WO1995023600A1 - Sublingual or buccal pharmaceutical composition - Google Patents

Sublingual or buccal pharmaceutical composition Download PDF

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Publication number
WO1995023600A1
WO1995023600A1 PCT/EP1995/000765 EP9500765W WO9523600A1 WO 1995023600 A1 WO1995023600 A1 WO 1995023600A1 EP 9500765 W EP9500765 W EP 9500765W WO 9523600 A1 WO9523600 A1 WO 9523600A1
Authority
WO
WIPO (PCT)
Prior art keywords
sublingual
pharmaceutical composition
oxepino
chloro
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP1995/000765
Other languages
English (en)
French (fr)
Inventor
Leonardus Petrus Carla Delbressine
Johannes Hubertus Wieringa
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Akzo Nobel NV
Original Assignee
Akzo Nobel NV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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Priority to DE69502939T priority Critical patent/DE69502939T2/de
Priority to EP95912188A priority patent/EP0746317B1/en
Priority to DK95912188T priority patent/DK0746317T3/da
Priority to JP52270395A priority patent/JP4099224B2/ja
Priority to MXPA/A/1996/003713A priority patent/MXPA96003713A/xx
Priority to KR1019960704774A priority patent/KR100330942B1/ko
Priority to CZ962541A priority patent/CZ284633B6/cs
Priority to PL95316080A priority patent/PL180465B1/pl
Priority to DE201012000050 priority patent/DE122010000050I2/de
Priority to NZ282394A priority patent/NZ282394A/en
Priority to AU19478/95A priority patent/AU692530B2/en
Application filed by Akzo Nobel NV filed Critical Akzo Nobel NV
Priority to US08/693,064 priority patent/US5763476A/en
Priority to BR9506924A priority patent/BR9506924A/pt
Priority to HK98109126A priority patent/HK1008417A1/en
Priority to HU9602383A priority patent/HU225051B1/hu
Priority to RU96120090/14A priority patent/RU2139051C1/ru
Priority to CA002182981A priority patent/CA2182981C/en
Publication of WO1995023600A1 publication Critical patent/WO1995023600A1/en
Priority to FI963398A priority patent/FI117923B/fi
Priority to NO19963639A priority patent/NO308772B1/no
Anticipated expiration legal-status Critical
Priority to LU91751C priority patent/LU91751I2/fr
Priority to NO2010024C priority patent/NO2010024I2/no
Priority to FR10C0056C priority patent/FR10C0056I2/fr
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals

Definitions

  • the invention relates to a sublingual or buccal pharmaceutical composition, and more specifically to a sublingual or buccal composition for the treatment of various mental disorders.
  • Org 5222 [5-chloro-2-methyl- 2,3,3a,12b-tetrahydro-lH-dibenz[2,3:6,7]oxepino[4,5-c]- pyrrole maleate (1:1)] is a very potent dopamine and serotonin antagonist with potential antipsychotic activity.
  • CONFIRMATION COW pyrrole has substantially less cardiovascular side effects.
  • the invention therefore relates to a sublingual or buccal pharmaceutical composition
  • a sublingual or buccal pharmaceutical composition comprising trans-5- chloro-2-methyl-2,3,3a,12b-tetrahydro-lH-dibenz- [2,3:6,7]oxepino[4,5-c]pyrrole or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable auxiliaries suitable for use in sublingual or buccal compositions.
  • compositions of the invention are useful in treating mammals, including humans, suffering from diseases which are susceptible to treatment by trans-5-chloro-2-methyl- 2,3,3a,12b-tetrahydro-lH-dibenz[2,3:6,7]oxepino[4,5-c]- pyrrole.
  • diseases include mental disorders, such as tension, excitation, anxiety, psychosis, and schizo ⁇ phrenia.
  • the compositions may also be used for antihistamine and for antiserotonin related diseases.
  • the pharmaceutical composition of the invention consists of an aqueous solution, for instance comprising 0.9% (w/v) of sodium chloride and the active compound 5-chloro-2-methyl-2,3,3a,12b-tetra- hydro-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole, or a pharmaceutically acceptable salt thereof.
  • the maleate salt (Org 5222) is a preferred salt.
  • the active compound is rapidly absorbed from these aqueous pharmaceutical compositions, when kept under the tongue or in the mouth of a patient.
  • Preferred pharmaceutical compositions are solid pharma ⁇ ceutical compositions which rapidly disintegrate in the mouth of a subject, upon insertion into the buccal pouch or upon placement under the tongue. Rapid disintegration means that the pharmaceutical composition is dis ⁇ integrated within 30 seconds in water at 37 °C, and preferably within 10 seconds, as measured according to the procedure described in Remington's Pharmaceutical Sciences, 18th Edition (Ed. A.R. Genaro) , 1990, pp 1640- 1641; see also US Pharmacopeia, Chapter ⁇ 701>.
  • the pharmaceutical composi ⁇ tions of the invention are tablets or lozenges which comprise a rapidly disintegrating composition of a pharmaceutically acceptable water-soluble or water- dispersable carrier material.
  • Tablets and lozenges comprising a rapidly disintegrating composition of a pharmaceutically acceptable water-soluble or water- dispersable carrier material are known in the art, for example as disclosed in USP 4,371,516.
  • Such tablets may be prepared by freeze-drying of an aqueous solution comprising 5-chloro-2-methyl-2,3,3a,12b-tetrahydro-lH- dibenz[2,3:6,7]oxepino[4,5-c]pyrrole, a water-soluble or water-dispersable carrier material and, optionally, pharmaceutically acceptable excipients.
  • excipients are known in the art, see for instance Remington's Pharmaceutical Sciences, 18th Edition (Ed. A.R. Genaro), 1990, pp 1635-1638, and are commonly used in pharmaceutical compositions, for instance surfactants, colouring agents, flavouring agents, preservatives and the like.
  • the water-soluble or water-dispersable carrier material is preferably water-soluble.
  • Suitable water-soluble carrier materials are (poly)saccharides like hydrolysed dextran, dextrin, mannitol, and alginates, or mixtures thereof, or mixtures thereof with other carrier materials like polyvinylalcohol, polyvinylpyrrolidine and water-soluble cellulose derivatives, like hydroxypropyl cellulose.
  • a preferred carrier material is gelatin, especially partially hydrolysed gelatin.
  • the partially hydrolysed gelatin can be prepared by heating of a solution of gelatin in water, for example in an autoclave at about 120 °C for up to 2 hours.
  • the hydrolysed gelatin is used in concentrations of about 1 to 6 % (w/v) , and preferably in concentrations of about 2 to 4% (w/v).
  • composition of the invention i.e. tablets or lozenges
  • aqueous composition comprising a predetermined amount of 5-chloro-2-methyl-2,3,3a,12b-tetrahydro-lH-dibenz- [2,3:6,7]oxepino[4,5-c]pyrrole, a pharmaceutically acceptable water-soluble or water-dispersable carrier material and optionally pharmaceutically acceptable auxiliaries and excepients, is transferred into a mould, after which the composition is frozen and the solvent is sublimed, preferably by freeze-drying.
  • the composition preferably contains a surfactant, for example Tween 80 (polyoxyethylene (20) sorbitan mono-oleate) , which may help to prevent the freeze-dried product from sticking to the surface of the mould.
  • the mould may comprise a series of cylindrical or other shape depressions, each having a size corresponding to the desired size of the dosage form.
  • the mould may have a larger size than the desired size of the dosage form, and after the contents are freeze-dried the product can be cut into the desired size.
  • the dosage form is freeze-dried in the form of a lyosphere, which is a freeze-dried spherical-shaped droplet containing the active ingredient.
  • a preferred mould would correspond to a depression in a sheet of film material, as for example disclosed in USP 4,305,502 and USP 5,046,618.
  • the film material may be similar to that employed in conventional blister packs.
  • Each dosage form of the pharmaceutical composition of the present invention comprises one dosage unit of 5- chloro-2-methyl-2,3,3a,12b-tetrahydro-lH-dibenz- [2,3:6,7]oxepino[4,5-c]pyrrole as active ingredient.
  • a dosage unit may contain between 0.005 mg and 15 mg of the active ingredient.
  • the dosage unit contains 0.03-0.50 mg of 5-chloro-2-methyl-2,3,3a,12b- tetrahydro-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole.
  • the invention further relates to the use of trans-5- chloro-2-methyl-2,3,3a,12b-tetrahydro-lH-dibenz- [2,3:6,7]oxepino[4,5-c]pyrrole for the manufacture of a sublingual or buccal pharmaceutical composition for treating mental disorders, such as psychosis and schizophrenia.
  • a method of providing therapy using the pharmaceutical composition of the present invention comprises the insertion of a dosage form according to this invention in the buccal pouch or under the tongue of a subject, such as a human.
  • the ultimate dosage to provide relief for the patient depends, apart from individual characteristics, on the patient's weight, condition and age. Usually, administration of 1-4 dosage units of the pharmaceutical composition of the invention per day is sufficient for obtaining a therapeutic effect. The therapy may be continued as long as necessary or desired.
  • Example 1 The invention is further illustrated by the following examples.
  • Example 1 The invention is further illustrated by the following examples.
  • a sheet of polyvinyl chloride (PVC) containing cylindrical depressions was cooled with solid carbon dioxide.
  • 0.2 g of Org 5222 [5-chloro-2-methyl- 2,3,3a,12b-tetrahydro-lH-dibenz[2,3:6,7]oxepino[4,5-c]- pyrrole maleate (1:1)] were dissolved in 1 1 of hydro ⁇ lysed gelatin under mixing. While mixing was continued, in each of the depressions 0.5 ml of the solution were placed. When the contents of the depressions were frozen, the PVC sheet was placed in a freeze-drying system. An aluminum foil was finally sealed to the sheet so as to close off the depressions containing the freeze-dried pharmaceutical dosage forms.
  • Each depression contains a pharmaceutical unit dosage comprising 0.10 mg of 5-chloro-2-methyl-2,3,3a,12b- tetrahydro-lH-dibenz[2,3:6,7]oxepino[4 ,5-c]pyrrole maleate (1:1) .
  • Example lb In a manner as described in Example lb a pharmaceutical composition was prepared comprising:
  • Example lb In a manner as described in Example lb a pharmaceutical composition was prepared comprising:
  • a pharmaceutical composition comprising: 0.2 g of 5-chloro-2-methyl-2,3,3a,12b-tetrahydro-lH-di- 15 benz[2,3:6,7]oxepino[4,5-c]pyrrole maleate (1:1) (Org 5222), 17 g of sodium alginate, 35 g of dextran (MW approx. 40.000), 17.5 g of dextrose, and distilled water to a volume of 1 1, which composition was freeze-dried into unit dosage forms.
  • a pharmaceutical composition comprising: 0.4 g of 5-chloro-2-methyl-2,3,3a,12b-tetrahydro-lH-di-
  • Lyospheres were prepared by dissolving 138.9 g of
  • a pharmaceutical composition comprising: 0.094 g of 5-chloro-2-methyl-2,3,3a,12b-tetrahydro-lH- dibenz[2,3:6,7]oxepino[4,5-c]pyrrole maleate (1:1) (Org 5222), 30 g of mannitol, 40 g of gelatine, and distilled water to a volume of 1 1, which composition was freeze- dried according to the method of Example lb into unit dosage forms, each of which comprises 10 ⁇ g of Org 5222.
  • a micromanometer Konigsberg Instruments
  • a pair of segment length piezoelectric crystals (Triton Technology) were sutured into the endocardial left ventricular wall at a distance of approximately 1 cm from each other. All connecting wires were tunneled subcutaneously and exteriorized at the back of the neck.
  • Two weeks postoperatively the dogs were placed in a Pavlov-stand and transducers connected to an eight- channel recorder (Gould ES3000).
  • An electrocardiogram standard lead II was also recorded using conventional bipolar limb leads.
  • Org 5222 (or placebo) was administered either orally (1, 2.5, 5, 10, or 50 mg/kg) or sublingually (0.01, 0.1, or 1 mg/kg) to conscious dogs.
  • Aortic arterial systolic, diastolic and mean blood pressures (mmHg) , heart rates (beats/min), ventricular systolic segmental shortenings (mm) and the QT intervals were continuously registered and automatically analysed every 15 minutes during the 5 hour observation period following Org 5222 administration.
  • QTc (which reflects cardiac repolarisation time) was calculated according to Bazett's formula.
  • Tilt responses refer to the maximum changes observed in aortic blood pressure and heart rate during the 30 second observation period and were assessed both 30 minutes and just before Org 5222 administration and then 15, 30, 60, 90, 120, 180, 240, and 300 minutes after administration. Blood samples were taken just before drug administration and at 15, 30, 60, 90, 120, 240, 300, 360 minutes and at 21 hours after administration in each case just after tilt challenge.
  • Table 1 Mean heart rate change due to tilt (corrected for placebo effects), calculated per concentration range (ng/ml) and for each of the two administration routes, oral (po) and sublingual (si).
  • Org 5222 plasma Mean heart rate change per concentration concentration range (ng/ml) po 1 si
  • Tachycardia accompanying orthostatic hypotension was more marked after oral than after sublingual adminis ⁇ tration of Org 5222.
  • Direct haemodynamic and electro- physiological effects were also less marked after sublingual than after oral administration with regard to negative inotropy and QTc prolongation.
  • dogs treated orally showed marked side effects such as excitation of long duration, whereas dogs treated sublingually showed only short excitation periods followed by long lasting sedation.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Organic Chemistry (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
PCT/EP1995/000765 1994-03-02 1995-03-01 Sublingual or buccal pharmaceutical composition Ceased WO1995023600A1 (en)

Priority Applications (22)

Application Number Priority Date Filing Date Title
HK98109126A HK1008417A1 (en) 1994-03-02 1995-03-01 Sublingual or buccal pharmaceutical composition
US08/693,064 US5763476A (en) 1994-03-02 1995-03-01 Sublingual or buccal pharmaceutical composition
DK95912188T DK0746317T3 (da) 1994-03-02 1995-03-01 Sublingual eller bukkal farmaceutisk sammensætning
JP52270395A JP4099224B2 (ja) 1994-03-02 1995-03-01 舌下又はバッカル医薬組成物
MXPA/A/1996/003713A MXPA96003713A (en) 1994-03-02 1995-03-01 Sublingual pharmaceutical composition or bu
KR1019960704774A KR100330942B1 (ko) 1994-03-02 1995-03-01 설하또는협측투여용약학조성물
CZ962541A CZ284633B6 (cs) 1994-03-02 1995-03-01 Farmaceutický prostředek a použití trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrolu pro výrobu farmaceutického prostředku
PL95316080A PL180465B1 (pl) 1994-03-02 1995-03-01 Kompozycja farmaceutyczna zawierajaca trans-5-chloro-2-metylo-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oksepino[4,5-c]pirol PL PL PL
DE201012000050 DE122010000050I2 (de) 1994-03-02 1995-03-01 Sublinguales oder bukkales arzneimittel.
EP95912188A EP0746317B1 (en) 1994-03-02 1995-03-01 Sublingual or buccal pharmaceutical composition
AU19478/95A AU692530B2 (en) 1994-03-02 1995-03-01 Sublingual or buccal pharmaceutical composition
DE69502939T DE69502939T2 (de) 1994-03-02 1995-03-01 Sublinguales oder bukkales arzneimittel
BR9506924A BR9506924A (pt) 1994-03-02 1995-03-01 Composição farmacêutica sublingual ou bucal e utilização do trans-5-cloro-2-metil-2,3,3a, 12b-tetraidro-1h-dibenz(2,3:6,7) oxepino(4,5-c)pirrol
CA002182981A CA2182981C (en) 1994-03-02 1995-03-01 Sublingual or buccal pharmaceutical composition
NZ282394A NZ282394A (en) 1994-03-02 1995-03-01 Dissolving tablets contain a dibenz[2,3:6,7] oxepino[4,5-c]pyrrole derivative for sublingual or buccal administration
HU9602383A HU225051B1 (en) 1994-03-02 1995-03-01 Sublingual or buccal pharmaceutical compositions containing trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1h-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole
RU96120090/14A RU2139051C1 (ru) 1994-03-02 1995-03-01 Сублингвальная или трансбуккальная фармацевтическая композиция
FI963398A FI117923B (fi) 1994-03-02 1996-08-30 Kielenalainen tai poskensisäinen farmaseuttinen koostumus
NO19963639A NO308772B1 (no) 1994-03-02 1996-08-30 Sublingual eller buckal farmasoytisk blanding inneholdende trans-5-klor-2-metyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oksepino[4,5-c]pyrrol, samt anvendelse av forbindelsen for fremstilling av farmasoytisk blanding
LU91751C LU91751I2 (fr) 1994-03-02 2010-11-04 Asenapin et ses dérivés pharmaceutiquement acceptables (SYCREST®)
NO2010024C NO2010024I2 (no) 1994-03-02 2010-12-13 Trans-5-klor-2-metyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oksepino[4,5-c]pyrrol eller et salt derav
FR10C0056C FR10C0056I2 (enExample) 1994-03-02 2010-12-23

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP94200521.6 1994-03-02
EP94200521 1994-03-02

Publications (1)

Publication Number Publication Date
WO1995023600A1 true WO1995023600A1 (en) 1995-09-08

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ID=8216678

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Application Number Title Priority Date Filing Date
PCT/EP1995/000765 Ceased WO1995023600A1 (en) 1994-03-02 1995-03-01 Sublingual or buccal pharmaceutical composition

Country Status (23)

Country Link
US (1) US5763476A (enExample)
EP (1) EP0746317B1 (enExample)
JP (2) JP4099224B2 (enExample)
KR (1) KR100330942B1 (enExample)
CN (1) CN1079670C (enExample)
AT (1) ATE167057T1 (enExample)
AU (1) AU692530B2 (enExample)
BR (2) BR9506924A (enExample)
CA (1) CA2182981C (enExample)
CZ (1) CZ284633B6 (enExample)
DE (2) DE122010000050I2 (enExample)
DK (1) DK0746317T3 (enExample)
ES (1) ES2118584T3 (enExample)
FI (1) FI117923B (enExample)
FR (1) FR10C0056I2 (enExample)
HK (1) HK1008417A1 (enExample)
HU (1) HU225051B1 (enExample)
LU (1) LU91751I2 (enExample)
NO (2) NO308772B1 (enExample)
NZ (1) NZ282394A (enExample)
PL (1) PL180465B1 (enExample)
RU (1) RU2139051C1 (enExample)
WO (1) WO1995023600A1 (enExample)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999032108A1 (en) * 1997-12-19 1999-07-01 Akzo Nobel N.V. Org-5222 in the treatment of depression
WO2004110437A1 (en) * 2003-06-12 2004-12-23 Organon Ireland Ltd. Asenapine for the treatment of schizophrenia in a patient with overweight or predisposition for overweight
EP2154134A1 (en) 2005-04-07 2010-02-17 N.V. Organon Process for the preparation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1h-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole.
US7741358B2 (en) 2005-04-14 2010-06-22 N.V. Organon Crystal form of asenapine maleate
US7750167B2 (en) 2006-07-05 2010-07-06 N.V. Organon Process for the preparation of asenapine and intermediate products used in said process
US7872147B2 (en) 2005-04-07 2011-01-18 N. V. Organon Intermediate compounds for the preparation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole
US7875729B2 (en) 2007-01-05 2011-01-25 Synthon Bv Process for making asenapine
WO2012013766A1 (en) 2010-07-29 2012-02-02 Laboratorios Lesvi, S.L. Novel process for the preparation of asenapine
WO2012038975A3 (en) * 2010-09-22 2012-05-18 Msn Laboratories Limited Processes for the preparation of asenapine and intermediates thereof
WO2012066565A2 (en) 2010-11-16 2012-05-24 Cadila Healthcare Limited Asenapine maleate amorphous and crystalline form and process for preparation thereof
WO2012080195A2 (en) 2010-12-13 2012-06-21 Chemo Iberica, S.A. Polymorphic forms of asenapine maleate and processes for their preparation
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WO2014064076A1 (en) 2012-10-24 2014-05-01 Chemo Iberica, S.A. Process for the preparation of a polymorph of asenapine maleate
US9597291B2 (en) 2012-12-11 2017-03-21 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Orally disintegrating tablet containing asenapine
US10307400B2 (en) 2012-12-11 2019-06-04 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Orally disintegrating tablet containing asenapine
WO2014127786A1 (en) 2013-02-22 2014-08-28 Zentiva, K.S. Orally disintegrating pharmaceutical composition comprising asenapine
TR201509009A1 (en) * 2014-12-11 2017-02-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi THIN FILM STRIP OF ASENAPINE
US11154510B2 (en) 2015-06-11 2021-10-26 Alrise Biosystems Gmbh Process for the preparation of drug loaded microparticles
US11931466B2 (en) 2015-06-11 2024-03-19 Ferring B.V. Process for the preparation of drug loaded microparticles

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ES2118584T3 (es) 1998-09-16
AU1947895A (en) 1995-09-18
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RU2139051C1 (ru) 1999-10-10
FI963398L (fi) 1996-08-30
DE69502939D1 (de) 1998-07-16
HUT76319A (en) 1997-08-28
HU9602383D0 (en) 1996-10-28
PL180465B1 (pl) 2001-02-28
NO2010024I1 (no) 2011-01-03
CN1143320A (zh) 1997-02-19
NO963639D0 (no) 1996-08-30
NO2010024I2 (no) 2012-04-10
DE122010000050I2 (de) 2011-07-21
FI117923B (fi) 2007-04-30
MX9603713A (es) 1997-12-31
NO308772B1 (no) 2000-10-30
CZ284633B6 (cs) 1999-01-13
CA2182981A1 (en) 1995-09-08
FR10C0056I1 (enExample) 2011-01-28
NZ282394A (en) 1997-12-19
ATE167057T1 (de) 1998-06-15
BR9506924A (pt) 1997-09-30
DK0746317T3 (da) 1999-03-22
LU91751I2 (fr) 2011-01-04
EP0746317B1 (en) 1998-06-10
JP2006342178A (ja) 2006-12-21
JP4616810B2 (ja) 2011-01-19
NO963639L (no) 1996-10-30
CN1079670C (zh) 2002-02-27
CA2182981C (en) 2006-10-17
DE122010000050I1 (de) 2011-05-05
HU225051B1 (en) 2006-05-29
AU692530B2 (en) 1998-06-11
HK1008417A1 (en) 1999-05-07
BR1100625A (pt) 1999-12-28
FR10C0056I2 (enExample) 2011-11-25
DE69502939T2 (de) 1998-10-22
KR100330942B1 (ko) 2002-11-16
JP4099224B2 (ja) 2008-06-11
PL316080A1 (en) 1996-12-23

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