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WO2002013789A1 - 4omposition pharmaceutique contenant 1'-[4-[1-(4-fluorophenyl)-1h-indole-3-yl] -1-butyl]-spiro[isobenzofuran-1(3h),4'-piperidine] - Google Patents

4omposition pharmaceutique contenant 1'-[4-[1-(4-fluorophenyl)-1h-indole-3-yl] -1-butyl]-spiro[isobenzofuran-1(3h),4'-piperidine] Download PDF

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Publication number
WO2002013789A1
WO2002013789A1 PCT/DK2001/000540 DK0100540W WO0213789A1 WO 2002013789 A1 WO2002013789 A1 WO 2002013789A1 DK 0100540 W DK0100540 W DK 0100540W WO 0213789 A1 WO0213789 A1 WO 0213789A1
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WO
WIPO (PCT)
Prior art keywords
compound
butyl
solution according
spiro
fluorophenyl
Prior art date
Application number
PCT/DK2001/000540
Other languages
English (en)
Inventor
Ken Liljegren
Original Assignee
H. Lundbeck A/S
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
Application filed by H. Lundbeck A/S filed Critical H. Lundbeck A/S
Priority to AU2001279607A priority Critical patent/AU2001279607A1/en
Publication of WO2002013789A1 publication Critical patent/WO2002013789A1/fr

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Classifications

    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • 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

Definitions

  • the present invention relates to a pharmaceutical composition containing l'-[4-[l-(4- fluorophenyl)-lH-indole-3-yl]-l-butyl]-spiro[isobenzofirran-l(3H),4'-piperidine] as the active ingredient.
  • the present invention relates to a solution of the active ingredient, which is contained in a capsule.
  • the compound of formula I and pharmaceutically acceptable salts thereof have a poor aqueous solubility, although the hydrohalogenides of the compound of formula I have improved aqueous solubility compared to other salts of the compound.
  • bioavailabihty of the compound of formula I shows a high degree of variation when the compound is administered in the form of a conventional tablet prepared by simple compression of the active ingredient and pharmaceutically acceptable excipients.
  • Micronisation of the compound of formula I was expected to improve bioavailabihty, but was found not to markedly improve the bioavailabihty of the compound. In addition, it was found that food intake had a pronounced effect on the bioavailabihty of the compound, which leads to undesirable variations of the blood serum level of the active compound.
  • the present invention relates to a pharmaceutical composition of the compound of formula I comprising a solution of the compound of formula I or a pharmaceutically acceptable salt thereof in a liquid, semi-solid or solid solvent system comprising polyethylene glycol and optionally a solubility enhancer.
  • the pharmaceutical composition of the invention comprises a solution of the compound of formula I in a solvent system comprising polyethylene glycol and up to 20 % w/w of a solubility enhancer.
  • the present invention relates to such solutions, which are contained in a capsule.
  • the molecular weight of the polyethylene glycol used affects the properties of the resulting solution of the invention.
  • polyethylene glycol having an average molecular weight from about 200-800 daltons, preferably from about 400-600 produces a solution, which is liquid.
  • the present invention relates to solutions as above wherein the solvent system is liquid at room temperature.
  • the polyethylene glycol is selected from polyethylene glycols with an average molecular weight of 400-600 (PEG 400 - PEG 600).
  • the present invention also relates to such liquid solutions, which may be contained in a soft capsule, preferably a soft gelatine capsule, or in a modified hard gelatine capsule..
  • Polyethylene glycols do not dissolve the gelatin capsule material and may therefore be used as a vehicle in gelatin capsule formulations. However, it is important that a suitable amount of the active ingredient can be completely dissolved in a volume of solvent small enough to be contained in a capsule of a size, which is acceptable to patients. It may thus be necessary to add a solubility enhancer or co-solvent to the polyethylene glycol phase to obtain complete dissolution of the active ingredient.
  • the solubility enhancers or co-solvents useful according to the invention are suitably more hydrophilic than the polyethylene glycol used and such an enhancer could suitably be a short chain alcohol. Such solubility enhancers will typically be less compatible with the gelatin capsule material than the polyethylene glycol. However, according to the present invention, it has been found that the amount of solubility enhancer to be added to the solution may be kept below the amount, which causes degradation, etc. of the gelatin capsule.
  • Suitable solubility enhancers or co-solvents used according to the invention are propyleneglycol, ethyleneglycol, glycerol, sorbitol, transcutol and low molecular alcohols.
  • the solubility enhancer is propyleneglycol, sorbitol, ethanol and /or glycerol.
  • solubility enhancer which may be added to the polyethylene glycol phase without causing degradation of the gelatine capsule, will depend on the solubility enhancer chosen.
  • the amount of solubility enhancer is kept below 20% w/w.
  • solubility enhancer When propylene glycol is used as the solubility enhancer, the amount of solubility enhancer is suitably up to 10% w/w, preferably about 5% w/w.
  • Peroxidation of the polyethylene glycol may lead to oxidation of the active ingredient, as well as oxidation of the gelatin in the capsule shell causing gelatin cross-linking, and it may be preferred to add an antioxidant to the composition of the invention.
  • the antioxidant used may be any antioxidant, which is pharmaceutically acceptable.
  • the antioxidant is selected from alpha-tocopherol, BHA (2-tert-butyl-4-methylphenol) or BHT (2,6-di-tert-butyl-4-methylphenol), propylgallate, ascorbylpalmitate and other antioxidants well-known in the art.
  • the pharmaceutical composition of the invention comprises a hydrohalogenide of the compound of formula I, preferably the hydrochloride (hereinafter referred to as compound II).
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising 1 ' - [4- [ 1 -(4-fluorophenyl)- lH-indole-3yl] - 1 -butyl] -spiro [isobenzo-furan- 1 (3H),- 4'-piperidine] hydrochloride, PEG 400, about 5% w/w propylene glycol and an antioxidant.
  • the solutions according to the invention may contain up to 27 mg/ml of compound II.
  • the solutions of the invention are prepared by heating the polyethylene glycol, the solubility enhancer, the antioxidant and other excipients in a vessel fitted with an agitator.
  • the active ingredient is added and the mixture is stirred until the active ingredient is completely dissolved.
  • the polyethylene glycol in question is a liquid at room temperature, it is not strictly necessary to apply heating, but heating to about 40 °C will allow a rapid dissolution of the active ingredient.
  • Liquid formulations are suitably filled in capsules, such as soft gelatin capsules, available from RP.Scherer, Banner Pharmacaps or Capsugel or modified hard gelatin capsules available from Shionogi Qualicaps, while solutions, which are semi-solid or solid when cooled to room temperature, may be filled in two-piece hard gelatin capsules available from Shionogi Qualicaps, Capsugel and others. Highly concentrated solutions that are solid at room temperature have the additional utility of being suitable for conversion into tablets.
  • the liquid solution of the invention may be introduced into the soft gelatin capsule using encapsulation equipment and techniques known in the art, such as those described in US patent No. 4.772.472, US 4.894.978 and WO 96/41622.
  • Encapsulation in hardshell capsules may be carried out using conventional techniques.
  • the solutions of the invention are most conveniently administered orally in unit dosage forms such as tablets or capsules, containing the active ingredient in an amount from about 10 ⁇ g/kg to lOmg/kg body weight, preferably 25 ⁇ g/day/kg to 1.0 mg/day/kg, most preferably 0.1 mg/day/kg to 1.0 mg/day/kg body weight.
  • solutions of the invention may also be administered orally as liquids.
  • Soft gelatin capsule containing compound II in a polyethylene glycol phase Soft gelatin capsule containing compound II in a polyethylene glycol phase.
  • composition of fill material :
  • PEG 400 and propyleneglycol are heated to 40 °C. Compound II is added and the mixture is stirred until the active compound is completely dissolved.
  • the liquid is then filled in soft gelatin capsules.
  • the capsule is sealed.
  • Soft gelatin capsule containing compound II in a polyethylene glycol phase Soft gelatin capsule containing compound II in a polyethylene glycol phase.
  • composition of fill material :
  • the liquid is then filled in soft gelatine capsules.
  • the capsule is sealed.
  • Hard gelatin/PEG capsule containing compound II in a polyethylene glycol phase Hard gelatin/PEG capsule containing compound II in a polyethylene glycol phase.
  • composition of fill material :
  • PEG 400, propyleneglycol and BHT are heated to 40 °C.
  • Compound II is added and the mixture is stirred until the active compound is completely dissolved.
  • the liquid is then filled in hard gelatine/PEG capsules (Shionogi Qualicaps®) and sealed by banding.
  • Hard gelatin capsule containing micronized compound of formula II Hard gelatin capsule containing micronized compound of formula II.
  • composition of fill material :
  • Lactose monohydrate 325 mesh 68.82% w/w Cetylpyridinium chloride 30.00% w/w
  • Micronized compound II is mixed with lactose monohydrate, 325 mesh (filler) and cetylpyridinium chloride (wetting agent).
  • the powder mix is then filled in hard gelatin capsules.
  • composition containing 2.7 mg compound II /mL solution Composition containing 2.7 mg compound II /mL solution:
  • Hydroxypropyl-beta-cyclodextrine is added to purified water and stirred until completely dissolved.
  • Compound II is added and the mixture is stirred until compound II is completely dissolved.
  • the liquid is then filled in glass vials and heat sterilised.
  • the bioavailabihty of the formulations according to the invention was compared to a formulation containing micronized compound II (Example 4) and an aqueous solution of 2- hydroxypropyl-beta-cyclodextrine complex with compound II (Example 5).
  • the three formulations were administered to Beagle dogs of about 12 kg body weight and 3- 4 years old. 5 mg of the compound of formula II was administered to each dog. The concentration of the compound of formula I in the blood was determined, whereafter C Pain t max and AUC were calculated.
  • the 2-hydroxypropyl-beta-cyclodextrin complex solution was administered by oral gavage, whereas other formulations were administered orally in the gelatine capsules.
  • the formulation containing micronized compound II has a much lower bioavailabihty compared to the two other formulations.
  • the formulation according to Example 5 has a good bioavailabihty but uses water as a solvent and it is therefore not suitable for filling in capsules.
  • the formulation according to the invention provides improved bioavailabihty and may be contained in capsules suitable for oral administration.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique contenant une solution de 1'-[4-[1-(4-fluorophényl)1H-indole-3-yl]-1-butyl]-spiro[isobenzo-furan-1(3H),4'-piperidine] dans un système de solvant liquide, solide ou semi-solide renfermant du glycol polyéthylénique et une quantité de co-solvant.
PCT/DK2001/000540 2000-08-15 2001-08-14 4omposition pharmaceutique contenant 1'-[4-[1-(4-fluorophenyl)-1h-indole-3-yl] -1-butyl]-spiro[isobenzofuran-1(3h),4'-piperidine] WO2002013789A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001279607A AU2001279607A1 (en) 2000-08-15 2001-08-14 Pharmaceutical composition containing 1'-(4-(1-(4-fluorophenyl)-1h-indole-3-yl) -1-butyl)-spiro(isobenzofuran-1(3h),4'-piperidine)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DKPA200001215 2000-08-15
DKPA200001215 2000-08-15

Publications (1)

Publication Number Publication Date
WO2002013789A1 true WO2002013789A1 (fr) 2002-02-21

Family

ID=8159653

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK2001/000540 WO2002013789A1 (fr) 2000-08-15 2001-08-14 4omposition pharmaceutique contenant 1'-[4-[1-(4-fluorophenyl)-1h-indole-3-yl] -1-butyl]-spiro[isobenzofuran-1(3h),4'-piperidine]

Country Status (3)

Country Link
AR (1) AR030453A1 (fr)
AU (1) AU2001279607A1 (fr)
WO (1) WO2002013789A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005058324A1 (fr) * 2003-12-19 2005-06-30 H. Lundbeck A/S Utilisation de la siramesine dans le traitement du cancer

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4088750A (en) * 1974-02-22 1978-05-09 Burroughs Wellcome Co. Method and preparation for increasing bioavailability of digoxin
EP0356143A1 (fr) * 1988-08-18 1990-02-28 Takeda Chemical Industries, Ltd. Solutions injectables
WO1999024436A1 (fr) * 1997-11-07 1999-05-20 H. Lundbeck A/S Hydrohalogenures de 1'-[4- [1-(4-fluorophenyl)- 1h-indole-3-yl]-1-butyl] -spiro-[isobenzofuran- 1(3h),4'- piperidine]
WO1999051229A1 (fr) * 1998-04-07 1999-10-14 H. Lundbeck A/S Traitement des crises de panique
WO2000015225A1 (fr) * 1998-09-15 2000-03-23 H. Lundbeck A/S Traitement de la depression

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4088750A (en) * 1974-02-22 1978-05-09 Burroughs Wellcome Co. Method and preparation for increasing bioavailability of digoxin
EP0356143A1 (fr) * 1988-08-18 1990-02-28 Takeda Chemical Industries, Ltd. Solutions injectables
WO1999024436A1 (fr) * 1997-11-07 1999-05-20 H. Lundbeck A/S Hydrohalogenures de 1'-[4- [1-(4-fluorophenyl)- 1h-indole-3-yl]-1-butyl] -spiro-[isobenzofuran- 1(3h),4'- piperidine]
WO1999051229A1 (fr) * 1998-04-07 1999-10-14 H. Lundbeck A/S Traitement des crises de panique
WO2000015225A1 (fr) * 1998-09-15 2000-03-23 H. Lundbeck A/S Traitement de la depression

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005058324A1 (fr) * 2003-12-19 2005-06-30 H. Lundbeck A/S Utilisation de la siramesine dans le traitement du cancer
JP2007514666A (ja) * 2003-12-19 2007-06-07 ハー・ルンドベック・アクチエゼルスカベット 癌の治療にシラメシンを使用する方法
EA011170B1 (ru) * 2003-12-19 2009-02-27 Х. Лундбекк А/С Применение сирамезина в лечении злокачественных опухолей

Also Published As

Publication number Publication date
AR030453A1 (es) 2003-08-20
AU2001279607A1 (en) 2002-02-25

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