JPH06507152A - Pharmaceutical composition containing granisetron and dexamethasone - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Pharmaceutical composition containing granisetron and dexamethacin The present invention is useful in the treatment of emesis. Compounds with 5-HTI receptor antagonist activity and dexamethacin (dexa methasone) and pharmaceutical compositions containing the two compounds. Regarding.

European Patent Publication No. 200444 (EP-A-200444) (Beacham ・Group Public Limited Company (Beecham Group) p p, 1. c, ) in Example 6, granisetro n), and as an antiemetic, especially for cytotoxic drug-induced nausea and vomiting. Discloses useful uses in therapy. Reference herein to granisetron are all pharmaceutically acceptable salts, such as hydrochlorides, and hydrates, such as solvates. includes.

The anti-emetic properties of granisetron make it possible for the compound to be used in systemic drugs such as dexamethacin. Potentially potentiated when administered in combination with ticosteroids. Dexa Metacin is a systemic anti-inflammatory corticosteroid, which has anti-emetic properties and Chemotherapy, particularly including the use of eg cisplatin It is known to be useful in the treatment of emesis resulting from cancer chemotherapy.

Therefore, the present invention provides simultaneous treatment and/or prevention of nausea and vomiting. , granisetron and dexamethacin as a combination preparation for separate or sequential use. The present invention provides a pharmaceutical product comprising:

The invention further provides granisetron and dexamethacin or their pharmaceutically acceptable Administering salts or esters to human or mammalian subjects. Provided are methods for treating and/or preventing heart disease and emesis.

Furthermore, the present invention provides dexamethacin or a pharmaceutically acceptable salt or salt thereof. Administered in combination with Stel to treat and/or prevent nausea and vomiting. Provided is the use of granisetron for the manufacture of a medicament for patients.

Coadministration of granisedrone and dexamethacin is recommended for chemotherapy with cytotoxic drugs. methods, in particular, for example, cisplatin or carboplatin (carboplatin) platinum complexes such as n) or cyclophosphamide (cylcophosph amide) or doxorubicin (doxorubicin) Particularly useful in the treatment and/or prevention of nausea and vomiting associated with cancer chemotherapy It is. Such co-administration may further reduce the risk of delayed or sustained chemotherapy associated with this type of chemotherapy. Type nausea and vomiting can be reduced. Additionally, the adverse effects associated with other cytotoxic drugs Used in the treatment of heart disease and vomiting, such as nausea associated with radiation therapy It can also be mentioned.

Granisetron and dexamethacin or a pharmaceutically acceptable salt or salt thereof Esters can be administered as a single pharmaceutical composition combining effective amounts of the two active ingredients. I can give. Alternatively, the two active ingredients may be combined for simultaneous or sequential use. Coadministration may also be in the form of two separate pharmaceutical compositions.

Suitable pharmaceutically acceptable salts of granisetron for use in accordance with the present invention may be organic or or acid addition salts formed with inorganic acids, such as hydrochlorides, hydrobromides, sulfates. , including phosphate, citrate, fumarate and maleate. solvate may be, for example, a hydrate. Preferred form L) for use according to the invention Lanisetron is its hydrochloride.

According to the invention, dexamethacin can also be used as dexamethacin alcohol. can be administered in the form of a pharmaceutically acceptable salt or ester. Appropriate salt and salt Stell is acetate, isonicotinoate, phenylpropionate, pinocula t-butyl acetate, trioxaundecanoate, metasulfobenzoate disodium phosphate and disodium phosphate.

Granicet used according to the invention when administered to humans (of 70 kg body weight) Ron's suggested dosage is for 0.05-25 mg/unit, calculated as free base weight. amount, more preferably 005 to 20 mg/unit dose, most preferably l;! 0.1~ 10 mg/unit dose. Preferred L1 of dexamethacin used according to the invention The dose ranges from 5 to 20 mg/dose unit calculated as the weight of the alcohol. (There it is.

A unit dose may be administered, for example, from 1 to 4 times on -day. The exact dose depends on the route of administration and depending on the age and weight of the patient and the condition being treated. It is recognized that it may be necessary to make routine variations in dosage depending on the severity. Will.

When the two active ingredients are administered as separate preparations, they may be administered enterically, e.g. orally. or parenterally (e.g., intramuscularly or even intravenously). is preferable.

According to a further aspect, the invention provides granisetron and dexamethacin or is a human or veterinary drug consisting of a pharmaceutically acceptable salt or ester thereof. The present invention provides a pharmaceutical composition for use in.

Compositions according to the invention include one or more physiologically acceptable carriers or excipients. It can be prescribed by conventional methods using excipients. Thus, the composition can be administered, for example, orally, May be formulated for cal, parenteral or rectal administration. The composition may be, for example, a tablet or is preferably for administration by the oral route in the form of a capsule.

Compositions for oral use, such as tablets and capsules, may be pre-filled with a binder (e.g. gelatin). Tinylated corn starch, polyvinylpyrrolidone or hydroxypropylene methyl cellulose): fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate), lubricants (e.g. magnesium stearate, talc) or silica): disintegrant (e.g. potato starch or sodium starch glycol) or a pharmaceutically acceptable wetting agent (e.g., sodium lauryl sulfate); It can be prepared by conventional means together with excipients. Tablets are well known in the field. It may be coated by a method described above. Liquid preparations for oral administration include, for example, solutions, It may be in the form of a liquid solution or suspension, or mixed with water or other suitable solution before use. It can be provided as a dry product that is reconstituted with a vehicle. This kind of liquid The product may contain suspending agents (e.g. sorbitol syrup, cellulose derivatives or hardened edible fats): emulsifiers (e.g. lecithin or acacia); non-aqueous vehicles (e.g. tonsil oil, oily esters, ethyl alcohol or fractionated vegetable oil); and preservatives (e.g. methyl or propyl p-hydroxybenzoate or sorbitol) It can be prepared by conventional means together with pharmaceutically acceptable additives such as phosphoric acid). Applicable The preparations may further contain buffer salts, flavoring agents, coloring agents and sweetening agents, as appropriate. You can stay there.

Preparations for oral administration suitably control the release of one or both of the active ingredients. It may be prescribed as follows.

For parenteral administration, the composition may be in a form suitable for porous injection or continuous infusion. can be provided. Formulations for injection are in unit dosage form with added preservatives. , for example, by syringe, ampoule, or multi-dose container. I can do it. The compositions may be prepared as suspensions, solutions or solutions in oily or aqueous vehicles. Can be in a emulsion-like form and contain suspending agents, stabilizers and/or may contain additives such as dispersants. Also, its active ingredients should be It may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water. stomach.

For rectal administration, the compositions may include, for example, cocoa butter or pond glycerides. It can be formulated as a suppository containing a conventional suppository base or as a retention enema.

The pharmaceutical compositions of the present invention are prepared according to conventional techniques well known in the pharmaceutical industry. Can be built. Thus, for example, granisetron and dexamethacin or Mix the sametasin salt or ester with suitable excipients, if desired. It's okay. Tablets can be manufactured, for example, by direct compression of such mixtures. Wear. Capsules are made by using a suitable filling machine and combining the blend with suitable excipients. It can be manufactured by filling it into gelatin capsules. for oral or rectal administration Modified release forms can be formulated in a manner conventional for modified release forms.

The compositions used in accordance with the invention may optionally be prepared in unit dosage forms containing the active ingredient. Can be administered in a bag or dispenser device that may contain Ru. The puncture may be made of metal or plastic, such as a blister bag. It may also consist of foil. The bag or dispenser device contains Instructions for use may be attached. granisetron and dexamethacin If they are to be administered as two separate compositions, they may e.g. It can be provided in the form of a book.

/Subratin (≧50mg/m2-induced nausea and vomiting prophylaxis) A randomized double trial comparing the use of nicetron and/or dexamethacin Blinded peer group experiments are conducted over a 7 day period. Randomized cisplatin Graded by dose (50-74 mg/m2 and ≧75 mg/m2).

The patient received granisetron for 7 days, granisetron and dexamethacin for 7 days, or granisetron and dexamethacin for 1 day, followed by dexamethacin for 6 days I'll either take it for a while.

Evaluate the following: ○ Both drugs granisetron and dexamethacin were administered for 24 hours and Improvement of the efficacy of granisetron by dexamethacin when administered for 7 days.

○ Delayed nausea and/or vomiting when granisetron is administered for 2 to 7 days. Improving the efficacy of dexamethacin in preventing vomiting morbidity.

Patients receiving cisplatin (≥50 mg/m2) therapy for malignant symptoms were tested in a double-blind manner. Randomized according to the method, graded according to subratin dose, administer.

The experimental design consists of three treatment arms.

1 15 minute injection of Bracepo (normal saline) and cisplatin injection (time 0) A 15-minute infusion of granisetron 3 mg (+, V,) was completed 20 minutes before Granisetron 1 mg (p , o, ). Granisetone on 1mg (p, o, , B, 1.D,) Start 24 hours later and continue for 6 consecutive days.

2 A 15-minute infusion of dexamethacin 10 mg (1, V,) was combined with a cisplatin injection. 20 minutes before admission (time 0), I finished the treatment and started taking granisetron 3mg (1,V,) for 15 minutes. The minute infusion was completed 5 minutes before time 0, followed by granicet injection at 6 and 12 hours. Do Ron 1mg (p, o,).

Granisetron 1mg (p, o, B, 1.D,) and dexamethacin 8m g(p, o, B, 1.D,) starting 24 hours later and continuing for 6 days.

3. A 15-minute infusion of dexamethacin 10 mg (1, V,), followed by a cisplatin injection. Completed 20 minutes before injection (time O), 15 minutes of granisetron 3 mg (1, V,) The inter-infusion was completed 5 minutes before time O, followed by granisetron 1 m at 6 and 12. g (p, o,) is administered. Dexamethacin 8mg (p, o, B, 1 ．． D,) starts 24 hours later and continues for 6 days.

The patient's disease symptoms are evaluated using the WHO classification system. The patient has 2 or less Must be rated. All patients are thin #2i! Inexperienced with toxic therapy Yes, prior vomiting is avoided.

Patients who develop nausea and vomiting after nosplatin therapy have up to 4 of prochlorperazine (10 mg suppository). Nausea and vomiting continue after this. If so, in that case, other antiemetics should be administered and the doctor should not administer the drug. Decide whether to stop the trial and/or treat with standard anti-emetics. Set. Patients should take their medications for as long as possible for a 7-day treatment period, as long as it is medically safe. Continue experimenting.

Primary efficacy in the experiment was determined by percentage of complete responders, time to first vomiting, and and the use of other antiemetics over a 7-day period.

A secondary efficacy assessment of nausea and vomiting during the first 24 hours was with dexamethacin. To measure the increase in granisetron efficacy. In addition, nausea after the first 24 hours and Evaluation of vomiting should be performed during the maintenance phase of treatment, including dexame treatment with granisetron. It measures the increase in the efficacy of Tacin.

A randomized, double-blind, homogeneous group study consisted of oral rogranisetron (1.0 mg, bd), oral logranisetron and dexamethacin (12 mg, iv) on the first day only, and in regulating cisplatin-induced nausea and vomiting over a 7-day period. , conventional antiemetic therapy (metoclopramide 7 mg/kg iv ± dexame on the first day) Combination with Tacin 12mg 1v, then metoclopramide 10mg tds po) Compare and match the results.

The primary efficacy assessment was as follows: percentage of complete responders over 07 days. ○ Time to incomplete response and use of other antiemetics over 7 days The next efficacy evaluation is as follows: o Percentage of complete responders over critical 24 hours o For nausea and vomiting Subjective symptom rating international survey report term PCl5A1? +Oτ4 square width v breath 1 s bit -1211-P9a11 1+6?1 International Search Report Continuation of front page (51) Int, C1,5 identification symbol Internal office reference number A61K 31/71 8 314-4C (72) Inventor: Dot Christopher Stuart, UK Countryside R.H. 2.9YF, Reigate, 47 London Road. No. 49 I

Claims (8)

[Claims] 1. Simultaneously, separately or sequentially in the treatment and/or prevention of nausea and vomiting Combination preparations for use, such as granisetron and dexamethasone A pharmaceutical product characterized in that: 2. Granisetron and dexamethasone or their pharmaceutically acceptable salts or treatment of nausea and vomiting consisting of administering esters to human or animal subjects. Methods of treatment and/or prevention. 3. Combining dexamethasone or its pharmaceutically acceptable salts or esters for the manufacture of medicaments for the treatment and/or prevention of nausea and vomiting Use of granisetron. 4. granisetron, and dexamethasone or a pharmaceutically acceptable salt thereof or ester for use in human or veterinary medicine. 5. Claim 1, 2, 3 or 4, wherein nausea and vomiting are induced by the cytotoxic agent. Products, methods, uses or compositions described. 6. The product, method, use or method of claim 5, wherein the cytotoxic agent is cisplatin. Composition. 7. 7. The production according to claim 5 or 6, wherein the nausea and vomiting is delayed nausea and vomiting. Articles, methods, uses or compositions. 8. Any one of the preceding claims, wherein granisetron is in the form of the hydrochloride salt. Products, methods, uses or compositions.