AU658169B2 - Pharmaceutical composition containing granisetron and dexamethasone - Google Patents

Description

OPI hATE 27/08/92 AOJP DATE 01/10/92 APPLN. ID 11 6l111. 9? 11 1 PCT NUMBER PCT/GR92/flO091 INTERN. N TREATY (PCT) (51) International Patent Classification 5 (11) International Publication Number: WO 92/12716 A61K 31/S7 (A61K 31/57 Al A61K 31:435) (43) International Publication Date: 6 August 1992 (06.08.92) (21) International Application Number: PCT/GB92/00091 (74) Agent: JONES, Pauline; SmithKline Beecham, Corporate Patents, Great Burgh, Yew Tree Bottom Road, Epsom, (22) International Filing Date: 16 January 1992 (16.01.92) Surrey KT18 5XQ (GB).

Priority data: (81) Designated States: AT (European patent), AU, BE (Euro- 9101221.1 19 January 1991 (19.01.91) GB pean patent), BR, CA, CH (European patent), CS, DE (European patent), DK (European patent), ES (European patent), FI, FR (European patent), GB (European (71) Applicant (for all designated States except US): SMITH- patent), GR (European patent), HU, IT (European pa- KLINE BEECHAM P.L.C. [GB/GB]; New Horizons tent), JP, KR, LU (European patent), MC (European pa- Court, Brentford, Middlesex TW8 9EP tent), NL (European patent), NO, PL, SE (European patent), US.

(72) Inventors; and Inventors/Applicants (for US only): SANGER, Gareth, John [GB/GB]; SmithKline Beecham Pharmaceuticals, Cold- Published harbour Road, The Pinnacles, Harlow, Essex CMI9 With international search report.

DOTT, Christopher, Stuart [GB/GB]; 47-49 Before the expiration of the time limit for amending the London Road, Reigate, Surrey RH2 9YF claims and to be republished in the event of the receipt of amendments.

658169 (54)Title: PHARMACEUTICAL COMPOSITION CONTAINING GRANISETRON AND DEXAMETHASONE (57) Abstract 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.

-1- PHARMACEUTICAL COMPOSITION CONTAINING GRANISETRON AND DEXAMETHASONE This invention relates to the use of a compound having 5-HT 3 receptor antagonist activity and dexamethasone in the treatment of emesis, and to pharmaceutical compositions containing the two compounds.

EP-A-200444 (Beecham Group 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.

DexamethaL. ne 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.

S 25 Accordingly, the present invention provides a pharmaceutical product comprising granisetron and a systemic antiinflammatory corticosteroid having anti-emetic properties or a pharmaceutically acceptable salt or ester thereof as a combined preparation for simultaneous use in the treatment and/or prevention of nausea and vomiting.

The present invention also provides a pharmaceutical product comprising granisetron and a systemic anti-inflammatory corticosteroid having anti-emetic properties or a pharmaceutically acceptable salt or ester thereof as a combined preparation when used separately or sequentially in the treatment and/or prevention of nausea and vomiting.

S950130,p:\opr\dab, 1164.spe, I la The present invention further provides a method of treatment and/or prophylaxis of nausea and vomiting, which comprises administering to a human or animal subject, granisetron and a systemic anti-inflammatory corticosteroid having antiemetic properties or a pharmaceutically acceptable salt or ester thereof.

Preferably the systemic anti-inflammatory corticosteroid is dexamethasone.

i l i io i o *o o i« 950130,p;\opc\dab,I 1641.spe,I WO 92/12716 PCT/GB92/00091 -2conjunction with dexamothac-one- o a pharmaceutically acceptable salt or ester therefe for the treatment and/or prevention of nausea and vomitinc- 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. 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 othei 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. Alternatively 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, -3phenylpropionate, 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 (of approximately body weight), is preferably 0.05 to 25mg, more preferably 0.05 to 20mg, and most preferably 0.1 to 10mg 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.

When the two active ingredients are administered as separate preparations, they are preferably given enterally, such as orally or parenterally intramuscularly or, more particularly, intravenously).

According to a further aspect the invention provides a S. pharmaceutical composition, for use in human or veterinary medicine, comprising granisetron and a systemic anti- S1 inflammatory corticosteroid having anti-emetic properties or a pharmaceutically acceptable salt or ester thereof.

SCompositions according to the invention may be formulated in conventional manner using one or more physiologically acceptable carriers or excipients. Thus the compositions may, for example, be formulated for oral, buccal, parenteral 950130,p:oper\dab, 1164 .spe,3 WO 92112716 PCTr/GB92/00091 -4or 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 lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricant magnesium stearate, talc or silica); disintegrants potato starch or sodium starch glycollate); or wetting agent sodium lauryl sulphate).

Tablets may be coated by methods well known in the art.

Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or t.hey 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 sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents lecithin or acacia); non-aqueous vehicles almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives methyl or propyl-2-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.

For parenteral administration the compositions may be presented in a form suitable for bolus injection or continuous infusion. Formulations for injection may be WO 92/12716 PCT/GB92/0009 I 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. Alternatively, the active ingredients may be in powder form fcr constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.

For rectal administration the compositions may be formulated as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.

The pharmaceutical compositions of the irnention may be prepared according to conventional techniques well known in the pharmaceutical industry. Thus, for example, 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.

The 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.

WO 92/12716 PCT/GB2/0009 1 -6- Clinical Studies FIRST STUDY A randomised, double blind, parallel group study comparing the use of granisetron and/or dexamethasone for prophylactic control of cisplatin (2 50 mg/m 2 induced nausea and vomiting is carried out for a period of seven days.

Randomisation is stratified by cisplatin dose (50-74 mg/m 2 and 2 75 mg/m 2 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.

The following are evaluated: o The improvement by dexamethasone of the efficacy of granisetron when both medications are given over a period of 24 hours and seven days.

o The efficacy improvement of dexamethasone in preventing delayed onset nausea and/or vomiting when granisetron is administered from day 2-7.

Patients receiving cisplatin (250 mg/m 2 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: 1. Placebo (saline) 15 minutes infusion to be completed minutes prior to cisplatin infusion (TIME 0) and granisetron 3 mg I.V. 15 minute infusion to be completed 5 min prior to TIME 0 followed by granisetron 1 mg p.o. at 6 and 12h. Granisetron 1 mg p.o. B.I.D. begins at 24h for 6 consecutive days.

WO 92/12716 PCT/GB92/00091 -7- 2. Dexamethasone 10 mg I.V. 15 minute infusion to be completed 20 munutes prior to cisplatin infusion (TIME 0) and granisetron 3 mg I.V. 15 minute infusion to be completed 5 min prior to TIME followed by granisetron 1 mg p.o. at 6 and 12h.

Granisetron 1 mg p.o. B.I.D. and dexamethasone 8 mg p.o. B.I.D. begins at 24h for 6 consecutive days.

3. Dexamethasone 10mg I.V. 15 minute infusion to be completed 20 minutes prior to cisplatin infusion (TIME 0) and granisetron 3 mg I.V. 15 minute infusion to be completed 5 min prior to TIME 0 followed by granisetron 1 mg p.o. at 6 and 12. 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 WO 92/12716 PCT/GB92/00091 -8vomiting, and the use of other anti-emetics over the seven day period.

Secondary efficacy assessments of nausea and vomiting during the first 24 hours determine the increase in efficacy of granisetron by dexamethasone. As well, nausea and vomiting assessments after the first 24 hours determine the increase in efficacy of dexamethasone by granisetron in the maintenance phase of treatment.

SECOND STUDY 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.

The following are primary efficacy assessments: o The percentage of complete responders over the seven day period.

o The time to less than complete response and use of other antiemetics using survival methods over the seven day period.

The following are secondary efficacy assessments: o The percentage of complete responders over the crtical 24 hour period.

o Subjective symptom scoring for nausea and vomiting.

8a Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusiol any other integer or group of integers.

a 941214,p:\oper\dab,1 1641.spe,8

Claims (10)

1. A pharmaceutical product comprising granisetron and a systemic anti-inflammatory corticosteroid having anti-emetic properties or a pharmaceutically acceptable salt or ester thereof as a combined preparation for simultaneous use in the treatment and/or prevention of nausea and vomiting.

2. A pharmaceutical product comprising granisetron and a systemic anti-inflammatory corticosteroid having anti-emetic properties or a pharmaceutically acceptable salt or ester thereof as a combined preparation when used separately or sequentially in the treatment and/or prevention of nausea and vomiting.

3. A method of treatment and/or prophylaxis of nausea and vomiting, which comprises administering to a human or animal subject, granisetron and a systemic anti-inflammatory corticosteroid having anti-emetic properties or a pharmaceutically acceptable salt or ester thereof.

4. A pharmaceutical composition, for use in human or a a veterinary medicine, comprising granisetron and a systemic anti-inflammatory corticosteroid having anti-emetic properties or a pharmaceutically acceptable salt or ester thereof. A product, method or composition according to any one of the preceding claims, wherein the systemic anti-inflammatory corticosteroid having anti-emetic properties is dexamethasone.

6. A product, method or composition according to any one of the preceding claims, wherein the nausea and vomiting is cytotoxic agent-induced. 950130,p:ope.dab, 164 1.spe,9

7. A product, method or composition according to claim 6, wherein the cytotoxic agent is cisplatin.

8. A product, method or composition according to claim 6 or 7, wherein the nausea and vomiting is delayed nausea and vomiting.

9. A product, method or composition according to any one of the preceding claims, wherein the granisetron is in the form of the hydrochloride salt. DATED this 30th day of January, 1995 SmithKline Beecham p.l.c. By Its Patent Attorneys DAVIES COLLISON CAVE e a 4 I Ste*I i n 95130&.p:opcrab 1641.spc,10 INTERNATIONAL SEARCH REPORT International Application No PCT/GB 92/00091 I, CLASSIFICATION OF SUBJECT MATTER (If several classification symbols apply, Indicate all)6 According to International Patent Classification (IPC) or to both National Classification and IPC A 61 K 31/57 61 K 31/57 A 61 K 31:435) II. FIELD5 SEARCHED Minimum Documentation Searched 7 Classification System Classification Symbols A 61 K Documentation Searched other than Minimum Documentation to the Extent that such Documents are Included in the Fields Searched$ ll. DOCUMENTS CONSIDERED TO BE RELEVANT 9 Category 0 Citation of Document, 11 with indication, where appropriate, of the relevant passages 12 Relevant to Claim No. 13 A FR,A,2627986 (GLAXO GROUP LTD) 8 1-8 September 1989, see abstract A Scand. J. Gastroenterol. Suppl., vol. 24, no. 1-8 171, 1989, (Norway), P.A. VAN LIESSUM et al.: "Nausea and vomiting induced by cytostatic agents", pages 106-111, see conclusion A Dialog 03809716 Cancerlit ICDB/9107518, D. 1-8 CUNNINGHAM: "Review of clinical results with 5HT3, antagonists in controlling emesis", (MeetingAbstract), BR. J. CANCER. VOL. 62(3), 1990, P. 480, see abstract i- 0 Special categories of cited documents :10 later document published after the international filing date Sdocument dining the general of the t ic t or priority date and not in conflict with the application but A document definig the general tate of the art which s not cited to understand the principle or theo underlying the considered to be of particular relevance invention arlier document but published on or after the international "X document of particular relevance; the claimed invention iling date cannot be considered novel or cannot be considered to document which may throw doubts on priority claim(s) or involve an inventive step which is cited to establish the publication date of another document of particular relevance; the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu- other means ments, such combination being obvious to a person skilled document published prior to the international filing date but in the art. later than the priority date claimed document member of the same patent family IV. CERTIFICATION Date of the Actual Completion of the International Search Date of Mailing of this lnternational Search Report

21-04-1992 0 0& 92 International Searching Authority EUROPEAN PATENT OFFICE Signature of Authorized Officer Els Vonk L., q-k- I- Fa. :&IISAI10 (sen shmIJ (Ju 19451 International Application No Pa~G 9209

111. DOCUMENTS CONSIDERED TO BE RELEVANT (CONTINUED-FROM THE SECOND SHEET) Category Citation of Document, with indication, Where appropriate, Of the reev2Qt PasSages Relevant to Claitm No. A Dialog 00789857 Cancerlit ICDB/90061960, M. LE 1-8 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. Form PCTISA/210 leOrs 5setI (Jmoy 19M5) International Application No. PCTI GB92100091 FURTHER INFORMATION CONTINUED FROM THE SECOND SHEET I a I OBSERVATION WHERE CERTAIN CLAIMS WERE FOUND UNSEARCHABLE This International search report has not been established In respect of certain claims under Article 17(2)(a) for the following reasons: 1. J Claim numbers because they relate to subject matter not required to be searched by this Authority, namely: Remark: Although claims 2, 5-8 are directed to a method of treatment of the human/animal body the search has been carried out and based on the alleged effects of the compound/composition. 2. D Claim numbers because they relate to parts of the International application that do not comply with the prescribed requirements to such an ixtdnt that no meaningful International search can be carried out, specifically: 3, I Claim numbers the second and third sentences of PCT Rule 6.4(a). because they are dependent claims and are not drafted in accordance with VI] OBSERVATIONS WHERE UNITY OF INVENTION IS LACKING 2 This International Searching Authority found multiple inventions in this Intemational application as follows: 1. As all required additional search fee wre timely paid by the applicant, this nternational search report covrs all searchable claims of the International application 2. As only some of the required additional search fees were timely paid by the applicant, this International search report covers only those claims of the International application for which fees were paid, specifically claims: 3. O No required additional surch fas were timely paid by the applicant. Consequently, this international search report Is restricted to the invention first mentioned in the claims; it Is coverd by claim numbers: 4. As all searchable claims could be searched without effort justifying an additional fee, the International Searching Authority did not invite payment of any additional fee. Remark on Protest The additional search fees were accompanied by applicant's protest. SNo protest accompanied the payment of additional search fees. Form PCT/ISA/210 (supplemental sheet P9412B 05/91 ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. GB 9200091 SA 55552 This annex lists the patent family members relating to the patent documnts cited in the above-mentioned international search report. The members are as contained in the European Patent Office EDP file on 18/05/92 Ihe European Patent Office is in no way liable for these particulars which are merely given for the purpose of information. Patent document Publication Patent family Publication cited in search report date member(s) -Tdate FR-A- 2627986 08-09-89 AU-A- 3097689 07-09-89 BE-A- 1002255 06-11-90 C 678149 15-08-91 GB-A, B 2216414 11-10-89 JP-A- 2096525 09-04-90 NL-A- 8900526 02-10-89 SE-A- 8900751 05-09-89 M For more details about thiI,'~ annex see Official Journal of the European Patent Office, No. 12/82