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 PDFInfo
- 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
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 10
- XWAONOGAGZNUSF-UHFFFAOYSA-N siramesine Chemical compound C1=CC(F)=CC=C1N1C2=CC=CC=C2C(CCCCN2CCC3(CC2)C2=CC=CC=C2CO3)=C1 XWAONOGAGZNUSF-UHFFFAOYSA-N 0.000 title abstract 2
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 26
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 22
- 239000007788 liquid Substances 0.000 claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 12
- 239000007787 solid Substances 0.000 claims abstract description 11
- 239000006184 cosolvent Substances 0.000 claims abstract description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical group CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 36
- 239000002775 capsule Substances 0.000 claims description 23
- 239000007903 gelatin capsule Substances 0.000 claims description 14
- 229960004063 propylene glycol Drugs 0.000 claims description 12
- 235000013772 propylene glycol Nutrition 0.000 claims description 12
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 9
- 239000003963 antioxidant agent Substances 0.000 claims description 9
- 230000003078 antioxidant effect Effects 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 4
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 3
- 239000000600 sorbitol Substances 0.000 claims description 3
- 229920002582 Polyethylene Glycol 600 Polymers 0.000 claims description 2
- 239000002738 chelating agent Substances 0.000 claims description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 2
- 239000002184 metal Substances 0.000 claims 1
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 25
- 150000001875 compounds Chemical class 0.000 description 22
- 239000000203 mixture Substances 0.000 description 21
- 239000000243 solution Substances 0.000 description 19
- 239000008137 solubility enhancer Substances 0.000 description 14
- 229920000159 gelatin Polymers 0.000 description 11
- 235000019322 gelatine Nutrition 0.000 description 11
- 239000004480 active ingredient Substances 0.000 description 10
- 238000009472 formulation Methods 0.000 description 9
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 8
- 239000001828 Gelatine Substances 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 235000006708 antioxidants Nutrition 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 229920000858 Cyclodextrin Polymers 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 239000001202 beta-cyclodextrine Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000003801 milling Methods 0.000 description 3
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 208000011688 Generalised anxiety disease Diseases 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 229960001927 cetylpyridinium chloride Drugs 0.000 description 2
- YMKDRGPMQRFJGP-UHFFFAOYSA-M cetylpyridinium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 YMKDRGPMQRFJGP-UHFFFAOYSA-M 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005538 encapsulation Methods 0.000 description 2
- 229960001021 lactose monohydrate Drugs 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000006193 liquid solution Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N (R)-alpha-Tocopherol Natural products OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
- IKEHOXWJQXIQAG-UHFFFAOYSA-N 2-tert-butyl-4-methylphenol Chemical compound CC1=CC=C(O)C(C(C)(C)C)=C1 IKEHOXWJQXIQAG-UHFFFAOYSA-N 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 1
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 206010033664 Panic attack Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000010385 ascorbyl palmitate Nutrition 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 229940093476 ethylene glycol Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229960005150 glycerol Drugs 0.000 description 1
- 239000007887 hard shell capsule Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 208000019906 panic disease Diseases 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 238000005502 peroxidation Methods 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 230000003236 psychic effect Effects 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000003982 sigma receptor ligand Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- 125000001020 α-tocopherol group Chemical group 0.000 description 1
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.
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Neurosurgery (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
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)
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)
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 |
-
2001
- 2001-08-14 WO PCT/DK2001/000540 patent/WO2002013789A1/fr active Application Filing
- 2001-08-14 AR ARP010103887A patent/AR030453A1/es unknown
- 2001-08-14 AU AU2001279607A patent/AU2001279607A1/en not_active Abandoned
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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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)
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 |
---|---|
AU2001279607A1 (en) | 2002-02-25 |
AR030453A1 (es) | 2003-08-20 |
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