illness.Maleic acid asenapine chemistry is by name
(3aRS, 12bRS)-5-Chloro-2-methyl-2,3,3a, 12b-tetrahydro-1
h-dibenzo [2,3:6,7] oxepino [4,5-c] pyrrole (2Z)-2-butenedioate (1:1), molecular formula is C
21h
20clNO
5.Maleic acid asenapine structural formula is:
In the process of this compound of synthesis, some important intermediate may be removed not exclusively, and in the process of transporting and storing this compound, also may produce degradation impurity, these remove incomplete intermediate and degradation impurity can affect pharmaceutical purity and quality.Need the impurity controlled to have 7 for maleic acid asenapine, be respectively impurity 1 ((
10S, 11S)-8-Chloro-11-methylamino-10,11-dihydro-dibenzo [
b,f] oxepine-10-carboxylic acid), impurity 2 ((
3aS, 12bS) 2-Methyl-2,3,3a, 12b-tetrahydro-1-
h-8-oxa-2-aza-dibenzo [
e,h] azulene), impurity 3 ((
3aR, 12bS)-5-Chloro-2-methyl-2,3,3a, 12b-tetrahydro-1
h-8-oxa-2-aza-dibenzo-[
e,h] azulene), impurity 4 ((
3aS, 12bS)-5-Chloro-2,3,3a, 12b-tetrahydro-1
h-8-oxa-2-aza-dibenzo [
e,h] azulene), impurity 5 ((
3aS, 12bS)-5-Chloro-2-hydroxy-2-methyl-2,3,3a, 12b-tetrahydro-1
h-8-oxa-2-azonia-dibenzo-[
e,h] azulene), impurity 6 ((
3aS, 12bS)-11-Chloro-2-methyl-2,3,3a, 12b-tetrahydro-8-oxa-2-aza-dibenzo [
e,h] azulen-1-one), impurity 7((
3aS, 12bR) 11-Chloro-2-methyl-2,3,3a, 12b-tetrahydro-8-oxa-2-aza-dibenzo [
e,h] azulen-1-one), structural formula is respectively:
。
For the impurity introduced in synthesis, transport and storage maleic acid asenapine process, need to carry out quality control in bulk drug, therefore, realize the separation of maleic acid asenapine and impurity thereof, have important practical significance in the quality control of maleic acid asenapine.
Summary of the invention
The object of the present invention is to provide and a kind ofly analyze maleic acid asenapine purity and be separated the method for its impurity, thus realize the separated island form of maleic acid asenapine and its impurity, thus ensure the purity of maleic acid asenapine, realize the quality control of its finished product bulk drug.
The purity of liquid chromatography analysis maleic acid asenapine of the present invention and be separated the method for its impurity adopts octyl silane group silica gel to be the chromatographic column of filler, with a certain proportion of buffer salt solution-organic phase for mobile phase.
Above-mentioned said chromatographic column for filler, is selected from Apollo C with octyl silane group silica gel
8.
Above-mentioned said organic phase is selected from following compound: methyl alcohol, acetonitrile, propyl alcohol, isopropyl alcohol, is preferably methyl alcohol.
Above-mentioned said method, its mobile phase buffer salt solution-organic phase adopts gradient elution.
In above-mentioned said method, buffer salt solution is selected from phosphate, formates, acetate, citrate, preferably phosphate.
The buffer salinity wherein comprised in buffer salt solution is 0.01 ~ 0.1mol/L, and preferred concentration is 0.02mol/L.
Method of separating and assaying of the present invention, can realize in accordance with the following methods:
1) get maleic acid asenapine sample appropriate, by methyl alcohol or mobile phase sample dissolution, be mixed with the sample solution of every 1mL containing maleic acid asenapine 0.1 ~ 1.5mg;
2) arranging flow rate of mobile phase is 0.5 ~ 1.5mL/min, the preferred 1.0mL/min of flow rate of mobile phase, and determined wavelength is 210 ~ 250nm, the preferred 220nm of determined wavelength, and column oven temperature is 20 ~ 50 DEG C, column oven temperature preferably 25 DEG C;
3) get 1) sample solution 10 ~ 50 μ L, injection liquid chromatography, completes the separation determination of maleic acid asenapine and its impurity.
Wherein:
The model of high performance liquid chromatograph, has no special requirements, and the chromatograph that the present invention adopts is Shimadzu: LC-20AT, CBM-20A, SIL-20AC, SPD-M20A, CTO-10ASvp
Chromatographic column: C
8(Apollo, 250 × 4.6mm, 5 μm)
Mobile phase: A:0.02mol/L potassium dihydrogen phosphate buffer solution (take potassium dihydrogen phosphate 2.72g, be dissolved in water and be settled to 1000mL, with phosphoric acid,diluted adjust pH to 3.5); B: methyl alcohol; Adopt gradient elution;
Flow velocity: 1.0mL/min
Determined wavelength: 220nm
Column temperature: 25 DEG C
Sampling volume: 10 μ L.
The present invention adopts C
8(Apollo, 250 × 4.6mm, 5 μm), can effectively be separated maleic acid asenapine and impurity thereof.The invention solves the separation determination problem of maleic acid asenapine and impurity thereof, thus ensure that the quality controllable of maleic acid asenapine bulk drug.
Accompanying drawing explanation
When Fig. 1 is embodiment 1, solvent HPLC schemes;
When Fig. 2 is embodiment 1, maleic acid asenapine and impurity HPLC thereof scheme;
When Fig. 3 is embodiment 1, maleic acid asenapine HPLC schemes;
When Fig. 4 is embodiment 2, maleic acid asenapine and impurity HPLC thereof scheme;
When Fig. 5 is embodiment 2, maleic acid asenapine HPLC schemes;
When Fig. 6 is embodiment 3, maleic acid asenapine and impurity HPLC thereof scheme;
The HPLC figure of maleic acid asenapine when Fig. 7 is embodiment 3.
Embodiment
Following examples are used for understanding the present invention further, but are not limited to the scope of this enforcement.
Embodiment 1
Instrument and condition:
High performance liquid chromatograph: Shimadzu: LC-20AT, CBM-20A, SIL-20AC, SPD-M20A, CTO-10ASvp;
Chromatographic column: C
8(Apollo, 250 × 4.6mm, 5 μm)
Mobile phase: A phase: 0.02mol/L potassium dihydrogen phosphate buffer solution (claim potassium dihydrogen phosphate 2.72g, be dissolved in water and be settled to 1000mL, with phosphoric acid,diluted adjust pH to 3.5), B phase: acetonitrile, adopts gradient elution;
| T(min) | 0 | 35 | 65 | 75 | 80 | 90 |
| B% | 23 | 30 | 60 | 60 | 23 | 23 |
Flow velocity: 1.0mL/min
Determined wavelength: 220nm
Column temperature: 25 DEG C
Sampling volume: 10 μ L.
Experimental procedure:
Get maleic acid asenapine and impurity thereof appropriate, use acetonitrile sample dissolution respectively, be mixed with the sample solution being about 0.5mg/mL containing maleic acid asenapine and impurity thereof; Separately get acetonitrile in right amount as blank solvent.Efficient liquid phase chromatographic analysis is carried out, record chromatogram by above-mentioned condition.The results are shown in accompanying drawing 1 ~ 3, Fig. 1 is solvent chromatogram; In Fig. 2, the chromatographic peak of retention time 39.435min is maleic acid asenapine, and all the other chromatographic peaks are the chromatographic peak of each impurity of maleic acid asenapine; In Fig. 3, the chromatographic peak of retention time 39.343min is maleic acid asenapine.
Embodiment 2
Instrument and condition:
High performance liquid chromatograph: Shimadzu: LC-20AT, CBM-20A, SIL-20AC, SPD-M20A, CTO-10ASvp;
Chromatographic column: C
8(Apollo, 250 × 4.6mm, 5 μm)
Mobile phase: A phase: 0.02mol/L potassium dihydrogen phosphate buffer solution (claim potassium dihydrogen phosphate 2.72g, be dissolved in water and be settled to 1000mL, with phosphoric acid,diluted adjust pH to 3.5), B phase: methyl alcohol, adopts gradient elution;
| T(min) | 0 | 30 | 40 | 60 | 61 | 70 |
| B% | 40 | 52 | 70 | 75 | 40 | 40 |
Flow velocity: 1.0mL/min
Determined wavelength: 220nm
Column temperature: 25 DEG C
Sampling volume: 10 μ L.
Experimental procedure:
Get maleic acid asenapine and impurity thereof appropriate, use methyl alcohol sample dissolution respectively, be mixed with the sample solution being about 0.5mg/mL containing maleic acid asenapine and impurity thereof; Separately get methyl alcohol in right amount as blank solvent.Efficient liquid phase chromatographic analysis is carried out, record chromatogram by above-mentioned condition.The chromatographic peak that the results are shown in retention time 27.714min in accompanying drawing 4 ~ 5, Fig. 4 is maleic acid asenapine, and all the other chromatographic peaks are the chromatographic peak of each impurity of maleic acid asenapine; In Fig. 5, retention time is the chromatographic peak of 27.355min is maleic acid asenapine.
Embodiment 3
Instrument and condition:
High performance liquid chromatograph: Shimadzu: LC-20AT, CBM-20A, SIL-20AC, SPD-M20A, CTO-10ASvp;
Chromatographic column: C
8(Apollo, 250 × 4.6mm, 5 μm)
Mobile phase: A phase: 0.02mol/L potassium dihydrogen phosphate buffer solution (claim potassium dihydrogen phosphate 2.72g, be dissolved in water and be settled to 1000mL, with phosphoric acid,diluted adjust pH to 3.5), B phase: methyl alcohol, adopts gradient elution;
| T(min) | 0 | 30 | 40 | 70 | 71 | 80 |
| B% | 40 | 50 | 50 | 75 | 40 | 40 |
Flow velocity: 1.0mL/min
Determined wavelength: 220nm
Column temperature: 25 DEG C
Sampling volume: 10 μ L.
Experimental procedure:
Get maleic acid asenapine and impurity thereof appropriate, use methyl alcohol sample dissolution respectively, be mixed with the sample solution being about 0.5mg/mL containing maleic acid asenapine.Efficient liquid phase chromatographic analysis is carried out, record chromatogram by above-mentioned condition.The results are shown in accompanying drawing 6 ~ 7, in Fig. 6, the chromatographic peak of retention time 28.587min is maleic acid asenapine, and all the other chromatographic peaks are the chromatographic peak of each impurity of maleic acid asenapine, as seen from the figure, maleic acid asenapine and each impurity can reach baseline separation, meet the requirement of Chinese Pharmacopoeia; In Fig. 7, the chromatographic peak of retention time 28.193min is maleic acid asenapine, can find out that maleic acid asenapine can be separated completely with its impurity under this condition.
Fig. 6-Fig. 7 shows: method of the present invention, effectively by maleic acid asenapine and its magazins' layout, and can accurately can carry out detection quantitatively, to calculate the content of maleic acid asenapine, thus effectively control the product quality of maleic acid asenapine.
Claims (10)
1. a method for liquid chromatography separation determination maleic acid asenapine and impurity thereof, is characterized in that: octyl silane group silica gel is the chromatographic column of filler, with a certain proportion of buffer salt solution-organic phase for mobile phase.
2. method of separating and assaying according to claim 1, chromatographic column is selected from the chromatographic column that brand is Apollo, Ultimate and ES.
3. method of separating and assaying according to claim 1, said organic phase is selected from the one in following compound: methyl alcohol, acetonitrile, propyl alcohol, isopropyl alcohol.
4. method of separating and assaying according to claim 3, said organic phase is methyl alcohol or acetonitrile.
5. method of separating and assaying according to claim 1, said buffer salt solution is selected from following buffer salt: phosphate, formates, acetate, citrate.
6. method of separating and assaying according to claim 5, the preferred 0.02mol/L of concentration of contained buffer salt in said buffer salt solution.
7. method of separating and assaying according to claim 5, buffer salt preferably phosphate in said buffer salt solution, the pH value of damping fluid is preferably 3.5.
8. method of separating and assaying according to claim 1, is characterized in that, comprises following step:
1) get maleic acid asenapine sample appropriate, respectively by methyl alcohol or acetonitrile sample dissolution, be mixed with the sample solution that every 1mL contains maleic acid asenapine and intermediate 0.1 ~ 1.5mg thereof;
2) arranging flow rate of mobile phase is 0.5 ~ 1.5mL/min, and determined wavelength is 205 ~ 250nm, and chromatographic column column oven temperature is 20 ~ 40 DEG C;
3) get 1) sample solution 10 ~ 50 μ L, injection liquid chromatography, completes the separation determination of maleic acid asenapine and impurity thereof.
9. method for separating and analyzing according to claim 7, buffer salt preferably phosphoric acid potassium dihydrogen.
10. method for separating and analyzing according to claim 8, step 2) the preferred 1.0mL/min of said flow rate of mobile phase, the preferred 220nm of determined wavelength.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410492993.9A CN104297366A (en) | 2014-09-24 | 2014-09-24 | Liquid phase analysis method of maleic acid asenapine and impurities thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410492993.9A CN104297366A (en) | 2014-09-24 | 2014-09-24 | Liquid phase analysis method of maleic acid asenapine and impurities thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104297366A true CN104297366A (en) | 2015-01-21 |
Family
ID=52317187
Family Applications (1)
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| CN201410492993.9A Pending CN104297366A (en) | 2014-09-24 | 2014-09-24 | Liquid phase analysis method of maleic acid asenapine and impurities thereof |
Country Status (1)
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10898449B2 (en) | 2016-12-20 | 2021-01-26 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| US11033512B2 (en) | 2017-06-26 | 2021-06-15 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer |
| US11337932B2 (en) | 2016-12-20 | 2022-05-24 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene |
| US11648213B2 (en) | 2018-06-20 | 2023-05-16 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| US12329862B2 (en) | 2018-06-20 | 2025-06-17 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10898449B2 (en) | 2016-12-20 | 2021-01-26 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| US10980753B2 (en) | 2016-12-20 | 2021-04-20 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| US11337932B2 (en) | 2016-12-20 | 2022-05-24 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene |
| US12138353B2 (en) | 2016-12-20 | 2024-11-12 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| US11033512B2 (en) | 2017-06-26 | 2021-06-15 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer |
| US11648213B2 (en) | 2018-06-20 | 2023-05-16 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| US12329862B2 (en) | 2018-06-20 | 2025-06-17 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
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Application publication date: 20150121 |