WO2004045612A1

WO2004045612A1 - Use of a proton pump inhibitor for preventing postoperative nausea and vomiting

Info

Publication number: WO2004045612A1
Application number: PCT/SE2003/001774
Authority: WO
Inventors: Ulrich Thissen
Original assignee: Astrazeneca Ab
Priority date: 2002-11-18
Filing date: 2003-11-14
Publication date: 2004-06-03
Also published as: AU2003279667A1; WO2004045612A8; SE0203410D0

Abstract

A method for preventing postoperative nausea and vomiting in patients following anaesthesia by prophylaxis and/or treatment with a proton pump inhibitor compound. The proton pump inhibitor compound may be administered alone and/or in combination with other drugs, such as an 5-HT3 receptor antagonist and/or a corticosteriod. The method is also applicable more in general in patients on high risk of nausea and vomiting.

Description

Use of a proton pump inhibitor for preventing postoperative nausea and vomiting

Field of the invention.

The present invention relates to a method for preventing postoperative nausea and vomiting in patients following anaesthesia by prophylaxis and/or treatment with a proton

+ + pump inhibitor compound, also named an H K ATPase inhibitor. In more general terms, the invention relates to a method for preventing nausea and vomiting in patients by administration of a proton pump inhibitor, and especially in patients following anaesthesia.

The proton pump inhibitor compound may be administered alone and/or in combination with other drugs. Such drugs are preferably found among drugs already approved for used in the prophylaxis and treatment of postoperative nausea and vomiting such as 5-HT3 receptor antagonists as well as drugs promoting gastric emptying.

Background of the invention

There are many reports in the literature on postoperative nausea and vomiting following anaesthesia (PONN = postoperative nausea and vomiting). It is reported that about 20-30 % of patients experience significant postoperative problems despite prophylaxis. (Apfel CC, Roewer Ν, Korttila K., How to study postoperative nausea and vomiting. Acta Anaesthesiol Scand 2002; 46(8): 921-8). The relative efficacy of antiemetics, such as ondansetrone, for the treatment of POΝV is poorly understood. The benefit of routine prophylactic antiemetic treatment has been questioned because antiemetics may have side effects and therefore patients' feeling may not necessarily improve. There are reports in the literature, which deal with risk stratification of patients and prophylaxis and therapy. (Empfehlungen fur randomisierte kontrollierte Studien zur Vorbeugung oder Therapie von Ubelkeit undErbrechen nach Narkosen. AnSsthesiologie und Intensivmedizin 2002; and Apfel CC, Laara E, Koivuranta M, Greim CA, Roewer Ν., A simplified risk score for predicting postoperative nausea and vomiting: conclusions from cross-validations between two centers. Anesthesiology 1999 Sep; 91(3): 693-700). According to Apfel et al established risk factors of PONN include: female gender, non-smokers, history of previous POΝN following anaesthesia or history of movement sickness, and treatment with opiates during and after operation. It is also known that specific operations may have a high risk of POΝN, such as gynaecological, abdominal, eye and ear-nose-throat surgery.

One of the predominant therapies is the administration of a 5-HT3 receptor antagonist, such as ondansetron. (Kazemi-Kjellberg F, Henzi I, Tramer MR. Treatment of established postoperative nausea and vomiting: a quantitative systematic review. BMC Anesthesiol 2001; 1(1): 2).

Proton pump inhibitors have in clinical studies been proven to be very effective in providing symptom resolution (usually within 24 - 48 hours) in patients with dyspepsia associated with gastric ulcers, duodenal ulcers, reflux esophagitis and gastroesophageal reflux without esophagitis. It is for instance established that omeprazole is superior to H2 receptor antagonists regarding healing of gastro duodenal and esophageal lesions as well as providing dyspeptic symptom resolution in these conditions. The newly launched esomeprazole has further advantages over omeprazole.

There are also proposals in the patent literature that a combination of drugs may be used in the treatment of gastrointestinal disorders. For instance, EP 813424 relates to a composition comprising an antacid/alginate and a proton pump inhibitor. EP 814840 relates to a composition comprising a motility stimulating agent and a proton pump inhibitor. Furthermore, EP 0 272 876 discloses a combination of a compound which is a 5- HT3 receptor antagonist promoting gastric emptying and a compound which is an H⁺K⁺ATPase inhibitor.

Nevertheless, issues concerning the patients' quality of life and comfort after surgical procedures have increasingly become important in the last few years. The tendency towards day-case surgery and a reduction in the length of stay in cost-intensive units (intensive care unit, recovery room, ward) has intensified the efforts to avoid and prevent especially postoperative nausea and vomiting (PONN) as well as nausea and vomiting in patients following anaesthesia generally.

There are no reports or suggestions in the literature so far about the use of a proton pump inhibitor in the prophylaxis and treatment of POΝN or following anaesthesia treatment in general.

One of the most well known proton pump inhibitors is omeprazole, i.e. the compound 5- methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole, and therapeutically acceptable salts thereof, are described in EP 5129. Specific alkaline salts of omeprazole are disclosed in EP 124495.

Omeprazole is a sulfoxide and a chiral compound, wherein the sulfur atom being the stereogenic center. Thus, omeprazole is a racemic mixture of its two single enantiomers, the R- and S-enantiomer of omeprazole, herein referred to as (RJ-omeprazole and (S)- omeprazole, the latter having the generic name esomeprazole. Certain salts of single enantiomers of omeprazole and a process for their preparation are disclosed in WO 94/27988. Esomeprazole has improved pharmacokinetic and metabolic properties compared with omeprazole, which will give an improved therapeutic profile such as lower degree of interindividual variation.

WO 96/02535 discloses an efficient process for the preparation of the single enantiomers of omeprazole and salts thereof.

Most proton pump inhibitors are susceptible to degradation/transformation in acidic reacting and neutral media. In respect to these stability properties, it is obvious that such proton pump inhibitor on oral administration must be protected from contact with acidic gastric juice for instance by an enteric coating layer. There are different enteric coating layered preparations of proton pump inhibitors described in the prior art, see for example US-A 4,786,505 and WO 96/01623. Outline of the invention

According to one aspect of the present invention it has been found that administration of a proton pump inhibitor to patients as a prophylaxis and/or treatment before and during anaesthesia is an effective method for preventing nausea and vomiting, and especially nausea and vomiting post-operatively (PONN).

According to another aspect of the invention the administration of a proton pump inhibitor applies also in a more general sense as a prevention and/or treatment of manifest vomiting especially to patients at high risk to develop these conditions. Such high-risk patients can be found among the female sex, non-smokers and people subjected to movement illness, such as for instance seasickness, and these taking opiates during and after surgery.

According to a further aspect of the invention the administration of the proton pump inhibitor may be a combined administration of the proton pump inhibitor and a 5-HT3 receptor antagonist, and/or a corticosteroid.

The proton pump inhibitor used according to the present invention is preferably such as for instance 5-methoxy-2- [[(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl] sulfinyl]-lH- benzimidazole, having the generic name omeprazole or one of its enantiomers, the (S)-5- methoxy-2- [[(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl] sulfinyl]-lH-benzimidazole, having the generic name esomeprazole. Other suitable proton pump inhibitor compounds are for instance lansoprazole, pantoprazole and rabeprazole as well as their single enantiomers and pharmaceutically acceptable salts thereof.

The proton pump inhibitor to be used in the claimed method is in neutral form or in the

2+ 2+ + + form of an alkaline salt, such as for instance the Mg , Ca , Νa , K or a primary amine salt. According to one aspect of the invention the proton pump inhibitor is omeprazole or

2+ + esomeprazole in the form of an alkaline salt such as the Mg or Νa salt. The active compound may be administered orally, rectally or parenterally (intravenously) depending on the type of administration route and available pharmaceutical formulation.

Since the effect on nausea and vomiting have been established in patients who have taken a proton pump inhibitor intravenously or by the oral route, it is believed that the improved effect of the proton pump inhibitor is a systemic effect which is not dependent on what mode of administration that is used, and that accordingly the improvement will be seen also with other routes of administration such as rectal or parenteral administration.

Commercially available pharmaceutical formulations of the proton pump inhibitors will normally be used in the claimed method, i.e. for preventing postoperative nausea and vomiting, especially those following anaesthesia. Presently commercially available formulations marketed under the tradename Losec and Losec MUPS (Losec is also

® ® named for instance Prilosec and Antra in some countries) are based on omeprazole and

® omeprazole magnesium, respectively. Losec for intravenously administration is based on

® omeprazole sodium. Another commercially available product is Nexium , based on esomeprazole magnesium and sold in the form of enteric coating layered pellets filed in a capsule or formulated into a multiple unit tablet, alternatively the recently available

® Nexium for intravenously administration based on esomeprazole sodium.

Being a labile compound with poor storage stability at neutral or acid pH, pharmaceutical formulations of the proton pump inhibitor compound must be produced with great care. Examples of ways of producing stable formulations are given in e.g. EP 247 983, EP 723 476, EP 652751 and WO01/28558 hereby incorporated by references.

The dose of the proton pump inhibitor compound to be administered in the treatment of invention will vary depending on factors such as the severity of the condition and the status of the patient. The dosage range at oral, rectal as well as intravenous administration may be in the interval from 1 to 100 mg per dosing. Normally, an amount of from 10 to 40 mg of the active ingredient per dosing and more preferred 20 mg and 40 mg is envisaged per dosing.

The method for prophylaxis and/or treatment of nausea and vomiting in patients following anaesthesia will include at least one administration of proton pump inhibitor before starting anaesthesia and optionally at least one administration after. One preferred method comprises administration of three separate doses of the proton pump inhibitor, two doses before anaesthesia and one dose after. If the anaesthesia is in connection to surgery, the doses are administered pre- and post-operatively. A combination of oral and intraveously administration may be used depending on the patient's status, a suitable administration regiment may include for instance 12 hours before anaesthesia intraveous or oral administration, 30 minutes before (preoperation) intravenous administration and 12 hours after (postoperatively) oral administration of the proton pump inhibitor. A suitable dosing includes for instance esomeprazole 40 mg per dosing, i.e a total of 120 mg esomeprazole, but also 120 mg esomeprazole by infusion may be used, or single injections of 40 mg.

The proton pump inhibitor may be administered alone and/or in combination with other drugs, such as a 5-HT3 antagonist. Furthermore, a combination of a proton pump inhibitor, and a corticosteroid, as well as a trippel combination of a proton pump inhibitor, a 5-HT3 antagonist and a corticosteriod is within the scope of the present invention.

The 5-HT3 antagonist is for instance ondansetrone, granisetrone, dolasetrone and tropisetrone with an administration in the interval from 1 to 8 mg per dosing.

A suitable corticosteroid is for instance dexamethasone.

A suitable combination according to the present invention will be 4 mg ondansetrone and 40 mg esomeprazole per dosing. Alternatively, 40 mg esomeprazole can be re-placed by 20 mg omeprazole in this regiment. The invention is further exemplified by the following non- limited case studies. The result from Study 1 shows that the use of a proton pump inhibitor as prophylaxis in patients at high risk of PONN is effective. Study 2 shows good response to administration of a proton pump inhibitor in the treatment of manifest vomiting. Study 3 is proposed and aimed to show that the use 40 mg esomeprazole as "pre-treatment" is particularly suited for the peri- and post-operative phase due to its rapid onset of action and long duration of effect.

Study 1

Intravenously administration of anaesthetics was used in all patients; i.e. TINA (total intravenous anaesthesia with propofol) as a pre-treatment of surgery.

Patients with high risk of POΝV were given antiemetic prophylaxis, for instance intravenous ondansetrone at the end of anaesthesia. Despite this prophylaxis, the incident of POΝV remained unacceptably high.

35 patients were successfully treated for POΝN. These patients obtained administration of

® Antra 40 mg intravenously (omeprazole sodium salt) in addition to a prophylaxis with an antiemetic drug such as intravenously administration of ondansetrone. Three patients complained about slight nausea and one vomited once, but the overall experience from the patients compared to previous anaesthesia was expressed as an improvement.

Study 2

Six patients suffering from severe vomiting postoperatively were given Antra 40 mg intravenously (omeprazole sodium salt) as a treatment of POΝV. The frequency of nauseas and vomiting were reduced in this group compared to the general frequency in this population.

Study 3 The effect of a proton pump inhibitor in the prophylaxis of nausea and vomiting following anaesthesia (PONN) will be confirmed in a study comprising 50 patients given esomeprazole and 50 patients given placebo.

®

50 patients will be treated with Nexium 40 mg orally (esomeprazole magnesium salt) the evening before operation, 2 hours before starting total anaesthesia and 24 hours after the second dose.

These results will be compared with the results from 50 patients given placebo as a prophylaxis of POΝN.

In addition, the patients may receive a combination of esomeprazole and the 5-HT3 receptor antagonist ondansetrone or the corticosteroid dexamethasone in this or in further studies.

Claims

Claims:

1. A method for prophylaxis and/or treatment of postoperative nausea and vomiting in patients following anaesthesia, wherein a therapeutically effective dose of a proton pump inhibitor compound or a pharmaceutically acceptable salt thereof is administered to a patient suffering therefrom. .

2. A method for prophylaxis and/or treatment of nausea and vomiting in a patient suffering from such a condition, wherein a therapeutically effective dose of a proton pump inhibitor compound or a pharmaceutically acceptable salt thereof is administered to the patient.

3. A method according to any of claims 1 or 2, wherein the method comprises administration of a combination of a proton pump inhibitor and a 5-HT3 receptor antagonist.

4 A method according to any of claims 1 or 2, wherein the method comprises administration of a combination of a proton pump inhibitor and a corticosteroid.

5. A method according to any of claims 1 or 2, wherein the method comprises administration of a combination of a proton pump inhibitor, a 5-HT3 receptor antagonist and a corticosteroid.

6. A method according to any of claims 1 - 5, wherein the proton pump inhibitor compound is 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-lH- - - -X- 4- -4- bbeennzziimmiiddaazzoollee ((oommeepprraazzole) or an alkaline salt thereof selected from Mg , Ca , Na ,K or a primary amine salt.

7. A method according to any of claims 1 - 5, wherein the proton pump inhibitor compound is (S)-5-methoxy-2- [[(4-methoxy-3 ,5-dimethyl-2-pyridinyl)methyl] sulfinyl] - 2+ 2+ lH-benzimidazole (esomeprazole) or an alkaline salt thereof selected from Mg , Ca ,

+ + Na , K , or a primary amine salt.

8. A method according to any of claims 1 - 5, wherein the proton pump inhibitor compound is lansoprazole, pantoprazole, rabeprazole or one of the single enantiomers thereof or a pharmaceutically active salt thereof.

9. A method according to any of claims 1 - 5 or 1, wherein the administered proton pump inhibitor is esomeprazole magnesium salt.

10. A method according to any of claims 1 - 5 or 7, wherein the administered proton pump inhibitor is esomeprazole sodium salt.

11. A method according to any of claims 1 - 5, wherein the proton pump inhibitor compound is administered orally.

12. A method according to any of claims 1 - 5, wherein the proton pump inhibitor is administered parenterally.

13. A method according to any of claims 1 - 12, wherein the proton pump inhibitor is administered in at least one dosing of from 1 to 100 mg before anaesthesia and optionally one dosing after.

14. A method according to claim 13 wherein the proton pump inhibitor is administered in a dose of from 10 to 40 mg.

15. A method according to claim 3 comprising administration of an effective amount of omeprazole or esomeprazole or a pharmaceutically acceptable salt thereof in combination with ondansetrone.

16. A method according to claim 4 comprising administration of an effective amount of omeprazole or esomeprazole or a pharmaceutically acceptable salt thereof in combination with dexamethasone.

17. Use of a proton pump inhibitor or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treatment and/or prophylaxis of nausea and vomiting following anaesthesia in a patient.

18. Use of a proton pump inhibitor or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for prophylaxis and/or treatment of nausea and vomiting in a patient suffering from such a condition.

19. Use according to any of claims 17 or 18 wherein the manufacure of a medicament comprises a combination of a proton pump inhibitor and an 5-HT3 receptor antagonist.

20. Use according to any of claims 17 or 18 wherein the manufacure of a medicament comprises a combination of a proton pump inhibitor and a corticosteroid.

21. Use according to any of claims 17 or 18 wherein the manufacure of a medicament comprises a combination of a proton pump inhibitor, an 5-HT3 receptor antagonist and a corticosteroid.

22. Use according to any of claims 17 - 21 characterised in that the proton pump inhibitor is 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-lH- benzimidazole (omeprazole) or an alkaline salt thereof.

23. Use according to any of claims 17 - 21 characterised in the proton pump inhibitor is (S)-5-methoxy-2- [ [(4-methoxy-3 ,5-dimethyl-2-pyridinyl)methyl] sulfinyl] - 1 H- benzimidazole (esomeprazole) or an alkaline salt thereof.

24. Use according to claim 20 characterised in that the manufacture comprises a combination of esomeprazole or a pharmaceutically acceptable salt thereof and ondansetrone or a pharmaceutically acceptable salt thereof.

25. Use according to claim 21 characterised in that the manufacture comprises a combination of esomeprazole or a pharmaceutically acceptable salt thereof and dexamethasone or a pharmaceutically acceptable salt thereof.