WO2002045753A2 - Oral extended release formulation of gepirone - Google Patents

Oral extended release formulation of gepirone Download PDF

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Publication number
WO2002045753A2
WO2002045753A2 PCT/EP2001/014189 EP0114189W WO0245753A2 WO 2002045753 A2 WO2002045753 A2 WO 2002045753A2 EP 0114189 W EP0114189 W EP 0114189W WO 0245753 A2 WO0245753 A2 WO 0245753A2
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Prior art keywords
gepirone
amount
extended release
formulation
polymer matrix
Prior art date
Application number
PCT/EP2001/014189
Other languages
French (fr)
Other versions
WO2002045753A3 (en
Inventor
Johannes Gerardus Joseph Egberink
John Francis Engelhart
Original Assignee
Akzo Nobel N.V.
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
Priority to CA002436692A priority Critical patent/CA2436692A1/en
Priority to HU0401021A priority patent/HUP0401021A2/en
Priority to AU2002226371A priority patent/AU2002226371A1/en
Priority to PL01362445A priority patent/PL362445A1/en
Priority to JP2002547535A priority patent/JP2004517083A/en
Priority to IL15585501A priority patent/IL155855A0/en
Priority to EP01995688A priority patent/EP1343504A2/en
Priority to SK694-2003A priority patent/SK6942003A3/en
Application filed by Akzo Nobel N.V. filed Critical Akzo Nobel N.V.
Priority to BR0115976-3A priority patent/BR0115976A/en
Priority to MXPA03005099A priority patent/MXPA03005099A/en
Priority to KR10-2003-7007555A priority patent/KR20040018314A/en
Publication of WO2002045753A2 publication Critical patent/WO2002045753A2/en
Publication of WO2002045753A3 publication Critical patent/WO2002045753A3/en
Priority to NO20032581A priority patent/NO20032581D0/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61P25/24—Antidepressants

Definitions

  • the invention relates to a pharmaceutical formulation for oral administration with extended release properties comprising an amount of gepirone hydrochloride, an amount of a cellulosic polymer matrix and an amount of microcrystalline cellulose.
  • Such pharmaceutical formulations are described in EP 700 680 for use in the treatment of CNS disorders such as anxiety, depression and panic disorders.
  • Gepirone is a drug which induces undesirable effects when high peak levels are reached. An even distribution of drug levels in blood is desirable to have a suitably tolerated therapeutic dose level. It was reported that optimal treatment of major depressive disorder was obtained with daily doses of up to 100 mg gepirone HCl (Wilcox et al;
  • This invention makes a pharmaceutical formulation according to the opening paragraph available in which the amount of the pharmaceutically acceptable cellulosic polymer matrix is from 70 to 85 wt %, the amount of carbohydrate binder is from 7 to 10 wt % and the amount of gepirone hydrochloride is from 13 to 21 wt %.
  • the formulation may optionally contain further pharmaceutically acceptable additives, such as glidants, lubricants and colorants.
  • the invention makes a once per day medical treatment available with gepirone HCl in a pharmaceutical formulation for oral administration having the above-defined composition.
  • This treatment is useful and well- tolerated by those patients treated for depression or a related central nervous system disorder, who are started on a treatment regime beginning with doses of about 20 mg gepirone HCl per day, and which is gradually built up to 60-100 mg gepirone HCl per day.
  • a pharmaceutical formulation for oral administration is usually a tablet or a capsule. Contrary to what would have been the weight of an 80 mg tablet according to EP 700 680, tablets according to the present invention can have a total weight of at most 450 mg. Despite the high relative amount of gepirone HCl over the cellulosic polymer matrix material and also over the carbohydrate binder, oral formulations, in particular tablets, could still be made with acceptable dissolution properties of gepirone and sufficient stability during production and handling.
  • a pharmaceutically acceptable cellulosic polymer matrix has the function of retaining gepirone HCl so that an extended release effect is obtained.
  • Suitable matrixes include hydroxyalkylsubstituted alkylcelluloses having a viscosity of 15,000 cps to 100,000 cps. Hydroxymethyl propylcellulose (HPMC) of grades K15M and K100M is preferred and grade K100M, Premium (Methocel) is in particular preferred.
  • HPMC Hydroxymethyl propylcellulose
  • the amounts of components in the pharmaceutical formulation of the invention are expressed as weight percentage (wt %) of the total weight of the formulation, which is usually a tablet.
  • alkyl as used here means a branched or unbranched saturated unsubstituted carbon chain. In view of the required viscosities, the alkyl groups referred to in this paragraph do not comprise more than 6 carbon atoms.
  • pharmaceutically acceptable for suitable additives for use in carrying out the invention refers to requirements set for pharmaceutical auxiliaries in general. These requirements with regard to safety and noninterference with the active principle in pharmaceutical formulations are generally known to the skilled person. A standard compilation of pharmaceutically acceptable carriers and excipients can be found in the Handbook of Pharmaceutical excipients (2 nd edition edited by A. Wade and P. J. Weller; Published by the American Pharmaceutical Association, Washington and The Pharmaceutical Press, London in 1994).
  • Additives to a pharmaceutical formulation such as carriers, binders, glidants, lubricants and colorants are used for example in order to obtain certain cohesiveness, coloration and flowability of the tablets.
  • magnesium stearate, colloidal silicon dioxide and iron oxide pigments are used.
  • Glidants and lubricants are agents reducing the adhesiveness of the powder mixture or tablets during production. Methods of use of such additives are known in the art of making pharmaceutical compositions as for example described in chapter 19 of Remington's Pharmaceutical Sciences (18th edition Editor A.R. Gennaro; Mack Publishing Comp; Easton, Pennsylvania).
  • Binders are agents used to impart cohesive properties to a pharmaceutical composition resulting in minimal loss from the pharmaceutical composition during production and handling.
  • Carbohydrate binders are for example cellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose, sugars, starches, amylopectin, dextrin, maltodextrin, gums and alginates.
  • Microcrystalline cellulose, and in particular Avicel pH 101, is a preferred binder for use in this invention.
  • a formulation according to the invention has a release rate of gepirone from the formulation such that about 18 to 24 hours are required to attain from about 90 to about 95% absorption of gepirone.
  • Oral pharmaceutical formulations according to the present invention can be prepared by methods known in the art, e.g. as described in the standard reference, Gennaro et al., Remington's Pharmaceutical Sciences, (18th ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture). Some caution in handling the compressed high strength formulations of this invention is advisable in order to avoid breaking and cracks in tablets.
  • Gepirone may be prepared by any method known in the art. Typically the compound is prepared by the methods described in US patent No. 4,423,049. Pharmaceutical extended release compositions containing gepirone are disclosed in EP 700 680. The contents of these documents are incorporated herein by reference.
  • Active pre-mixture Transfer the colloidal silicon dioxide, NF, colorant (40 mg: Euroxide Yellow E 7056; 60 mg:Euroxide Yellow E 7055; 80 mg: Euroxide yellow E 7055 and Euroxide Red E 7016), gepirone HCl powder and 20% of hydroxypropyl methylcellulose USP in 2 cu.
  • Ft. planetary mixer Hobart mixer
  • Mix ingredients for 15 minutes in a planetary mixer Hobart Mixer.
  • Label as 'Active Pre-Mix'. Blend for slugging
  • V'-blender without an I-bar Transfer the Active Pre-Mix in a 10 cu. Ft. "V'-blender without an I-bar, while passing through #12 mesh screen and transfer the balance of 80% HPMC, microcrystalline cellulose, NF and 50% of magnesium stearate, NF in the V-blender without an I-bar. Blend ingredients in the V-blender without an I bar for 24 minutes and label as "Blend for Slugging".

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

Abstract

This invention makes a pharmaceutical formulation for oral administration with extended release properties available comprising an amount of gepirone hydrochloride, an amount of a cellulosic polymer matrix and an amount of microcrystalline cellulose characterised in that the amount the pharmaceutically acceptable cellulosic polymer matrix is from 70 to 85 wt%, the amount of carbohydrate binder is from 7 to 10 wt% and the amount of gepirone hydrochloride is from 13 to 21 wt%. The formulation is useful for a treatment for depression or a related central nervous system disorder with gepirone administered in a once-a-day oral formulation for extended release of gepirone.

Description

PHARMACEUTICAL FORMULATION OF GEPIRONE FOR ORAL ADMINISTRATION
The invention relates to a pharmaceutical formulation for oral administration with extended release properties comprising an amount of gepirone hydrochloride, an amount of a cellulosic polymer matrix and an amount of microcrystalline cellulose.
Such pharmaceutical formulations are described in EP 700 680 for use in the treatment of CNS disorders such as anxiety, depression and panic disorders. Gepirone is a drug which induces undesirable effects when high peak levels are reached. An even distribution of drug levels in blood is desirable to have a suitably tolerated therapeutic dose level. It was reported that optimal treatment of major depressive disorder was obtained with daily doses of up to 100 mg gepirone HCl (Wilcox et al;
Psychopharmacology Bulletin). The administration of the total daily amount of gepirone was spread over the day by providing 20 mg gepirone HCl extended release tablets at intervals during the day. This was done not only because it was indicated in the prior art (EP 700 680) that extended release formulations can reliably be produced and have slow release properties when the content is at most 12% gepirone HCl of the total content, with a preferred maximum of 11 wt %, and the content of microcrystalline cellulose at least 10% with a preferred minimum of 11 wt %, but also because it could be expected that once-a-day high doses will be badly tolerated even when given as an extended release formulation.
Contrary to what is to be expected it was found that suitable higher strengths extended release tablets can be prepared and are well tolerated in a once a day dosage form in those patients already habituated to lower dosages.
Clearly, it is more accommodating for such patients to have a once-a-day formulation available.
This invention makes a pharmaceutical formulation according to the opening paragraph available in which the amount of the pharmaceutically acceptable cellulosic polymer matrix is from 70 to 85 wt %, the amount of carbohydrate binder is from 7 to 10 wt % and the amount of gepirone hydrochloride is from 13 to 21 wt %. The formulation may optionally contain further pharmaceutically acceptable additives, such as glidants, lubricants and colorants.
The invention makes a once per day medical treatment available with gepirone HCl in a pharmaceutical formulation for oral administration having the above-defined composition. This treatment is useful and well- tolerated by those patients treated for depression or a related central nervous system disorder, who are started on a treatment regime beginning with doses of about 20 mg gepirone HCl per day, and which is gradually built up to 60-100 mg gepirone HCl per day.
A pharmaceutical formulation for oral administration is usually a tablet or a capsule. Contrary to what would have been the weight of an 80 mg tablet according to EP 700 680, tablets according to the present invention can have a total weight of at most 450 mg. Despite the high relative amount of gepirone HCl over the cellulosic polymer matrix material and also over the carbohydrate binder, oral formulations, in particular tablets, could still be made with acceptable dissolution properties of gepirone and sufficient stability during production and handling.
A pharmaceutically acceptable cellulosic polymer matrix has the function of retaining gepirone HCl so that an extended release effect is obtained. Suitable matrixes include hydroxyalkylsubstituted alkylcelluloses having a viscosity of 15,000 cps to 100,000 cps. Hydroxymethyl propylcellulose (HPMC) of grades K15M and K100M is preferred and grade K100M, Premium (Methocel) is in particular preferred. The amounts of components in the pharmaceutical formulation of the invention are expressed as weight percentage (wt %) of the total weight of the formulation, which is usually a tablet. The term alkyl as used here means a branched or unbranched saturated unsubstituted carbon chain. In view of the required viscosities, the alkyl groups referred to in this paragraph do not comprise more than 6 carbon atoms.
The term pharmaceutically acceptable for suitable additives for use in carrying out the invention refers to requirements set for pharmaceutical auxiliaries in general. These requirements with regard to safety and noninterference with the active principle in pharmaceutical formulations are generally known to the skilled person. A standard compilation of pharmaceutically acceptable carriers and excipients can be found in the Handbook of Pharmaceutical excipients (2nd edition edited by A. Wade and P. J. Weller; Published by the American Pharmaceutical Association, Washington and The Pharmaceutical Press, London in 1994). Additives to a pharmaceutical formulation, such as carriers, binders, glidants, lubricants and colorants are used for example in order to obtain certain cohesiveness, coloration and flowability of the tablets. In a preferred embodiment of this invention magnesium stearate, colloidal silicon dioxide and iron oxide pigments are used.
Glidants and lubricants are agents reducing the adhesiveness of the powder mixture or tablets during production. Methods of use of such additives are known in the art of making pharmaceutical compositions as for example described in chapter 19 of Remington's Pharmaceutical Sciences (18th edition Editor A.R. Gennaro; Mack Publishing Comp; Easton, Pennsylvania).
Binders are agents used to impart cohesive properties to a pharmaceutical composition resulting in minimal loss from the pharmaceutical composition during production and handling. Carbohydrate binders are for example cellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose, sugars, starches, amylopectin, dextrin, maltodextrin, gums and alginates. Microcrystalline cellulose, and in particular Avicel pH 101, is a preferred binder for use in this invention.
The term pharmaceutical formulation for oral administration with extended release properties is used in this description to refer to the characteristics of extended release of gepirone according to the disclosure in EP 700 680. Specifically, a formulation according to the invention has a release rate of gepirone from the formulation such that about 18 to 24 hours are required to attain from about 90 to about 95% absorption of gepirone.
Oral pharmaceutical formulations according to the present invention can be prepared by methods known in the art, e.g. as described in the standard reference, Gennaro et al., Remington's Pharmaceutical Sciences, (18th ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture). Some caution in handling the compressed high strength formulations of this invention is advisable in order to avoid breaking and cracks in tablets.
Gepirone may be prepared by any method known in the art. Typically the compound is prepared by the methods described in US patent No. 4,423,049. Pharmaceutical extended release compositions containing gepirone are disclosed in EP 700 680. The contents of these documents are incorporated herein by reference.
The following examples will serve to illustrate how to perform the invention.
Example 1
Manufacturing procedure of batches of 160,000 tablets
Figure imgf000005_0001
Active pre-mixture: Transfer the colloidal silicon dioxide, NF, colorant (40 mg: Euroxide Yellow E 7056; 60 mg:Euroxide Yellow E 7055; 80 mg: Euroxide yellow E 7055 and Euroxide Red E 7016), gepirone HCl powder and 20% of hydroxypropyl methylcellulose USP in 2 cu. Ft. planetary mixer (Hobart mixer). Mix ingredients for 15 minutes in a planetary mixer (Hobart Mixer). Label as 'Active Pre-Mix'. Blend for slugging
Mill the Active Pre-Mix in a Fitzmill using a perforated plate No. 0020 at high speed, impact forward to deagglomerate lumps, if any.
Transfer the Active Pre-Mix in a 10 cu. Ft. "V'-blender without an I-bar, while passing through #12 mesh screen and transfer the balance of 80% HPMC, microcrystalline cellulose, NF and 50% of magnesium stearate, NF in the V-blender without an I-bar. Blend ingredients in the V-blender without an I bar for 24 minutes and label as "Blend for Slugging".
Slugging
Compress the blend into slugs using 7/8" round flat face bevelled edge (40) bevelled plain (60, 80) tooling using a rotary Kikusui-Hercules compression machine. In rocess controls:
Figure imgf000006_0001
Final Blend
Mill the slugs in an S.S. Fitzmill with screw feeder using a perforated plate No. 0093 at medium speed, knives forward and screw feeder setting of 3.5 ± 0.5. Transfer the milled mass into a 10 cu. Ft. S.S. V-blender without I- bar. Screen the balance of 50% magnesium stearate, NF through # 18 mesh and transfer also into the V-blender. Blend for 6 minutes.
Compress tablets with a rotary Kikusui-Libra compression machine using 0.338" X 0.405" Ovoid rectangular dies. In rocess controls:
Figure imgf000006_0002
Store in tight containers untill further use or testing. Drug release profile of tablets prepared as described in this example. Additional 20 mg tablets were made according to the procedure described in EP 700 680 for comparison of the drug release profile of the 60 and 80 tablets according to this invention,:
Gepirone release pattern of tablets (Numbers in the table represent the ercenta e dissolution of the theoretical content of the tablets
Figure imgf000008_0001
Example 2
For upscaling the manufacturing for batches of 800,000 tablets certain adaptations were applied:
Thus, procedures are according to the methods described in example 1, but the active pre-mix is blended in a 340 qt. AZMF Glen mixer for 28 minutes, the size of the V-blender used is 30 cu. Ft. and final blending is done for 7 minutes. Tablets had similar properties as measured in example 1. Special attention is given to the problem of friability of the 80 mg strength tablets. It is preferred to compress 80 mg tablets at a speed of the compression machine of 20 rotations per minute, i.e. in general at a speed of less than 30 rpm, set at the tablet compression machine in order to reduce the number of tablets with cracks.

Claims

Claims
1. A pharmaceutical formulation for oral administration with extended release properties comprising an amount of gepirone hydrochloride, an amount of a cellulosic polymer matrix and an amount of microcrystalline cellulose characterised in that the amount the pharmaceutically acceptable cellulosic polymer matrix is from 70 to 85 wt %, the amount of carbohydrate binder is from 7 to 10 wt % and the amount of gepirone hydrochloride is from 13 to 21 wt %.
2. The pharmaceutical formulation according to claim 1, characterised in that the cellulosic polymer matrix is a hydroxymethyl propylcellulose having a viscosity of 15,000 cps to 100,000 cps.
3. The pharmaceutical formulation according to claim 1, characterised in that the microcrystalline cellulose is Avicel pH 101.
4. A treatment for depression or a related central nervous system disorder with gepirone administered in a once-a-day oral formulation for extended release of gepirone, characterised in that the formulation is according to claim 1.
PCT/EP2001/014189 2000-12-08 2001-11-30 Oral extended release formulation of gepirone WO2002045753A2 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
EP01995688A EP1343504A2 (en) 2000-12-08 2001-11-30 Pharmaceutical formulation of gepirone for oral administration
AU2002226371A AU2002226371A1 (en) 2000-12-08 2001-11-30 Oral extended release formulation of gepirone
PL01362445A PL362445A1 (en) 2000-12-08 2001-11-30 Oral extended release formulation of gepirone
JP2002547535A JP2004517083A (en) 2000-12-08 2001-11-30 Oral sustained release formulation of Jepilone
IL15585501A IL155855A0 (en) 2000-12-08 2001-11-30 Pharmaceutical formulation of gepirone for oral administration
CA002436692A CA2436692A1 (en) 2000-12-08 2001-11-30 Oral extended release formulation of gepirone
SK694-2003A SK6942003A3 (en) 2000-12-08 2001-11-30 Oral extended release formulation of gepirone
HU0401021A HUP0401021A2 (en) 2000-12-08 2001-11-30 Oral pharmaceutical composition containing gepiron
BR0115976-3A BR0115976A (en) 2000-12-08 2001-11-30 Pharmaceutical formulation and treatment for depression or for a central nervous system disorder
MXPA03005099A MXPA03005099A (en) 2000-12-08 2001-11-30 Oral extended release formulation of gepirone.
KR10-2003-7007555A KR20040018314A (en) 2000-12-08 2001-11-30 Oral extended release formulation of gepirone
NO20032581A NO20032581D0 (en) 2000-12-08 2003-06-06 Pharmaceutical formulation of gepirone for oral administration

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP00204388.3 2000-12-08
EP00204388 2000-12-08

Publications (2)

Publication Number Publication Date
WO2002045753A2 true WO2002045753A2 (en) 2002-06-13
WO2002045753A3 WO2002045753A3 (en) 2002-08-29

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PCT/EP2001/014189 WO2002045753A2 (en) 2000-12-08 2001-11-30 Oral extended release formulation of gepirone

Country Status (19)

Country Link
EP (1) EP1343504A2 (en)
JP (1) JP2004517083A (en)
KR (1) KR20040018314A (en)
CN (1) CN1479620A (en)
AR (1) AR031461A1 (en)
AU (1) AU2002226371A1 (en)
BR (1) BR0115976A (en)
CA (1) CA2436692A1 (en)
CZ (1) CZ20031589A3 (en)
EC (1) ECSP034627A (en)
HU (1) HUP0401021A2 (en)
IL (1) IL155855A0 (en)
MX (1) MXPA03005099A (en)
NO (1) NO20032581D0 (en)
PL (1) PL362445A1 (en)
RU (1) RU2003120446A (en)
SK (1) SK6942003A3 (en)
WO (1) WO2002045753A2 (en)
ZA (1) ZA200303915B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004028507A1 (en) * 2002-09-24 2004-04-08 Akzo Nobel N.V. Method to improve pharmaceutical tablets having a matrix of cellulose ether
EP1809255A1 (en) * 2004-11-05 2007-07-25 Fabre-Kramer Pharmaceuticals, Inc. High-dosage extended-release formulation of gepirone

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3657966A1 (en) * 2017-07-26 2020-06-03 Abbott Laboratories Nutritional tablets and methods of making the same
CN109745323A (en) * 2017-11-01 2019-05-14 四川科瑞德制药股份有限公司 Azapirone compound improves the active purposes of parasympathetic nerve

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0700680A1 (en) * 1994-09-06 1996-03-13 Bristol-Myers Squibb Company Gepirone dosage form

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0700680A1 (en) * 1994-09-06 1996-03-13 Bristol-Myers Squibb Company Gepirone dosage form

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FEIGER A.D.: "A double-blind comparison of gepirone extended release, imipramine, and placebo in the treatment of outpatient major depression." PSYCHOPHARMACOLOGY BULLETIN, (1996) 32/4 (659-665). , XP001069219 *
WILCOX C.S.: "A double-blind trial of low- and high-dose ranges of gepirone-ER compared with placebo in the treatment of depressed outpatients" PSYCHOPHARMACOLOGY BULLETIN, (1996) 32/3 (335-342). , XP001069224 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004028507A1 (en) * 2002-09-24 2004-04-08 Akzo Nobel N.V. Method to improve pharmaceutical tablets having a matrix of cellulose ether
EP1809255A1 (en) * 2004-11-05 2007-07-25 Fabre-Kramer Pharmaceuticals, Inc. High-dosage extended-release formulation of gepirone
JP2008519071A (en) * 2004-11-05 2008-06-05 ファーブル−クレイマー・ホールディングス・インコーポレイテッド High-dose sustained-release formulation of gepirone
EP1809255A4 (en) * 2004-11-05 2011-08-03 Fabre Kramer Holdings Inc High-dosage extended-release formulation of gepirone

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MXPA03005099A (en) 2004-02-12
AU2002226371A1 (en) 2002-06-18
CN1479620A (en) 2004-03-03
EP1343504A2 (en) 2003-09-17
ZA200303915B (en) 2004-08-20
ECSP034627A (en) 2004-09-28
WO2002045753A3 (en) 2002-08-29
SK6942003A3 (en) 2003-10-07
JP2004517083A (en) 2004-06-10
KR20040018314A (en) 2004-03-03
RU2003120446A (en) 2005-02-20
AR031461A1 (en) 2003-09-24
IL155855A0 (en) 2003-12-23
BR0115976A (en) 2003-12-30
CZ20031589A3 (en) 2003-11-12
HUP0401021A2 (en) 2004-09-28
NO20032581L (en) 2003-06-06
PL362445A1 (en) 2004-11-02
CA2436692A1 (en) 2002-06-13
NO20032581D0 (en) 2003-06-06

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