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WO2012038975A2 - Procédé de préparation de maléate de (3ars,12brs)-5-chloro-2-méthyl- 2,3,3a,12b-tétrahydro-1h-dibenzo[2,3:6,7]oxépino[4,5-c]pyrrole et composition pharmaceutique le contenant - Google Patents

Procédé de préparation de maléate de (3ars,12brs)-5-chloro-2-méthyl- 2,3,3a,12b-tétrahydro-1h-dibenzo[2,3:6,7]oxépino[4,5-c]pyrrole et composition pharmaceutique le contenant Download PDF

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Publication number
WO2012038975A2
WO2012038975A2 PCT/IN2011/000648 IN2011000648W WO2012038975A2 WO 2012038975 A2 WO2012038975 A2 WO 2012038975A2 IN 2011000648 W IN2011000648 W IN 2011000648W WO 2012038975 A2 WO2012038975 A2 WO 2012038975A2
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formula
compound
methyl
chloro
oxepino
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WO2012038975A3 (fr
Inventor
Manne Satyanarayana Reddy
Srinivasan Thirumalai Rajan
Sajja Eswaraiah
Elevathingal Nicholas Madhu
Komati Satyanarayana
Peri Seetha Rama Sarma
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MSN Laboratories Pvt Ltd
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MSN Laboratories Pvt Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention relates to an improved process for the preparation of (3a tS , ,12b/?-S)-5-Chloro-2-methyl-2,3,3a, 12b-tetrahydro-lHdibenzo[2,3:6,7]oxepino
  • Formula- 1 Formula- la Asenapine is an antipsychotic drug used for the treatment of schizophrenia and acute mania associated with bipolar disorder. It has an antagonistic activity for dopamine (D 2 receptor) as well as serotonin receptor.
  • the present invention also relates to an improved process for the preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3,6,7]oxepino[4,5c]pyrrol- 1-one compound of formula- 10. Further, the present invention relates to a novel and orally disintegrating sublingual pharmaceutical composition comprising asenapine and its pharmaceutically acceptable salts thereof, and methods of preparing the same. In particular, the invention relates to granulated pharmaceutical composition of asenapine and its salts thereof.
  • Asenapine and its pharmaceutically acceptable salts, specifically asenapine maleate and process for its preparation were disclosed in US 4145434.
  • the disclosed process comprises of reducing 1 l-chloro-2,3-dihydro-2-methyl-lH-dibenz[2,3:6,7] oxepino[4,5-c]pyrrol-l-one with magnesium in methanol/toluene to provide a mixture of desired trans-l l-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7] oxepino [4,5-c]pyrrol-l-one and unwanted cis-1 l-chloro-2,3,3a,12b-tetra1iydro-2-methyl-lH- dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-l-one in 1:4 ratio.
  • the ratio of wanted trans isomer was improved by repeated isomerization of unwanted cis isomer, followed by chromatographic separation with the yield of 38%.
  • the obtained product was reacted with lithium aluminium hydride and aluminium chloride to provide asenapine, which on further reaction with maleic acid provides asenapine maleate.
  • the said process involves chromatographic separation and repeated racemisation and hence not suitable for commercial scale up. The yield and purity of the intermediates and final compounds were also not satisfactory.
  • EP 1710241 Bl also disclosed a process for the preparation of asenapine, which comprises of hydrolyzing a mixture of lactams i.e. trans-1 l-chloro-2,3,3a,12b- tetrahydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-l-one and cis-11-chloro- 2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-l-one or pure cis isomer with strong alkali in alcohol which resulted in formation of a mixture of trans-8-chloro- 10, 11 -dihydro- 11 -[(methylamino)methyl]-dibenz[b,f]oxepin- 10- carboxylic acid and cis-8-chloro- 10, 11 -dihydro- l l-[(methylamin
  • trans isomer was subsequently isolated using methanol-water, which on further cyclization followed by reduction with lithium aluminium hydride provided trans isomer of asenapine with an yield of 62%. It also disclosed the preparation of asenapine from a mixture of cis and trans-5-chloro- 2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7] oxepino[4,5-c] pyrrole-l-one or from cis isomer alone using the same above said process. Eventhough yields are high the said process involves more steps to get the desired compound and hence increases the production time and overall cost.
  • An Orally Disintegrating Tablet was defined as 'solid-dosage form containing medicinal substances which disintegrates rapidly, usually in less than a minute when placed on the tongue.
  • Orally disintegrating pharmaceutical compositions including granules, tablets are convenient oral delivery systems, designed to disintegrate rapidly upon contact with aqueous fluids like water, saliva to form a dispersion which can be swallowed easily.
  • Orally disintegrating pharmaceutical compositions are particularly advantageous for pediatric or geriatric patients, who have difficulty in swallowing conventional tablets or capsules, and for individuals who may not have difficulty in swallowing, but may have an aversion to swallowing conventional tablets or capsules.
  • Orally disintegrating pharmaceutical compositions can be administered without water, they are also convenient oral dosage forms while traveling.
  • US5763476 patent discloses sublingual or buccal pharmaceutical composition of asenapine maleate and a water soluble carrier material like hydrolysed gelatin, mannitol and distill water comprising quickly freeze-drying (Lyophilization) soluble composition.
  • Pharmaceutical compositions disclosed in this patent are produced by using freeze-drying (Lyophilization) process which can disintegrate within 10 seconds in water at 37 0C.
  • Manufacturing process involved in the preparation of sublingual or buccal pharmaceutical composition requires expensive and speciality equipment (Lyophilizer) with increased processing times.
  • As the final dosage form manufactured by using the disclosed process are fragile and hence requires speciality packaging. Increased manufacturing time, requirement of speciality equipment increases the cost of the final product and hence it is not affordable for common needy people.
  • Figure- 1 is a graph showing the result of dissolution test of asenapine in pH 1.2 (0.1N HCl) medium of sublingual tablet in Example-(ii) of the present invention and Saphris [the reference drug].
  • Figure-2 is a graph showing the result of dissolution test of asenapine in pH 4.5 medium of sublingual tablet in Example-(ii) of the present invention and Saphris [the reference drug].
  • Figure-3 is a graph showing the result of dissolution test of asenapine in pH 6.5 medium of sublingual tablet in Example-(ii) of the present invention and Saphris [the reference drug].
  • Figure-4 is a graph showing the result of dissolution test of asenapine in pH 7.4 medium of sublingual tablet in Example-(ii) of the present invention and Saphris [the reference drug].
  • Figure-5 is the PXRD pattern of crystalline form-H of Asenapine maleate compound of formula- la.
  • the first aspect of the present invention is to provide an improved process for the preparation of asenapine compound of formula- 1, which comprising of reducing trans-5-chloro-2,3,3a, 12b-tetrahydro-2-methyl- lH-dibenz[2,3 :6,7]oxepino[4,5- c]pyrrol-l-one, compound of formula- 10 with a suitable reducing agent in a suitable solvent to provide compound of formula- 1.
  • the second aspect of the present invention is to provide an improved process for the preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz[2,3:6,7] oxepino[4,5-c]pyrrol-l-one compound of formula- 10, which comprising of reducing 5-chloro-2,3-dihydro-2-methyl-lH- dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-l-one compound of formula-9 with a suitable reducing agent in a suitable solvent followed by recrystallization from a suitable solvent to provide compound of formula- 10.
  • the third aspect of the present invention is to provide an improved process for the preparation of asenapine maleate salt compound of formula- la, which comprising of the following steps;
  • the fourth aspect of the present invention is to provide an improved process for the preparation of asenapine maleate salt compound of formula- la, which comprising of the following steps;
  • the fifth aspect of the present invention is to provide stable crystalline form-H of asenapine maleate.
  • the sixth aspect of the present invention is to provide novel amine salts of 2-(2- (4-chlorophenoxy)phenyl)acetic acid and process for their preparation.
  • the seventh aspect of the present invention is to provide an improved process for the preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz [2,3,6,7] oxepino[4,5-c]pyrrol-l-one compound of formula-10, which comprising of, a) Suspending a mixture of cis-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz[2,3,6,7] oxepino[4,5-c]pyrrol-l-one compound of formula- 11 and 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU) in a suitable inert solvent, and heating the reaction mixture at a suitable temperature for a suitable period of time, b) distilling off the solvent to provide a residue,
  • DBU 1,8- Diazabicyclo[5.4.0]undec-7-ene
  • step-b) adding isopropyl alcohol to the residue obtained in step-b) and heating the suspension to high temperature to get a clear solution
  • step-e distilling off the solvent from the filtrate obtained in step-e), to provide trans-5- chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3,6,7]oxepino[4,5-c]pyrrol- 1-one compound of formula- 10.
  • the eighth aspect of the present invention is to provide an improved process for the preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3,6,7] oxepino[4,5-c]pyrrol-l-one compound of formula- 10, which comprising of,
  • step-b) adding a suitable solvent selected from methyl tertiarybutyl ether, hexane, heptane, cyclohexane, diethyl ether, diisopropyl ether, petroleum ether to the residue obtained in step-b) and heating the suspension to high temperature to get a clear solution,
  • a suitable solvent selected from methyl tertiarybutyl ether, hexane, heptane, cyclohexane, diethyl ether, diisopropyl ether, petroleum ether
  • the ninth aspect of the present invention is to provide a process for the preparation of trans-5-chloro-2,3 ,3 a, 12b-tetrahydro-2 -methyl- 1 H-dibenz[2,3,6,7] oxepino[4,5-c] pyrrol- 1 -one compound of formula- 10, which comprising of,
  • step-b) adding isopropyl alcohol to the residue obtained in step-b) and heating the suspension to higher temperature
  • the tenth aspect of the present invention is to provide a process for the preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3,6,7] oxepino[4,5-c] pyrrol- 1 -one compound of formula- 10, which comprising of;
  • step-c) distilling off the solvent from the filtrate obtained in step-c) to provide trans-5- chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3,6,7]oxepino[4,5-c]pyrrol- 1-one compound of formula- 10.
  • the eleventh aspect of the present invention is to provide a process for the preparation of cis-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3,6,7] oxepino [4,5-c]pyrrol-l-one compound of formula- 11, which comprising of, a) Reacting 5-Chloro-2,3-dihydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c] pyrrol- 1 -one compound of formula-9 with magnesium in presence of catalytic amount of iodine in methanol,
  • step-a) concentrating the solvent from the mixture obtained in step-a) and adding appropriate amount of isopropyl alcohol to the concentrate to precipitate cis-5- chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3,6,7]oxepino[4,5-c]pyrrol- 1-one compound of formula- 11 as a solid,
  • the twelfth aspect of the present invention is to provide an orally disintegrating pharmaceutical composition
  • an orally disintegrating pharmaceutical composition comprising asenapine or its pharmaceutically acceptable salts thereof, particularly asenapine maleate compound of formula- la as an active ingredient in an amount from about 1% to 30%, preferably 2% to 25% by total weight of the composition.
  • the thirteenth aspect of the present invention is to provide an orally disintegrating pharmaceutical composition comprising asenapine or its pharmaceutically acceptable salts thereof, particularly asenapine maleate, wherein orally disintegrating pharmaceutical composition is an uncoated or coated tablet and the diameter of the tablet ranging from 5 mm to 7 mm.
  • the fourteenth aspect of the present invention is to provide an orally disintegrating tablet comprising asenapine or its pharmaceutically acceptable salts thereof, particularly asenapine maleate having hardness not less than 20 N ( ⁇ 2 kgs).
  • the fifteenth aspect of the present invention is to provide an orally disintegrating tablet comprising asenapine or its pharmaceutically acceptable salts thereof having low friability not more than 0.5%.
  • the sixteenth aspect of the present invention is to provide an orally disintegrating tablet comprising asenapine or its pharmaceutically acceptable salts thereof and having dispersion time in the range of 35-60 seconds.
  • the seventeenth aspect of the present invention is to provide orally disintegrating pharmaceutical composition comprising asenapine or its exammaceutically acceptable salts thereof, wherein orally disintegrating pharmaceutical composition is in the form of granules.
  • the eighteenth aspect of the present invention is to provide a method for producing orally disintegrating pharmaceutical compositions of asenapine maleate by conventional methods known in the art.
  • the method of producing orally disintegrating pharmaceutical compositions comprises direct compression, dry granulation or wet granulation.
  • the nineteenth aspect of the present invention relates to an orally disintegrating pharmaceutical composition having dissolution time from 5 minutes (80% to 90%) to 10 minutes (90% to 100%).
  • suitable solvents are selected from “ester solvents” like ethyl acetate, methyl acetate, isopropyl acetate; “ether solvents” like tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane, pet.
  • hydrocarbon solvents like toluene, xylene, hexane, heptane and cyclohexane
  • polar aprotic solvents like dimethylacetamide, dimethylformamide, dimethyl sulfoxide, acetonitrile
  • ketone solvents like acetone, methyl ethyl ketone, methyl isobutyl ketone
  • alcoholic solvents like methanol, ethanol, n-propanol, isopropanol, n-butanol, and isobutaol
  • chloro solvents like dichloromethane, dichloroethane, carbon tetrachloride, chloroform and ethylene chloride
  • polar solvents like water; and also mixtures there of.
  • orally disintegrating pharmaceutical compositions refers to the ability of a pharmaceutical composition (e.g., granules, a tablet for oral administration) to disintegrate rapidly when contacted with a fluid, particularly an aqueous fluid (e.g.,water, bodily fluids (e.g., saliva), and the like), to form a suspension, slurry or dispersion, which facilitates administration of the contents of the composition (e.g., by forming a suspension, slurry or dispersion, which is easily swallowed).
  • a pharmaceutical composition e.g., granules, a tablet for oral administration
  • a fluid particularly an aqueous fluid (e.g.,water, bodily fluids (e.g., saliva), and the like)
  • a suspension, slurry or dispersion which facilitates administration of the contents of the composition (e.g., by forming a suspension, slurry or dispersion, which is easily swallowed).
  • oral granular formulations such as
  • orally includes the region within the interior of the mouth, including, but not limited to, the buccal cavity (e.g., anterior to the teeth and gums) as well as the sublingual and supralingual spaces, and the like.
  • the diluents are selected from but are not limited to various cellulose derivatives such as microcrystalline cellulose(MCC) and the like, mannitol, lactose, dextrose, sorbitol, starch, xylitol, pearlitol flash, F-Melt, maltose, dicalcium phosphate and their derivatives thereof, and the preferred diluents are microcrystalline cellulose, pearlitol flash and F-Melt.
  • MMCC microcrystalline cellulose
  • the binders are selected from but are not limited to various cellulose derivatives such as low molecularweight hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and the like, methacrylate copolymers, amino alkyl methacrylate copolymers and the like, povidone and the like, sodium alginate and the like, and the preferred binders are hydroxypropylmethyl cellulose , hydroxypropylcellulose and povidone K 30.
  • various cellulose derivatives such as low molecularweight hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and the like, methacrylate copolymers, amino alkyl methacrylate copolymers and the like, povidone and the like, sodium alginate and the like
  • the preferred binders are hydroxypropylmethyl cellulose , hydroxypropylcellulose and povidone K 30.
  • the dintegrants are selected from but are not limited to starch or its derivative like pregelatinised starch, sodium carboxymethyl starch, sodium starch glycolate and the like, various cellulose derivatives like crosslinked sodiumcarboxymethyl cellulose, low substituted hydroxypropylcellulose, croscarmellose calcium and the like, crosspovidone and the like, alginic acid and various ion exchange resins, and the preferred disintegrants are cross linked sodium carboxymethyl cellulose (Ac-di- sol),croscarmellose calcium and crospovidone.
  • the lubricants may be selected from but are not limited to talc, magnesium stearate, calcium stearate, stearic acid,sodium stearyl fumarate and the like, and the preferred lubricants are magnesium stearate, calcium stearate, stearic acid,sodium stearyl fumarate.
  • the sweeteners may be selected form but are not limited to aspartame, acesulfam potassium, sucralose, xylitol, saccharine, saccharine potassium, sugars and the like, and the preferred sweetners are aspartame, sucralose, acesulfam potassium and sugars.
  • the flavors may be for example mint flavors, orange flavor, lemon flavor, banana flavor, strawberry flavor, magnasweet, grape flavor and the like, and the preferred flavouring agents are peppermint flavour, strawberry flavor, magnasweet, grape flavor and black cherry flavor.
  • the suitable coloring agent is selected from brilliant blue, iron oxide red, iron oxide blue, FD&C, D&C lakes, Ti0 2) Talc, Pyrogenic silica, channel black and natural colorants, preferably brilliant blue.
  • binder fluids or solvents are selected from but are not limited to aqueous or non-aqueous or their mixtures thereof, for example may be isopropyl alcohol, acetone and ethanol.
  • compounds represented by structural formulae having a pair of bold and hashed wedged bonds as shown, e.g., in compound of formula- 1 or a pair of bold wedged bonds as shown, e.g., in compound of formula-2 refer to "trans" or "cis" diastereoisomers respectively.
  • Each of the compounds may exist as a single enantiomer having the absolute stereo chemical configuration indicated by the wedged bonds, or having the opposite absolute configuration or as a mixture of enantiomers having the relative stereo chemical configuration indicated by the wedged bonds.
  • the first aspect of the present invention is to provide an improved process for the preparation of asenapine co
  • a suitable reducing agent in a suitable solvent to provide compound of formula- 1 , characterized in that the reducing agent is selected from BF3-etherate/sodium borohydride, lithium aluminium hydride (LAH), vitride, sodium borohydride/ aluminium chloride or borane/aluminium chloride, sodiumborohydride/iodine and 9- BBN.
  • LAH lithium aluminium hydride
  • the second aspect of the present invention provides an improved process for the preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7] oxepino[4,5-c]pyrrol-l-one compound of formula-10, which comprises of reducing 5- chloro-2,3-dihydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-l-one compound of formula-9
  • the suitable reducing agent is selected from magnesium, zinc or iron and the activator is iodine or dibromoethane.
  • the usage of proton donor such as formic acid or acetic acid in the above reduction provides the desired trans-isomer in high ratio compared to the prior art process and hence the present process is more advantageous over the prior art.
  • the third aspect of the present invention is to provide an improved process for the preparation of asenapine maleate compound of formula- la, which comprising of the following steps;
  • R is Q-C 4 alkyl
  • alcohol refers to methanol, ethanol, propanol, isopropanol, butanol, isobutanol, secondary butanol, tertiary butanol, preferably methanol
  • acid is selected from sulfuric acid, para toluene sulfonic acid, methane sulfonic acid and trifluoro aetic acid, preferably sulfuric acid;
  • the suitable base is selected from K 2 C0 3 , Cs 2 C0 3 , preferably Cs 2 C0 3 ;
  • Cu (I) catalyst selected from Cu 2 0, CuX, CuXPPh 3 , CuX(PPh 3 ) 3 , Copper bi pyridyl complexes, (wherein X refers to halogens i.e.
  • CI, Br and I preferably CI
  • CuCl and a ligand selected from Me 4 Phen, l,l,l-tris(hydroxymethyl)ethane, diphenyl glycine, dimethyl glycine, Chxn-Py-Al, 1,10-phenonthroline, preferably dimethylglycine
  • amine is selected from mono, di and trialkyl amine, preferably tributylamine;
  • the suitable reagents is selected from dehydrating agents, like carbodiimides optionally in combination with N-hydroxy benzotriazole or N-hydroxy succinamide, N ⁇ '-diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethyl amino propyl)carbodiimide (EDC), 1-hydroxybenzotriazole (HOBt), l-hydroxy-7-azatriazole (HO At), N-hydroxy succinamide (HOSu), 3-hydroxy-3,4-dihydro-l,2,3-benzotriazin- 4-one, diethyl phosphoraro cyanidate- triethylamine, di phenylphosphoroazidate (DPPA), 3-(diethoxyphosphoryloxy)-l,2,3-benzotriazine-4(3H)-one (DEPBT), 1- hydroxy- lH-1, 2,3 -triazole-4-carboxylate(HOCt), P 2
  • the suitable base is selected from sodium tertiary butoxide, potassium tertiary butoxide, sodium methoxide, preferably potassium tertiary butoxide;
  • step e) the suitable reagent is selected from polyphosphoric acid or P 2 0 5 and phosphoric acid.
  • the usage of a solvent in the cyclisation reaction improves the yield and purity when compared to the prior art
  • the suitable reducing agent is magnesium in presence of an activator, i.e. I 2 or dibromoethane and in the presence of proton donor like formic acid or acetic acid;
  • the suitable reducing agent is selected from BF 3 -etherate and sodium borohydride, vitride, sodium borohydride and aluminium chloride or borane and aluminium chloride, 9-BBN.
  • step h) the suitable solvent is selected from alcoholic solvents like methanol, ethanol, propyl alcohol and isopropyl alcohol, preferably isopropyl alcohol.
  • alcoholic solvents like methanol, ethanol, propyl alcohol and isopropyl alcohol, preferably isopropyl alcohol.
  • the fourth aspect of the present invention is to provide an improved process for the preparation of asenapine maleate salt compound of formula- la, which comprising of the following steps;
  • the fifth aspect of the present invention is to provide stable asenapine maleate crystalline form-H.
  • Asenapine maleate compound of formula- la prepared as per the present invention is stable and the crystalline characteristics are well matches with the known crystalline form H of asenapine maleate.
  • the crystalline form H of asenapine maleate is not stable during micronisation and converted into crystalline form-L or mixture of form-L and form-H.
  • asenapine maleate prepared as per the present invention is stable even after micronisation and does not converted in to crystalline form-L during micronisation or its storage after micronisation.
  • the following table shows the stability of asenapine maleate of the present invention before micronisation, after micronisation and during storage of the same. And the stability data generated for 10 kg scale-up batch is given below:
  • the present invention further provides a process for the preparation of stable form-H of asenapine maleate, which comprises of the following steps:
  • the sixth aspect of the present invention is to provide novel amine salts of 2-(2 (4-chlorophenoxy)phenyl)acetic acid represented by the following structural formula,
  • amine is selected from mono, di and trialkyl amine, preferably methyl amine, ethyl amine, n-propyl amine, isopropyl amine, n-butyl amine, isobutyl amine, sec-butyl amine, tertiarybutyl amine, dimethyl amine, diethyl amine, di(n-propyl)amine, di(isopropyl)amine, di(n-butyl)amine, di(isobutyl)amine, di(sec-butyl)amine, di(tertiarybutyl)amine, trimethyl amine, triethyl amine, tri(n-propyl)amine, tri(isopropyl)amine, tri(n-butyl)amine, tri(isobutyl)amine, tri(sec-butyl)amine, tri(tertiarybutyl)amine, most preferably tri(n-butyl) amine.
  • the present invention provides a process for the preparation of novel amine salts of 2-(2-(4-chlorophenoxy)phenyl)acetic acid salt compound of general formula-5, which comprises of reacting the 2-(2-(4-chlorophenoxy)phenyl)acetic acid with a suitable amine as discussed above in a suitable solvent and isolating the corresponding salt compound of formula-5 in a convenient manner.
  • the seventh aspect of the present invention is to provide an improved process for the preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz [2,3,6,7]oxepino [4,5-c]pyrrol-l-one compound of formula- 10, which comprises of,
  • step-b) adding isopropyl alcohol to the residue obtained in step-b) and heating the suspension to high temperature to get a clear solution
  • the eighth aspect of the present invention is to provide an improved process for the preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3,6,7] oxepino[4,5-c]pyrrol-l-one compound of formula- 10, which comprising of,
  • step-b) adding a suitable solvent selected from methyl tertiarybutyl ether, hexane, heptane, cyclohexane, diethyl ether, diisopropyl ether, petroleum ether to the residue obtained in step-b) and heating the suspension to high temperature to get a clear solution,
  • a suitable solvent selected from methyl tertiarybutyl ether, hexane, heptane, cyclohexane, diethyl ether, diisopropyl ether, petroleum ether
  • step-e distilling off the solvent from the filtrate obtained in step-e), to provide trans-5- chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3,6,7]oxepino[4,5-c]pyrrol- 1-one compound of formula- 10.
  • the ninth aspect of the present invention is to provide a process for the preparation of trans-5-chloro-2,3,3a, 12b-tetrahydro-2 -methyl- 1 H-dibenz[2,3,6,7] oxepino [4,5-c]pyrrol-l-one compound of formula- 10, which comprising of,
  • step-b) adding isopropyl alcohol to the residue obtained in step-b) and heating the suspension to higher temperature
  • the tenth aspect of the present invention is to provide a process for the preparation of trans-5-chloro-2,3 ,3 a, 12b-tetrahydro-2 -methyl- 1 H-dibenz[2,3 ,6,7] oxepino [4,5-c] pyrrol- 1 -one compound of formula- 10, which comprises of;
  • step-c distilling off the solvent from the filtrate obtained in step-c), to provide trans-5- chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3,6,7]oxepino[4,5-c]pyrrol-
  • the solvent used in step-a) is isopropyl alcohol, methyl tertiary butyl ether, hexane, heptane, diethyl ether, di isopropyl ether, cyclohexane and pet. ether.
  • the eleventh aspect of the present invention is to provide a process for the preparation of cis-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz[2,3,6,7] oxepino [4,5-c]pyrrol-l-one compound of formula- 11, which comprising of,
  • step-c) concentrating the organic layer obtained in step-c) and adding an appropriate amount of isopropyl alcohol and concentrate to obtain cis-5-chloro-2,3,3a,12b- tetrahydro-2 -methyl- 1 H-dibenz[2,3,6,7] oxepino[4,5-c]pyrrol- 1 -one compound of formula- 11 as a solid,
  • EP 1710241 discloses a process which involves the reduction of double bond in 1 l-chloro-2,3-dihydro-2-methyl-lH-dibenz[2,3,6,7]oxepino[4,5-c]pyrrol-l-one by treating with magnesium/I 2 in methanol toluene solvent to provide a mixture of required 'trans' isomer and the unwanted 'cis' isomer of 1 l-chloro-2,3,3a,12b- tetrahydro-2-methyl-lH-dibenz[2,3,6,7]oxepino[4,5-c]pyrrol-l-one in a ratio of 1:4 respectively.
  • the trans and cis isomers are separated from the racemic mixture using chromatography over silica gel.
  • the reduction of 5-chloro-2,3-dihydro-2-methyl-lH- dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-l-one compound of formula-9 is carried out using 5-8 equivalents of magnesium/I 2 in methanol providing a mixture 'trans' and 'cis' isomers of 5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz [2,3,6,7] oxepino [4,5- c]pyrrol-l-one in a ratio of around 2:8.
  • the present invention provides a process in which the pure cis isomer is isolated as pure solid without the use of column chromatography.
  • 6,7,8 and 9 of the present invention can be practiced using the l l-chloro-2,3-dihydro-2 -methyl- lH-dibenz[2,3:6,7] oxepino [4,5-c] pyrrol- 1 -one compound of formula- 12, as an input material to prepare 'cis' isomer of 11-chloro- 2,3 ,3 a, 12b-tetrahydro-2-methyl- 1 H-dibenz[2,3 ,6,7]oxepino[4,5-c]pyrrol- 1 -one compound of formula-13 and 'trans' isomer of 1 l-chloro-2,3,3a,12b-tetrahydro-2- methyl-lH-dibenz[2,3,6,7]oxepino[4,5-c] pyrrol- 1 -one compound of formula- 14.
  • the twelfth aspect of the present invention relates to an orally disintegrating pharmaceutical composition
  • an orally disintegrating pharmaceutical composition comprising of, asenapine or its salts in combination with one or more of,
  • an orally disintegrating pharmaceutical composition comprising of, asenapine maleate in an amount from 2% to 25% by total weight of the composition in combination with one or more of,
  • the thirteenth aspect of the present invention provides orally disintegrating pharmaceutical compositions comprising asenapine and pharmaceutically acceptable salts thereof, particularly asenapine maleate, wherein the orally disintegrating pharmaceutical composition (e.g., granules, a tablet for oral administration), particularly in an uncoated or coated tablet form and the diameter of the tablet preferably ranging from 5 mm to 7 mm preferably 6 mm of diameter.
  • the orally disintegrating pharmaceutical composition e.g., granules, a tablet for oral administration
  • the diameter of the tablet preferably ranging from 5 mm to 7 mm preferably 6 mm of diameter.
  • the fourteenth aspect of the present invention refers to hardness of orally disintegrating tablet comprising asenapine or its pharmaceutically acceptable salts thereof, particularly asenapine maleate.
  • Hardness refers to the diametral breaking strength as measured by conventional pharmaceutical tablet hardness determination "methods, which are well known in the art.
  • a higher hardness value, sometimes measured in Newtons (N) and kilograms (kg) the hardness of the tablet of the present invention preferably ranges from about 20 N ( ⁇ 2 kg) to about 50 N ( ⁇ 5 kg), and more preferably from about 35 N ( ⁇ 3.5 kg) to about 45 N ( ⁇ 4.5 kg), and most preferably from about 20 N ( ⁇ 2 kg) to about 40 N ( ⁇ 4 kg).
  • the fifteenth aspect of the present invention provides orally disintegrating tablet comprising asenapine or its pharmaceutically acceptable salts thereof having low friability not more than 1%, preferably 0.8%, more preferably 0.5%.
  • the sixteenth aspect of the present invention provides orally disintegrating sublingual tablet comprising asenapine or its pharmaceutically acceptable salts thereof and having dispersion time of about 35-60 seconds, when contacted with an aqueous fluid (e.g., water, saliva, or a buffered solution), to form a slurry, a dispersion or a suspension, which can be administered (e.g., swallowed) easily.
  • an aqueous fluid e.g., water, saliva, or a buffered solution
  • the dispersion time of the pharmaceutical compositions of the present invention can range from within about 35 seconds to 60 seconds, more preferably from within about 40 seconds to 50 seconds.
  • the seventeenth aspect of the present invention provides orally disintegrating pharmaceutical compositions comprising asenapine or its pharmaceutically acceptable salts thereof, wherein orally disintegrating pharmaceutical composition is in form of granules.
  • the eighteenth aspect of the present invention provides a process for preparation of an oral disintegrating sublingual pharmaceutical composition by wet granulation method comprising;
  • the nineteenth aspect of the present invention relates to orally disintegrating pharmaceutical composition having dissolution time from 5 minutes (80% to 90%) to 10 minutes (90% to 100%).
  • the present invention relates to orally disintegrating pharmaceutical composition
  • pharmaceutical composition comprising asenapine and its pharmaceutically acceptable salts thereof, particularly asenapine maleate is in either crystalline or in amorphous form.
  • impurities which are formed during the preparation of asenapine and its salts. These impurities are identified, synthesized and characterized: (Sa ⁇ S.nb - ⁇ -methyl ⁇ .S ⁇ b-tetrahydro- ' lHdibenzo ⁇ ,?] oxepino[4,5- c]pyrrole herein designated as "deschloroimpurity”; (3a-3 ⁇ 4S , ,12b/3 ⁇ 4S)-5-chloro-2,3,3a,12b- tetrahydro-lHdibenzo[2,3:6,7] oxepino[4,5-c]pyrrole, herein designated as "desmethylimpurity”; (3a&S, 12b J 3 ⁇ 4S)-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro- lHdibenzo[2,3:6,7]oxepino[4,5-c]pyrrole-N-oxide, herein designated
  • Asenap ne ma eate prepare as per t e present nvent on s av ng pur ty than 99% by HPLC and the impurities which are mentioned above are well controlled with in the limits as per the ICH guidelines.
  • Asenapine and its related compounds were analyzed by HPLC using the following conditions: Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector and integrator; Column: Inertsil C8-3, 250 x 4.6 mm, 5 ⁇ or equivalent; Flow rate: 1.0 ml/min; Wavelength: 220 nm; Temperature: 40°C; injection volume : 10 ⁇ L; Run time: 40 minutes; Diluent: Acetonitrile:water (50:50 v/v); Elution: Isocratic; Buffer: 3.48 grams of Dipotassium hydrogen ortho phosphate in 1000 ml of water and added triethylamine, adjust pH to 6.8 with diluted orthophosphoric acid. Filtered this solution through 0.45 um Nylon membrane filter paper and sonicate to degas it.
  • a dispersion liquid has made consisting of (0.7 mg/mL) lecithin (used as surfactant) in iso-octane saturated with asenapine maleate. This solution is stirred over night. Subsequently the solution is filtered over a 0.22/0.45 ⁇ filter. The samples were prepared by weighing approximately 30mg of asenapine maleate in a 25 ml measurable tube and adding 2 ml of the dispersion liquid. Ultrasonic treatment of the samples was performed for 2 minutes in an ultrasonic bath (Hydro2000S). Subsequently, the particle size distribution of the sample was analyzed using laser diffraction (Malvrn Mastersizer2000). The particle sized distribution has been calculated using the Fraunhofer algorithm.
  • the present invention is schematically represented as follows:
  • Potassium carbonate (109 gm) was charged into a clean and dry RBF at below 20°C under N 2 atmosphere. To this toluene (400 ml) and 4-chloro phenol (56.5 gm) were added at the same temperature. To the resulting mixture 0.5 gm of CuCl was added at 20°C and the temperature of the reaction mixture was slowly raised to 100°C. To this 2-chloro phenyl acetic acid (50 gm) was added at 100°C and the obtained mixture was stirred for 1 hr at the same temperature. The reaction mixture was refluxed for 8 hrs at 110°C. K 2 C0 3 (80 gm) was added to the resulting mixture and stirred for 12 hrs at the same temperature. Then the reaction mixture was cooled to room temperature and water (250 ml) was added. The resulting mixture was acidified with HC1 and again
  • Phosphorous pentoxide (90 g) was added to ortho phosphoric acid (90 g) slowly at 140°C and then stirred for 90 minutes at 1 15-120°C.
  • Phosphorous pentoxide (90 g) was added to ortho phosphoric acid (90 g) slowly at 140°C and then stirred for 90 minutes at 115-120°C.
  • Phosphorous pentoxide ( 15 g) and ortho phosphoric acid (7.5 g) was added to the reaction mass. Both the aqueous and organic layers were separated; the organic layer was distilledoff completely.
  • Methanol was added to the reaction mass and stirred for 2 hours at 0-5 °C. Filtered the obtained solid and dried the compound to get the title compound. Yield: 12.8 grams
  • Example-8 Purification process for 5-chIoro-2,3-dihydro-2-methyl-lH-dibenz
  • Example-12 Purification of asenapine maleate (formula-la): Stirred the crude asenapine maleate (45 grams) in ethanol (225 ml) for 15 minutes at 65-70°C and followed by 3 hours at RT. The reaction mass was filtered, washed thrice with ethanol and dried to yield pure asenapine maleate compound of formula- la. Yield: 25.7 gms
  • lithium aluminium hydride solution prepared by dissolving 1.57 gm lithium aluminium hydride in 40 ml of THF at 5-10°C
  • aluminium chloride solution prepared by dissolving aluminium chloride (3.11 gm) in portion wise to THF (40 ml) at below 5°C and stirred for 15 minutes
  • aluminium chloride solution prepared by dissolving aluminium chloride (3.11 gm) in portion wise to THF (40 ml) at below 5°C and stirred for 15 minutes
  • Ethyl acetate 600 ml was added to the reaction mixture and stirred for 30 minutes. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with 10% NaCl solution. Distilled off the solvent completely under reduced pressure. 120 ml of isopropyl alcohol was added to the obtained residue and the reaction mixture was cooled to 0-5°C. Stirred the reaction mixture for 2 hrs at 0-5°C. Filtered the obtained solid, washed with isopropyl alcohol and dried to get the title compound.
  • Example-18 Preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz[2,3,6,7] oxepino[4,5-c]pyrrol-l-one (formuIa-10).
  • Example-20 Preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz [2,3,6,7] oxepino[4,5-c]pyrrol-l-one (formula-10).
  • Example-21 Preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz [2,3,6,7] oxepino[4,5-c]pyrrol-l-one (formula-10).
  • Example-23 Preparation of trans-ll-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz [2,3,6,7] oxepino[4,5-c]pyrrol-l-one (formuIa-14).
  • Example-24 Preparation of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH- dibenz [2,3,6,7] oxepino[4,5-c]pyrrol-l-one (formula-10).
  • To a solution of cis-l l-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz [2,3,6,7]oxepino[4,5-c]pyrrol-l-one compound of formula- 13 15 grams
  • toluene 225 ml
  • DBU 3.8 grams
  • Table- 1 Composition of Tablets equivalent to 10 mg and 5mg of asenapine.
  • Asenapine maleate was mixed with microcrystalline cellulose to get uniform mass. Then povidone taken in isopropyl alcohol was added to the mixture of Asenapine maleate and microcrystalline cellulose to provide granules, which were air dried and and passed through 30 mesh. The mixture of F-Melt, croscarmellose sodium, Aspartame, Peppermint was prepared and passed through 40 mesh. The mixture was then added to the the air dried granules. Magnesium stearate was then passed though 60 mesh and mixed with the above ingredients throughly to get a uniform mass, which was compressed into tablets. Example-(ii):
  • Table-2 Composition of 10 mg asenapine sublingual tablets:
  • Table-4 Composition of Tablets equivalent to 10 mg and 5mg of asenapine.
  • Table-5 Composition of Tablets equivalent to 10 mg and 5mg of asenapine.
  • Asenapine maleate was mixed with microcrystalline cellulose to get uniform mass. Then povidone taken in isopropyl alcohol was added to the mixture of Asenapine maleate and microcrystalline cellulose to provide granules, which were air dried and and passed through 30 mesh. The mixture of Pearlitol flash , croscarmellose sodium, Aspartame, Peppermint was prepared and passed through 40 mesh. The mixture was then added to the the air dried granules. Magnesium stearate was then passed though 60 mesh and mixed with the above ingredients throughly to get a uniform mass, which was compressed into tablets.
  • Table-6 Composition of Tablets equivalent to 10 mg and 5mg of asenapine.
  • Table-7 Composition of 5 mg asenapine sublingual tablets:
  • Asenapine maleate was mixed with macrocrystalline cellulose to get uniform mass. Then PVP K-90 taken in isopropyl alcohol was added to the mixture of Asenapine maleate and microcrystalline cellulose to provide granules, which were air dried and sieved. The mixture of F-Melt, crospovidone, aspartame, peppermint flavour, brilliant blue was prepared and sieved. The mixture was then added to the air dried granules. Magnesium stearate was then sieved and mixed with the above ingredients thoroughly to get a uniform mass, which was compressed into tablets.
  • the sublingual tablets of example (ii) of the present invention were evaluated as per the ICH guide lines.
  • the sublingual tablets were stored at 40°C and 75%RH for 1, 2, 3 & 6 months.
  • the sublingual tablets made in accordance with the present invention displayed excellent stability characteristics under accelerated stability conditions of 40°C/75%RH even after 6 months.
  • Dissolution apparatus USP type-II, 50RPM
  • Dissolution apparatus USP type-II, 50RPM
  • Dissolution apparatus USP type-II, 50RPM
  • Dissolution apparatus USP type-II, 50RPM

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
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Abstract

Cette invention concerne un procédé amélioré de préparation de maléate de (3aRS,12bRS)-5-chloro-2-méthyl-2,3,3a,12b-tétrahydro-1H-dibenzo- [2,3:6,7]oxépino[4,5-c]pyrrole représenté par le composé de formule 1a et une composition pharmaceutique le contenant.
PCT/IN2011/000648 2010-09-22 2011-09-21 Procédé de préparation de maléate de (3ars,12brs)-5-chloro-2-méthyl- 2,3,3a,12b-tétrahydro-1h-dibenzo[2,3:6,7]oxépino[4,5-c]pyrrole et composition pharmaceutique le contenant Ceased WO2012038975A2 (fr)

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IN2766/CHE/2010 2010-09-22
IN2766CH2010 2010-09-22
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IN1719CH2011 2011-05-20
IN1719/CHE/2011 2011-05-20

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CN102746209A (zh) * 2012-06-20 2012-10-24 盛世泰科生物医药技术(苏州)有限公司 一种3-（2-（4-氯苯氧基）苯基）-1-甲基-2,4-二酮的合成方法
WO2012156676A1 (fr) * 2011-05-18 2012-11-22 Laboratorios Lesvi S.L. Forme cristalline monoclinique de maléate d'asénapine présentant une granulométrie spécifique
WO2012156677A1 (fr) * 2011-05-18 2012-11-22 Laboratorios Lesvi S.L. Forme monoclinique micronisée stable de maléate d'asénapine et sa synthèse
WO2013035109A1 (fr) * 2011-09-08 2013-03-14 Mylan Laboratories Ltd Procédé amélioré de préparation de maléate d'asénapine
CN103342707A (zh) * 2013-06-28 2013-10-09 甘肃皓天化学科技有限公司 用于制备阿塞纳平中间体的制备方法
CN103893139A (zh) * 2012-12-28 2014-07-02 石药集团中奇制药技术（石家庄）有限公司 一种阿塞那平组合物及其制备方法
WO2014127786A1 (fr) 2013-02-22 2014-08-28 Zentiva, K.S. Composition pharmaceutique à désintégration orale comprenant de l'asénapine
CN104098580A (zh) * 2014-07-22 2014-10-15 成都百裕科技制药有限公司 一种阿塞那平关键中间体的制备方法
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
JP2022543894A (ja) * 2019-08-13 2022-10-14 チョーチアン オウスン ファーマシューティカル カンパニー リミテッド アセナピンを調製する方法
US11648213B2 (en) 2018-06-20 2023-05-16 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
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CN101175741B (zh) * 2005-04-07 2011-06-22 欧加农股份有限公司 用于制备反式-5-氯-2-甲基-2,3,3a,12b-四氢-1H-二苯并[2,3:6,7]-氧杂䓬并[4,5-C]吡咯的中间体化合物
WO2007046554A1 (fr) * 2005-10-21 2007-04-26 Sumitomo Chemical Company, Limited Procédé pour la production d'un composé de dibenzoxépinopyrrole, intermédiaire pour la production du composé et procédé pour la production de l'intermédiaire
WO2008078482A1 (fr) * 2006-12-22 2008-07-03 Sumitomo Chemical Company, Limited Procédé de fabrication d'un intermédiaire de synthèse de l'asénapine

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WO2012156676A1 (fr) * 2011-05-18 2012-11-22 Laboratorios Lesvi S.L. Forme cristalline monoclinique de maléate d'asénapine présentant une granulométrie spécifique
WO2012156677A1 (fr) * 2011-05-18 2012-11-22 Laboratorios Lesvi S.L. Forme monoclinique micronisée stable de maléate d'asénapine et sa synthèse
US9533994B2 (en) 2011-05-18 2017-01-03 Laboratorios Lesvi S.L. Monoclinic crystalline form of asenapine maleate with a specific particle size distribution
WO2013035109A1 (fr) * 2011-09-08 2013-03-14 Mylan Laboratories Ltd Procédé amélioré de préparation de maléate d'asénapine
CN102746209A (zh) * 2012-06-20 2012-10-24 盛世泰科生物医药技术(苏州)有限公司 一种3-（2-（4-氯苯氧基）苯基）-1-甲基-2,4-二酮的合成方法
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WO2014127786A1 (fr) 2013-02-22 2014-08-28 Zentiva, K.S. Composition pharmaceutique à désintégration orale comprenant de l'asénapine
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CN104098580A (zh) * 2014-07-22 2014-10-15 成都百裕科技制药有限公司 一种阿塞那平关键中间体的制备方法
US12138353B2 (en) 2016-12-20 2024-11-12 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
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
US12485099B2 (en) 2016-12-20 2025-12-02 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
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
EP4015519A4 (fr) * 2019-08-13 2023-07-12 Zhejiang Ausun Pharmaceutical Co., Ltd. Procédé de préparation d'asénapine
US11958858B2 (en) 2019-08-13 2024-04-16 Zhejiang Ausun Pharmaceutical Co., Ltd. Method for preparation of Asenapine
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