PT100033B - PHARMACEUTICAL PRODUCTS CONTAINING GRANISETRON AND DEXAMETHASONE USED IN THE TREATMENT OF NAUSEA AND VOMITING - Google Patents

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.

Description

The present invention relates to the use of a compound with dexamethasone ^5_HT ₃ ® receptor antagonist activity in the treatment of emesis, as well as to pharmaceutical compositions containing these two compounds.

Example 6 of EP-A-200444 (Beecham Group p.l.c.), discloses granisetron and its use as an anti-emetic, which is particularly useful in the treatment of nausea and vomiting induced by a cytotoxic agent. All references in this document to granisetron include pharmaceutically acceptable salts, such as hydrochlorides, 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. Dexamethasone is a systemic anti-inflammatory corticosteroid that 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.

Accordingly, the present invention features 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 for the treatment and / or prophylaxis of nausea and vomiting, which comprises administering to a human or animal granisetron and dexamethasone or a pharmaceutically acceptable salt or ester thereof.

The invention further discloses the use of granisetron in the manufacture of a medicament to be administered in conjunction with dexamethasone or its pharmaceutically acceptable salt or ester in the treatment and / or prevention of nausea and vomiting.

Co-administration of granisetron with dexamethasone is particularly useful in the treatment and / or prevention of nausea and vomiting, associated with chemotherapy using cytotoxic drugs, in particular cancer chemotherapy involving the use of, for example, platinum complexes, such as such as cisplatin or carboplatin, cyclophosphamide or doxorubicin. This co-administration can also reduce the delayed or prolonged nausea and vomiting associated with this type of chemotherapy. It should also be noted, in particular, the use made in the treatment of nausea and vomiting resulting from other cytotoxic agents, such as those associated with radiation treatment.

granisetron and dexamethasone or a pharmaceutically acceptable salt or ester thereof can be administered as a simple pharmaceutical composition comprising effective amounts of the two drugs. Alternatively, the two active ingredients can be co-administered in the form of two separate pharmaceutical compositions for simultaneous or sequential use.

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, sulfates, phosphates, citrates, fumarates and maleates. Solvates can, for example, be hydrates. A preferred form of granisetron for use according to the invention is hydrochloride.

Dexamethasone can 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 acetates, isonicotinoates, phenylpropionates, pivalates, t-butyl acetates, trioxaundecanoates, disodium metessulfobenzoates and disodium phosphates.

The granisetron dosage proposed for use according to [

H with the invention for human administration (with a body weight of; approximately 70 kg), is from 0.05 to 25 mg, preferably from 0.05¾ to 20 mg and, above all, from 0.1 to 10 mg per unit of dosage, | already expressed as weight of the free base. A preferred dose of dexamethasone for use according to the invention is within the range | 0.5 to 20 mg per dosage unit., expressed as alcohol weight.

Dosage units can be administered, for example, 1 to 4 times a day. The exact dose will depend on the route of administration and the disease to be treated and it should be borne in mind that it may be necessary to vary the dosing routine according to the age and weight of the patient, as well as the severity of the disease to be treated.

When the two active ingredients are administered as separate preparations, they are given, preferably enterically, for example orally or parenterally (for example, intramuscularly or, more particularly, intravenously).

In another aspect, the invention further provides a pharmaceutical composition for use in human and veterinary medicine, comprising granisetron and dexamethasone or a pharmaceutically acceptable salt or ester thereof.

The compositions according to the invention can be formulated in a conventional manner using one or more pharmaceutically acceptable vehicles or excipients. Thus, the compositions can, for example, be formulated for oral, buccal, parenteral or rectal administration. Compositions for oral administration, in the form of, for example, tablets or capsules, are preferred.

Compositions for oral use, such as tablets and capsules, can be prepared by conventional means with pharmaceutically acceptable excipients such as binders (for example, pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose; fillers (for example, lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (for example, magnesium stearate, talc or silica); disintegrants (for example, potato starch or sodium starch glycolate); or wetting agents (for example, sodium sulfate and The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may be in the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product. for reconstitution with water or another suitable vehicle before use. These liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives, such as suspending agents (for example, sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (for example, lecithin or acacia); non-aqueous vehicles (for example, almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (for example, methyl or propyl-p-hydroxybenzoates or sorbic acid). The preparations can also contain buffer salts, flavoring agents, colors and sweeteners if appropriate.

Preparations for oral administration can be formulated suitably to provide a controlled release of one or both of the active ingredients.

For parenteral administration the compositions can be presented in a form suitable for bolus injection or continuous infusion. Injection formulations can be in the form of dosage units, for example, in syringes, ampoules or in multi-dose containers, to which a preservative is added. The compositions can take forms such as suspensions, solutions or emulsions in oily or aqueous vehicles and can contain formulation agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredients can be presented in powder form, for reconstitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.

For rectal administration the compositions can be formulated as suppositories or retention enemas, containing, for example, conventional suppository bases such as cocoa butter or other glycerides.

The pharmaceutical compositions of the invention can be prepared according to conventional techniques well known in the pharmaceutical industry. Thus, for example, granisetron and dexamethasone or the salt or ester of dexamethasone can be mixed with each other, if desired with suitable excipients. Tablets can be prepared, for example, by direct compression of such a mixture. Capsules can be prepared by introducing the mixture into gelatin capsules together with suitable excipients and using an appropriate filling machine. Controlled release forms for administration

I

oral or rectal can be formulated in a conventional manner, associated with a controlled release form.

The compositions to be used according to the invention can, if desired, be presented in a packaging or dispensing device and may include one or more unit dosage forms containing the active ingredients. The package may comprise, for example, a metal or plastic sheet, as is the case with packages with perforable vesicles. The packaging or dispensing device may be accompanied by instructions for administration. When granisetron and dexamethasone are to be administered as two separate compositions, they can be presented in the form of, for example, a double pack.

Clinical studies

First Study

A randomized, double-blind, parallel group study was carried out over a seven-day period comparing the use of granisetron and / or dexamethasone for the prophylactic control of cisplatin-induced nausea and vomiting (> 50 mg / m). The random character is staggered through the dose of cisplatin (50-74 mg / m and> 75 mg / m). Patients receive 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 is assessed:

improvement through dexamethasone of the effectiveness of granisetron when the two drugs are administered over a 24-hour period for seven days.

* The increased effectiveness of dexamethasone in preventing the onset of nausea and / or delayed vomiting when granisetron is administered from day 2 to day 7.

Patients who are undergoing a therapy. . 2 cisplatin (> 50 mg / m) due to a malignant disease are randomly distributed in a double blind manner, staggered according to the dosage of cisplatin, in order to receive the medication being studied.

study scheme consists of 3 treatment routes:

1. A 15-minute placebo (saline) infusion to be completed 20 minutes before cisplatin infusion (TEMPO 0) and a 15-minute infusion of 3 mg of granisetron to be completed 5 minutes before TIME 0 followed by 1 mg of granisetron po at 6 and 12 o'clock. Making granisetron p.o. b.i.d. (bis in die = twice a day) starts at 24 hours for 6 consecutive days.

2. A 15 minute infusion of 10 mg of dexamethasone iv to be completed 20 minutes before the cisplatin infusion (TEMPO 0) and a 15 minute infusion of 3 mg of granisetron iv to be completed 5 minutes before the (TEMPO 0) followed by 1 mg of granisetron po at 6 and 12 o'clock.

Taking 1 mg of granisetron p.o. b.i.d. starts at 6 am for consecutive days.

3. A 15-minute infusion via i.v. to be completed with cisplatin (TEMPO 0) and 3 mg of granisetron per minute before (TEMPO 0) tron p.o. at 6 and 12 o'clock.

10 mg dexamethasone per minute before infusion a 15 minute i.v. infusion to be completed 5 followed by 1 mg of graniseThe taking of 8 mg of granisetron p.o. b.i.d. starts at

hours for 6 consecutive days.

The patients' clinical status is assessed using the WHO classification, and they must have a score of 2 or less. None of the patients are aware of cytotoxic therapy in order to avoid anticipatory emesis.

Patients who experience nausea and vomiting after cisplatin therapy may be given up to four doses of prochloroperazine (10 mg suppositories) per day. If nausea and vomiting continue after taking it in such a way that other anti-emetics must be administered, the doctor will decide whether or not to stop the study medication and / or treat with usual anti-emetics. Insofar as it is clinically safe, patients maintain the study medication for as many of the seven days of the treatment period as possible.

The main assessments of effectiveness in the study are the percentage of complete responses, the time to first vomiting and the use of other antiemetics during the seven-day period.

Secondary evaluations of efficacy in the study of nausea and vomiting during the first 24 hours determine the increased effectiveness of granisetron by dexamethasone. Likewise, assessments of nausea and vomiting after the first 24 hours determine the increased effectiveness of dexamethasone by granisetron in the treatment maintenance phase.

Second Study

A randomized, double-blind, parallel group study was carried out over a seven-day period comparing the oral use of granisetron (1.0 mg bd) combined with dexamethasone (12 mg iv) only on the first day, and conventional anti-emetic therapy. (metoclopramide 7 mg / kg iv plus dexamethasone 12 mg

i.v. on the first day, followed by metoclopramide 10 mg p.o. t.d.s (ter die sumendum = taken 3 times a day) for a period of 7 days to control nausea and vomiting induced by cisplatin.

The following are the main efficacy assessments:

* Percentage of complete responses over the seven-day period.

* Non-complete response time and use of other antiemetics using survival methods over the seven-day period.

The following are secondary efficacy assessments:

Percentage of complete responses during a critical 24-hour period.

* Number of subjective symptoms related to nausea and vomiting.

Claims (7)

1 ^a . - Pharmaceutical product, characterized by comprising granisetron and dexamethasone, in the form of a combined preparation, to be used simultaneously, separately or sequentially in the treatment and / or prevention of nausea and vomiting, with the amount of granisetron from 0.05 to 25 mg per dosage unit and dexamethasone from 0.5 to 20 mg per dosage unit. 2 ^a . - Use of granisetron, characterized in that granisetron is used in the manufacture of a medicine to be administered in conjunction with dexamethasone or a pharmaceutically acceptable salt or ester in the treatment and / or prevention of nausea and vomiting. 3 ^a . - Pharmaceutical composition, for use in human and veterinary medicine, characterized by comprising granisetron and dexamethasone or a pharmaceutically acceptable salt or ester thereof, with the amount of granisetron from 0.05 to 25 mg per dosage unit and dexamethasone of 0.5 to 20 mg per dosage unit. 4 ^a . - Product, use or composition according to claims 1, 2, or 3, characterized in that nausea and vomiting are induced by a cytotoxic agent. 5 ^a . - Product, use or composition according to claim 4, characterized in that the cytotoxic agent is cisplatin. χ ¹ * 6 ^a . - Product, use or composition according to claim 4 or 5, characterized in that the nausea and vomiting are nausea and delayed vomiting. 7 ^a . - Product, use or composition according to any one of the preceding claims, characterized in that the granisetron is in the form of the hydrochloride salt.