WO1992012716A1 - Composition pharmaceutique contenant du granisetrone et du dexamethasone - Google Patents

Composition pharmaceutique contenant du granisetrone et du dexamethasone Download PDF

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Publication number
WO1992012716A1
WO1992012716A1 PCT/GB1992/000091 GB9200091W WO9212716A1 WO 1992012716 A1 WO1992012716 A1 WO 1992012716A1 GB 9200091 W GB9200091 W GB 9200091W WO 9212716 A1 WO9212716 A1 WO 9212716A1
Authority
WO
WIPO (PCT)
Prior art keywords
granisetron
dexamethasone
vomiting
nausea
treatment
Prior art date
Application number
PCT/GB1992/000091
Other languages
English (en)
Inventor
Gareth John Sanger
Christopher Stuart Dott
Original Assignee
Smithkline Beecham P.L.C.
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 Smithkline Beecham P.L.C. filed Critical Smithkline Beecham P.L.C.
Priority to JP50278692A priority Critical patent/JP3521143B2/ja
Priority to AU11641/92A priority patent/AU658169B2/en
Priority to CA002100777A priority patent/CA2100777C/fr
Publication of WO1992012716A1 publication Critical patent/WO1992012716A1/fr
Priority to KR1019930702140A priority patent/KR930702991A/ko

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes

Definitions

  • composition containing granisetron and dexamethasone
  • This invention relates to the use of a compound having 5-HT3 receptor antagonist activity and dexamethasone in the treatment of emesis, and to pharmaceutical compositions containing the two compounds.
  • EP-A-200444 (Beecham Group p.l.c).
  • Example 6 discloses granisetron, and its use as an anti-emetic, especially useful in treating cytotoxic agent-induced nausea and vomiting. All references herein to granisetron include pharmaceutically acceptable salts, such as the hydrochloride, and solvates, such as hydrates.
  • the anti-emetic properties of granisetron are potentially enhanced by administering the compound in conjunction with systemic corticosteroids, such as dexamethasone.
  • systemic corticosteroids such as dexamethasone.
  • Dexamethasone is a systemic anti-inflammatory corticosteroid, which is known to have anti-emetic properties and to be useful in the treatment of emesis resulting from chemotherapy, especially cancer chemotherapy involving the use of, for example, cisplatin.
  • the present invention provides a pharmaceutical product comprising granisetron and dexamethasone as a combined preparation for simultaneous, separate or sequential use in the treatment and/or prevention of nausea and vomiting.
  • the present invention also provides a method of treatment and/or prophylaxis of nausea and vomiting, which comprises administering to a human or animal subject, granisetron and dexamethasone or a pharmaceutically acceptable salt or ester thereof.
  • the invention further provides the use of granisetron for the manufacture of a medicament for administration in conjunction with dexamethasone or a pharmaceutically acceptable salt or ester thereof, for the treatment and/or prevention of nausea and vomiting.
  • Co-administration of granisetron with dexamethasone is particularly useful for the treatment and/or prevention of nausea and vomiting associated with chemotherapy using cytotoxic drugs, especially cancer chemotheraphy involving the use of, for example, platinum complexes such as cisplatin or carboplatin, or cylcophosphamide or doxorubicin.
  • cytotoxic drugs especially cancer chemotheraphy involving the use of, for example, platinum complexes such as cisplatin or carboplatin, or cylcophosphamide or doxorubicin.
  • Such co-administration may also reduce delayed or prolonged nausea and vomiting associated with this type of chemotherapy.
  • Particular note should also be made of the use in the treatment of nausea and vomiting associated with other cytotoxic agents, such as that associated with radiation treatment.
  • Granisetron and dexamethasone or a pharmaceutically acceptable salt or ester thereof may be administered as a single pharmaceutical composition comprising effective amounts of the two active ingredients.
  • the two active ingredients may be co-administered in the form of two separate pharmaceutical compositions for simultaneous or sequential use.
  • Suitable pharmaceutically acceptable salts of granisetron for use according to the invention include acid addition salts formed with organic or inorganic acids for example, hydrochlorides, hydrobromides, sulphates, phosphates, citrates, fumarates and maleates.
  • the solvates may, for example, be hydrates.
  • a preferred form of granisetron for use according to the invention is the hydrochloride.
  • Dexamethasone may be administered according to the invention as dexamethasone alcohol or in the form of a pharmaceutically acceptable salt or ester.
  • Suitable salts and esters include the acetate, isonicotinoate, phenylpropionate, pivalate, t-butyl acetate, trioxaundecanoate, disodium metasulphobenzoate and disodium phosphate.
  • a proposed dosage of granisetron for use according to the invention for administration to man is 0.05 to 25mg., more preferably 0.05 to 20mg, and most preferably 0.1 to lOmg per unit dose, expressed as the weight of free base.
  • a preferred dose of dexamethasone for use according to the invention is in the range of 0.5 to 20mg per dosage unit, expressed as the weight of the alcohol.
  • the unit doses may be administered, for example, 1 to 4 times per day.
  • the exact dose will depend on the route of administration and the condition being treated, and it will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient as well as the severity of the condition to be treated.
  • the two active ingredients are administered as separate preparations, they are preferably given enterally, such as orally or parenterally (e.g. intramuscularly or, more particularly, intravenously) .
  • the invention provides a pharmaceutical composition, for use in human or veterinary medicine, comprising the granisetron, and dexamethasone or a pharmaceutically acceptable salt or ester thereof.
  • compositions according to the invention may be formulated in conventional manner using one or more physiologically acceptable carriers or excipients.
  • the compositions may, for example, be formulated for oral, buccal, parenteral or rectal administration.
  • Compositions for administration by the oral route in the form of for example tablets or capsules, are preferred.
  • compositions for oral use such as tablets and capsules may be prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose) ; fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate) ; lubricant (e.g. magnesium stearate, talc or silica) ; disintegrants (e.g. potato starch or sodium starch glycollate) ; or wetting agent (e.g. sodium lauryl sulphate). Tablets may be coated by methods well known in the art.
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricant e.g. magnesium stearate, talc or silica
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils) ; and preservatives (e.g. methyl or propyl-p_-hydroxybenzoates or sorbic acid) .
  • the preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
  • Preparations for oral administration may be suitably formulated to give controlled release of one or both active ingredients.
  • compositions may be presented in a form suitable for bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form e.g. in syringes, ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredients may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • compositions may be formulated as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • compositions of the invention may be prepared according to conventional techniques well known in the pharmaceutical industry.
  • the granisetron and the dexamethasone or dexamethasone salt or ester may be admixed together, if desired, with suitable excipients.
  • Tablets may be prepared, for example, by direct compression of such a mixture.
  • Capsules may be prepared by filling the blend along with suitable excipients into gelatin capsules, using a suitable filling machine.
  • Controlled release forms for oral or rectal administration may be formulated in a conventional manner associated with controlled release forms.
  • compositions for use according to the invention may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredients.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration. Where the granisetron and the dexamethasone are intended for administration as two separate compositions these may be presented in the form of, for example, a twin pack.
  • a randomised, double blind, parallel group study comparing the use of granisetron and/or dexamethasone for prophylactic control of cisplatin (> 50 mg/m **1 ) induced nausea and vomiting is carried out for a period of seven days. Randomisation is stratified by cisplatin dose (50-74 mg/m and ⁇ 75 mg/m ) . Patients receive either granisetron for seven days, granisetron and dexamethasone for seven days, or granisetron and dexamethasone for one day followed by dexamethasone for six days.
  • Patients receiving cisplatin (>50 mg/m ) therapy for malignant disease are randomised in a double blind fashion, stratified according to cisplatin dosage, to receive the study medication.
  • the study design consists of 3 treatment arms:
  • Granisetron 1 mg p.o. B.I.D. begins at 24h for 6 consecutive days.
  • Granisetron 1 mg p.o. B.I.D. and dexamethasone 8 mg p.o. B.I.D. begins at 24h for 6 consecutive days.
  • Dexamethasone 8 mg p.o. B.I.D. begins at 24h for 6 consecutive days.
  • Patients disease state is assessed using the WHO classification and they must have a score of 2 or less. All patients are naive to cytotoxic therapy to avoid anticipatory emesis.
  • Patients who develop nausea and vomiting after their cisplatin therapy may be given up to four doses of prochlorperazine (10 mg suppositories) per day. If nausea and vomiting continue after this such that other anti-emetics have to be given, the physician decides whether or not to stop the study medication and/or treat with standard anti-emetics. As far as is medically safe, patients remain on the study medication for as much of the 7 day treatment period as possible.
  • the primary efficacy assessments in the study are the percentage of Complete Responders, the time to first vomiting, and the use of other anti-emetics over the seven day period.
  • a randomised, double blind, parallel group study is carried out, comparing oral granisetron (1.0 mg bd) with oral granisetron in combination with dexamethasone (12 mg iv) on the first day only and a conventional anti-emetic therapy, (metoclopramide 7mg/kg iv plus dexamethasone 12 mg iv on the first day, followed by metoclopramide 10 mg tds po) over a 7 day period in controlling cisplatin induced nausea and vomiting.

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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)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Otolaryngology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hospice & Palliative Care (AREA)
  • Toxicology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Produit pharmaceutique comprenant du granisétrone et du dexaméthasone sous forme d'une préparation combinée destinée à être utilisée de façon simultanée, séparée ou séquentielle pour le traitement et/ou la prévention de nausées et de vomissements.
PCT/GB1992/000091 1991-01-19 1992-01-16 Composition pharmaceutique contenant du granisetrone et du dexamethasone WO1992012716A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP50278692A JP3521143B2 (ja) 1991-01-19 1992-01-16 グラニセトロンおよびデキサメタゾン含有の医薬組成物
AU11641/92A AU658169B2 (en) 1991-01-19 1992-01-16 Pharmaceutical composition containing granisetron and dexamethasone
CA002100777A CA2100777C (fr) 1991-01-19 1992-01-16 Composition pharmaceutique contenant du granisetron et de la dexamethasone
KR1019930702140A KR930702991A (ko) 1991-01-19 1993-07-16 그라니세트론 및 덱사메타손을 함유하는 제약학적 조성물

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9101221.1 1991-01-19
GB919101221A GB9101221D0 (en) 1991-01-19 1991-01-19 Pharmaceuticals

Publications (1)

Publication Number Publication Date
WO1992012716A1 true WO1992012716A1 (fr) 1992-08-06

Family

ID=10688722

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1992/000091 WO1992012716A1 (fr) 1991-01-19 1992-01-16 Composition pharmaceutique contenant du granisetrone et du dexamethasone

Country Status (12)

Country Link
EP (1) EP0567498A1 (fr)
JP (1) JP3521143B2 (fr)
KR (1) KR930702991A (fr)
AU (1) AU658169B2 (fr)
CA (1) CA2100777C (fr)
GB (1) GB9101221D0 (fr)
IE (1) IE920148A1 (fr)
MX (1) MX9200214A (fr)
NZ (1) NZ241337A (fr)
PT (1) PT100033B (fr)
WO (1) WO1992012716A1 (fr)
ZA (1) ZA92343B (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008103852A1 (fr) * 2007-02-21 2008-08-28 Victory Pharma, Inc. Distribution transdermique de dexaméthasone et de prométhazine
CN103222977A (zh) * 2013-05-22 2013-07-31 南京工业大学 一种格拉司琼和地塞米松复方经皮控释贴剂及其制备方法
US9446052B2 (en) 2010-12-27 2016-09-20 Samyang Biopharmaceuticals Corporation Composition for prevention of nausea or vomiting

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MY164077A (en) * 1999-05-13 2017-11-30 Pharma Mar Sa Compositions and uses of et743 for treating cancer
US20060263421A1 (en) * 2005-05-18 2006-11-23 Abeille Pharmaceuticals Inc Transdermal Method and Patch for Nausea
JP5537104B2 (ja) * 2009-09-16 2014-07-02 テルモ株式会社 制吐剤

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2627986A1 (fr) * 1988-03-04 1989-09-08 Glaxo Group Ltd Composition pharmaceutique a base de 1,2,3,9-tetrahydro-9-methyl-3-((2-methyl-1h-imidazol-1-yl)methyl)-4h-carbazol-4-one ou d'un de ses sels et de dexamethasone, son procede de preparation et ses utilisations

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3687080T2 (de) * 1985-04-27 1993-03-25 Beecham Group Plc Azabicyclononyl-indazol-carboxamid mit 5-ht-antagonistischer wirkung.

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2627986A1 (fr) * 1988-03-04 1989-09-08 Glaxo Group Ltd Composition pharmaceutique a base de 1,2,3,9-tetrahydro-9-methyl-3-((2-methyl-1h-imidazol-1-yl)methyl)-4h-carbazol-4-one ou d'un de ses sels et de dexamethasone, son procede de preparation et ses utilisations

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Dialog 00789857 Cancerlit ICDB/90061960, M. LE BONNIEC et al.: "Single-blinded randomised comparison study with crossover of granisteron versus standard antiemetics in the treatment of chemotherapy-induced emesis", (Meeting Abstract), & PROC. ANNU. MEET. AM. SOC. CLIN. ONCOL.; VOL. 9:A1277 (1990), see abstract *
Dialog 03809716 Cancerlit ICDB/9107518, D. CUNNINGHAM: "Review of clinical results with 5HT3, antagonists in controlling emesis", (Meeting Abstract), & BR. J. CANCER. VOL. 62(3), 1990, P. 480, see abstract *
Scand. J. Gastroenterol. Suppl., vol. 24, no. 171, 1989, (Norway), P.A. VAN LIESSUM et al.: "Nausea and vomiting induced by cytostatic agents", pages 106-111, see conclusion *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008103852A1 (fr) * 2007-02-21 2008-08-28 Victory Pharma, Inc. Distribution transdermique de dexaméthasone et de prométhazine
US9446052B2 (en) 2010-12-27 2016-09-20 Samyang Biopharmaceuticals Corporation Composition for prevention of nausea or vomiting
CN103222977A (zh) * 2013-05-22 2013-07-31 南京工业大学 一种格拉司琼和地塞米松复方经皮控释贴剂及其制备方法

Also Published As

Publication number Publication date
NZ241337A (en) 1994-07-26
CA2100777A1 (fr) 1992-07-20
IE920148A1 (en) 1992-07-29
ZA92343B (en) 1992-12-30
CA2100777C (fr) 2003-08-19
AU1164192A (en) 1992-08-27
MX9200214A (es) 1992-08-01
JPH06507152A (ja) 1994-08-11
AU658169B2 (en) 1995-04-06
PT100033A (pt) 1993-02-26
KR930702991A (ko) 1993-11-29
PT100033B (pt) 1999-09-30
JP3521143B2 (ja) 2004-04-19
EP0567498A1 (fr) 1993-11-03
GB9101221D0 (en) 1991-02-27

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