HK40013552A - Rescue treatment of post operative nausea and vomiting - Google Patents

Description

Remedial treatment of postoperative nausea and vomiting

Technical Field

The present invention relates to the use of amisulpride in the treatment of post-operative nausea and/or vomiting (PONV).

Background

PONV is a condition that occurs in approximately 30% of all surgical patients and 70% of high risk patients. Risk factors for PONV include: type of surgery, sex, history of smoking, past history of PONV or motion sickness, length of surgery, use of volatile anesthetics, and use of opioid analgesics. Generally, women are more prone to developing PONV than men, as are non-smokers and women who have previously experienced PONV or motion sickness.

PONV is an important issue for patients and healthcare providers. It is often the most daunting complication for patients, occurs at a higher rate than post-operative pain, and is therefore a significant cause of anxiety and patient distress. PONV can delay patient discharge from a hospital or lead to a post-hospitalization readmission, and may require outpatient admission. This has a significant economic and social impact. As the rate of hospital-acquired drug-resistant infections increases, it may also translate into an impact on clinical outcome.

Many mechanisms are involved in PONV, the most prominent of which are the release of 5-hydroxytryptamine from the intestinal wall and the activation of chemical receptor trigger zones in the brain. Thus, several different receptors appear to be involved in PONV and represent effective targets for drug therapy. Of which the most important is 5-hydroxytryptamine energy 5HT₃And dopaminergic D₂And possibly D₃A receptor.

Despite the routine use of prophylactic antiemetics in moderate and high risk patients, PONV still occurs in about 30-40% of cases, even when receiving current 5HT₃The same is true for patients with standard treatment regimens for antagonists and corticosteroids, and there is still a great need for effective and safe additional agents, especially agents with different mechanisms of action.

The use of amisulpride as an antiemetic is described in WO2011/110854 published on 9/15/2011, which claims priority from uk patent application GB 1004020.2 filed on 3/11/2010. Both of these documents are incorporated in their entirety into the present specification.

Adult surgical patients at moderate to high risk of PONV were (prophylactically) administered intravenously with amisulpride at doses of 1mg, 5mg and 20mg in a multicenter, double-blind, randomized, dose-range phase II trial (by the applicant), the fourth group receiving placebo. The incidence of PONV was lower in all amisulpride groups compared to placebo (69%), significantly in the cases of 1mg (48%, p < 0.05) and 5mg (40%, p < 0.01). This indicates that 5mg is at or near the bottom of the U-shaped dose response curve when assessing the incidence of PONV.

In two multicenter, double-blind, randomized, placebo-controlled phase III clinical trials carried out by the applicant and involving 626 evaluable adult surgical patients (prophylaxis) with moderate to high risk of developing PONV, administration of amisulpride at 5mg successfully reduced the incidence of PONV to 48% (p < 0.01) compared to 59% with placebo.

In a multicenter, double-blind, randomized, phase III trial (again by the applicant) involving 1147 evaluable adult surgical patients (prophylaxis) with a high risk of developing PONV, amisulpride 5mg in combination with a standard antiemetic successfully reduced the incidence of PONV to 42% (p < 0.001) compared to 53% with placebo in combination with a standard antiemetic.

In another clinical trial conducted by the applicant, amisulpride at doses of 5mg and 10mg was compared to placebo for treatment of PONV in patients who had not previously received prophylaxis. There was no difference in clinical efficacy between the 5mg and 10mg doses, indicating that both doses are in the plateau phase of the U-shaped dose response curve. Both doses were significantly better than placebo in treating PONV.

Disclosure of Invention

The present invention is based, at least in part, on the results of a study of amisulpride as a remedial treatment for PONV (i.e., in patients who have previously received PONV prophylaxis but who subsequently had PONV despite the prophylaxis), which study was conducted by the applicant. As expected, amisulpride was found to be effective as a remedial treatment in PONV (after the onset of emesis and/or nausea), but after a detailed analysis of the data, a dose of 10mg of amisulpride was unexpectedly found to be more effective as a remedial treatment for PONV than a dose of 5mg of amisulpride. This is completely unexpected, especially in view of the results of the above clinical trials (indicating that there should be no difference between the two doses).

According to a first aspect, amisulpride may be used for the treatment of postoperative nausea and/or vomiting in a patient, wherein the patient has been administered a prophylactic agent for postoperative nausea and/or vomiting, and wherein the dose of amisulpride is from 7.5 to 15 mg.

According to a second aspect, there is provided a method of treating postoperative nausea and/or vomiting in a patient, comprising administering amisulpride to the patient, wherein the patient has been administered a prophylactic agent for postoperative nausea and/or vomiting, and wherein the dose of amisulpride is from 7.5 to 15 mg.

Detailed Description

Amisulpride has one chiral center and exists in two enantiomers, namely (S-) -amisulpride and (R +) -amisulpride. It may be preferred to use a racemate or (S-) amisulpride which is substantially free of the (R +) -enantiomer. Almost all therapeutic activity is reported to be found in the (S-) enantiomer, and thus the use of this enantiomer means that the dose can be reduced by at least 50% (e.g., 50%, 60%, 70%, 80%, or 90%, or 50% -60%, 60% -70%, 70% -80%, or 80-90%) compared to the racemate.

A racemic mixture or racemate of amisulpride means that amisulpride contains both the (S-) -amisulpride and the (R +) -enantiomer. For example, a racemic mixture may comprise 40% to 60% of (S-) -amisulpride and 60% to 40% of the (R +) -enantiomer. In some embodiments, the racemic mixture may comprise about 50% of (S-) -amisulpride and about 50% of the (R +) -enantiomer.

(S-) -amisulpride substantially free of the (R +) -enantiomer comprises less than 10%, less than 5%, less than 4%, less than 3%, less than 2% or less than 1% of the (R +) -enantiomer. For example, (S-) -amisulpride, which is substantially free of the (R +) -enantiomer, contains less than 2% or less than 1% of the (R +) -enantiomer.

As used herein, the term postoperative nausea and/or vomiting (PONV) takes its conventional meaning in the art. It is well known in the art that it means that one or more episodes of emesis (vomiting and/or retching) or the desire to emesis (nausea) occur after surgery. Retching involves the same physiological mechanisms as vomiting, but occurs in a closed glottis. PONV can be defined as nausea and/or vomiting occurring within 48 hours after the end of surgery. It can be defined as nausea and/or vomiting occurring within 24 hours after the end of surgery.

As used herein, "vomiting episode" means the occurrence of an episode of emesis and/or retching.

As used herein, "a nausea episode" means the occurrence of a nausea episode. This may be indicated by a patient reporting an urge to vomit or requiring an antiemetic.

As used herein, "surgery" takes its conventional meaning in the art. It preferably comprises administration of general anesthesia, for example general inhalation anesthesia. The surgery may be selective surgery under general anesthesia (open or laparoscopic techniques). Preferably, the duration from induction of anesthesia to extubation is arranged to last at least one hour. Before extubation, the wound was closed.

As used herein, the term "surgical end" takes its conventional meaning in the art and is well known to the skilled artisan. It usually coincides with wound closure at the end of the procedure.

As used herein, the term "about" or "approximately" when used in conjunction with a numerical value (e.g., 5, 10%, 1/3) refers to a range of numerical values that may be less than or greater than the number. For example, "about 5" refers to a numerical range that is 10%, 5%, 2%, or 1% less than or greater than 5, such as 4.5 to 5.5, or 4.75 to 5.25, or 4.9 to 5.1, or 4.95 to 5.05. In some instances, "about 5" refers to a numerical range that is 2% or 1% less or greater than 5. Such as 4.9 to 5.1 or 4.95 to 5.05.

In one aspect of the invention, the dose of amisulpride is from 7.5mg to 15 mg. Preferably, the effective amount (i.e. dose) of amisulpride comprises 8 to 15mg of amisulpride, more preferably 8.5, 9 or 9.5 to 15 mg. The dose of amisulpride may also be 7.5 to 14.5, 14, 13.5, 13, 12.5, 12, 11.5, 11 or 10.5. The limits of any of the above ranges may be combined with each other. Preferably, the dose is from 8 to 12mg, more preferably from 9 to 12mg, most preferably about 10mg amisulpride. Most preferably, the dose is 10 mg. Preferably, amisulpride is in the form of a racemic mixture.

Preferably, amisulpride is administered in a single daily dose.

Preferably, amisulpride is administered in the form of the racemate. If it is administered in the form of the S-enantiomer, the dosage may be varied accordingly (e.g. it may be halved).

Amisulpride is used according to the invention for the "treatment" of PONV. This means that the patient has been suffering from PONV (as defined above). Also in accordance with the present invention, the patient has been administered a prophylactic agent for PONV. Thus, by definition, PONV prevention was unsuccessful.

According to the present invention, PONV is administered "prophylaxis" prior to PONV treatment. By "prophylactic agent" is meant an agent intended/intended to be administered for the prevention of PONV. Suitable drugs are known to those skilled in the art. Examples are given below.

It may be advantageous to administer amisulpride in combination with other anti-emetics (i.e. other than amisulpride). The "other antiemetic" is preferably selected from other classes of antiemetics that may add additional efficacy benefits. Thus, preferably, the different antiemetic is not D₂An antagonist. These include, but are not limited to, steroids, most preferably dexamethasone; 5HT₃Antagonists, including but not limited to ondansetron (ondansetron), granisetron (granisetron) and palonosetron (palonosetron); and NK₁Antagonists such as aprepitant, netupitant or roupidant. Amisulpride can be reacted with a compound having D₂And 5HT₃The metoclopramide with the characteristics of the two is combined. Preferably, the other antiemetic is ondansetron, granisetron or dexamethasone. Amisulpride may be combined with one or more (e.g. 2 or 3) different anti-emetics. Other classes of drugs may be administered by any suitable route of administration (e.g., by a route typical for such drugs, such as oral, intravenous, or intramuscular). In some cases, other types of drugs may be administered within 6 hours after the end of the surgery. In other cases, other types of drugs may be administered 6 hours after the end of the surgery.

The prophylactic agent is preferably administered prior to the conclusion of the surgical procedure. In a preferred embodiment, prevention is administered over a period of time starting about 4 hours before surgery until wound closure/surgery is complete. Preferably not later than the time of wound closure/end of surgery, more preferably prophylactic administration at the time of anesthesia (more preferably at the time of induction of anesthesia).

There are many prophylactic agents suitable for use in the present invention, and these are well known to those skilled in the art. The particular prophylactic agent may be selected based on a number of different factors, such as age and weight, or whether the person is receiving some other agent. Preferably, the prophylactic agent is an antiemetic agent that is not amisulpride. More preferably, the prophylactic agent is not dopamine-2 (D)₂) An antagonist.

In some embodiments, the prophylactic agent is an antiemetic selected from the group consisting of: 5HT₃Antagonists, corticosteroids, antihistamines (H)₁) Anticholinergic agents, H₂-antagonists or NK₁-an antagonist. The prophylactic agent may be selected from any of the antiemetics listed above (i.e. combination therapy).

5HT₃The-antagonist may be ondansetron, granisetron, palonosetron, tropisetron or dolasetron. Ondansetron, granisetron or palonosetron are preferred. More preferably, it is ondansetron. The corticosteroid can be dexamethasone, hydrocortisone, betamethasone, methylprednisolone or prednisolone. Dexamethasone is preferred. Antihistamines (H)₁) Can be dimenhydramine, hydroxyzine, diphenhydramine, promethazine, cyclizine or meclizine. The anticholinergic can be scopolamine (scopolamine/hysosine). H₂The antagonist may be famotidine (famotidine). NK₁The antagonist may be aprepitant. If D is used₂Antagonists as antiemetic agents, which may then be haloperidol (haloperidol), haloperidol (droperidol) or domperidone (domperidone).

Typical dosages of the different antiemetics listed above are known to those skilled in the art. For example, the dose of ondansetron is typically from 2 to 20mg, or from 2 to 15mg, or about 10mg or about 4 mg. For granisetron, the dose is typically 1 to 3mg, for example 1 mg. For dexamethasone, a typical dose is 4-20mg, e.g. 4 mg.

Amisulpride for use according to the invention may be packaged for sale with accompanying instructions for use. The instructions for use (drug labeling) preferably specify that the patient to be treated should have undergone surgery and that they should be selected from a group of patients who have previously received unsuccessful PONV prevention (i.e., remedial treatment). They also preferably specify a dose of amisulpride of 10 mg.

Amisulpride for use in the present invention is preferably formulated (and intended for intravenous administration) as an intravenous formulation. Amisulpride may be in the form of a salt, hydrate or solvate. Salts include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, such as hydrochlorides, hydrobromides, p-toluenesulphonates, phosphates, sulphates, perchlorates, acetates, trifluoroacetates, propionates, citrates, malonates, succinates, lactates, oxalates, tartrates and benzoates.

Salts may also be formed with bases. Such salts include those derived from inorganic or organic bases, for example alkali metal salts such as sodium and potassium salts and alkaline earth metal salts such as magnesium and calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine and diethylamine salts.

The intravenous formulation of amisulpride for use in the present invention may be in the form of a sterile injectable aqueous or non-aqueous (e.g. oleaginous) solution or suspension. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable carriers and solvents that may be employed are water, phosphate buffered saline, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of intravenous formulations of the present invention. Suspensions may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents.

Aqueous suspensions contain the active ingredient in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as naturally occurring phosphatides, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol (heptadecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Compositions for injection are typically aqueous and contain a buffer, such as citrate buffer. No other ingredients may be required. The pH of such compositions may be, for example, 4 to 7, e.g., about 5.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in combination with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are known.

The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil; or mineral oils, such as liquid paraffin; or a mixture of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth; naturally occurring phospholipids, such as soy, lecithin; and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.

The intravenous unit dose of amisulpride suitable for use in the present invention is preferably a single injection containing amisulpride. In a preferred embodiment, this may be in the form of a vial of active agent in combination with a syringe and needle or pre-filled syringe/needle.

In some embodiments, amisulpride is a non-IV injectable formulation. It may be in the form of a solid or liquid formulation and may be formulated for oral administration. Solid formulations may be in the form of tablets or capsules, melt tablets, or dispersible powders or granules (which may require addition to water). Liquid formulations may be in the form of aqueous or oily suspensions or syrups, and they may be packaged in vials.

Amisulpride may be in the form of a suppository for rectal administration of the medicament. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.

For topical delivery, transdermal and transmucosal patches, creams, ointments, gels, solutions or suspensions may be used. For sublingual delivery, fast dissolving tablet formulations, as well as several forms described above, may be used. For oral administration, which is preferred, amisulpride may be administered in tablets, capsules or liquid formulations.

In a preferred embodiment, the oral unit dose of amisulpride is in the form of one or more tablets or one or more capsules. The unit dose of amisulpride may be provided in a blister pack.

Amisulpride formulations may contain any number of pharmaceutically acceptable excipients, such as sweetening agents and preservatives.

Formulations of amisulpride suitable for use in the present invention are described in WO 2011/110854.

Where the use or method of the invention provides for the administration of more than one drug, they may be administered simultaneously, sequentially or separately. It is not necessary to package them together (but this is one embodiment of the invention). Nor are they necessarily administered simultaneously. As used herein, "separate" administration means that the drugs are administered as part of the same total dosage regimen (which may include several days), but preferably on the same day. As used herein, "simultaneously" means that the drugs are taken together or formulated into a single composition. As used herein, "sequentially" means that the drugs are administered at about the same time, preferably within about 1 hour of each other.

Prophylactic agents should be administered prior to the onset of emesis. It is preferably administered in a single prophylactic dose.

Preferably, amisulpride is administered by IV infusion (bolus injection), preferably over a period of about 20 seconds up to about 20 minutes. Longer infusion times may be preferred, for example, if the patient is painful at the time of injection. In some embodiments, amisulpride is administered within about 1 to 15, 1 to 10, 1 to 5, or 1 or 2 minutes. Amisulpride is preferably administered in a single dose.

Amisulpride should be administered as soon as possible after the first episode of emesis and/or after the first episode of nausea (e.g., the first request for an antiemetic drug to treat nausea or the reporting of a desire to vomit). Preferably, amisulpride is administered within 1 hour of the first episode of emesis and/or within 1 hour of the first episode of nausea. More preferably, it is administered within 30 minutes of the first episode of emesis and/or within 30 minutes of the first episode of nausea. More preferably, it is administered within 15 minutes of the first episode of emesis and/or within 15 minutes of the first episode of nausea.

In some embodiments, no additional doses of amisulpride are administered within 24 hours after the initial dose. In some embodiments, the initial dose of the present invention is followed by at least one additional dose within about 24 hours, preferably within about 12 hours, from the first dose.

In a preferred embodiment, the patient is a human.

The following study illustrates the present invention.

Study 1

Scheme(s)

A randomized, double-blind, placebo-controlled study of amisulpride for IV injection as a treatment for established postoperative nausea and vomiting in patients who had previously undergone prophylaxis was conducted. The main objective of this study was to compare the efficacy of 5mg and 10mg amisulpride as a treatment of established PONV in patients who had previously undergone PONV prevention with placebo.

The study was conducted in adult patients (> 18 years) who had previously undergone PONV prevention and experienced PONV within 24 hours post-surgery, with the duration of inhalation anesthesia expected to be at least 1 hour.

Amisulpride or a matching placebo at a dose of 5mg or 10mg is administered once in about 2 minutes by slow IV administration.

The main efficacy variables are the dichotomous variables: success or failure of primary PONV treatment, where success is defined as no episodes of emesis (vomiting or retching) 30 minutes to 24 hours after study drug administration, and no antiemetic remedial drug is given at any time within 24 hours after study drug administration ("complete response").

Secondary efficacy variables include:

the occurrence and severity of nausea (VRS score > 0) and the occurrence and severity of significant nausea (VRS score ≧ 4), including a measure of the temporal course of nausea, such as the area under the nausea score curve for a period of up to 24 hours.

Emesis (including retching) following study drug administration.

Use of antiemetic remedies.

Time to failure of the initial PONV treatment.

Sub-analysis of success and failure based on various parameters, including PONV start time and gender relative to the end of the procedure.

Results

The Complete Reaction (CR) rates were as follows:

placebo (235 patients) 28.5%

Amisulpride 5mg (237 cases of patients) 33.8% (p ═ 0.109)

Amisulpride 10mg (230 patients) 41.7%, (p ═ 0.003)

Conclusion

When amisulpride is used as a "remedial" treatment, i.e. when it is used to treat a patient with a PONV episode when the patient has previously received an unsuccessful prophylaxis, it is beneficial to administer amisulpride at a dose of 10mg (as compared to a dose of 5 mg). Amisulpride at a dose of 10mg has been shown to be particularly effective in this case. This can make the length of stay in the post-anesthesia monitoring room (post-anetherysiacare unit) very beneficially reduced, and thus can provide benefits to healthcare providers.

Claims (12)

1. Amisulpride for use in the treatment of postoperative nausea and/or vomiting in a patient, wherein the patient has been administered a prophylactic agent for postoperative nausea and/or vomiting, and wherein the dose of amisulpride is from 7.5 to 15 mg.

2. Amisulpride for use according to claim 1, wherein the dose of amisulpride is 10 mg.

3. Amisulpride for use according to claim 1 or claim 2, wherein the prophylactic agent is not amisulpride.

4. Amisulpride for use according to any preceding claim, wherein the prophylactic agent is not dopamine-2 (D)₂) An antagonist.

5. Amisulpride for use according to any preceding claim, wherein the prophylactic agent is an antiemetic selected from the group consisting of: 5HT₃Antagonists, corticosteroids, antihistamines (H)₁) Anticholinergic agents, H₂-antagonists or NK₁-an antagonist.

6. Amisulpride for use according to any preceding claim, wherein the amisulpride is administered separately, sequentially or simultaneously in combination with another antiemetic.

7. Amisulpride for use according to claim 6, wherein the other antiemetic is 5HT₃Antagonists, NK₁An antagonist or a steroid.

8. Amisulpride for use according to claim 6 or claim 7, wherein the other antiemetic is dexamethasone, ondansetron, granisetron, palonosetron, aprepitant, netupitant or lapitant.

9. Amisulpride for use according to any preceding claim, wherein the amisulpride is substantially in the form of the racemate.

10. Amisulpride for use according to any preceding claim, wherein the amisulpride is administered by the intravenous route.

11. A method of treating postoperative nausea and/or vomiting in a patient, comprising administering amisulpride to the patient, wherein the patient has been administered a prophylactic agent for postoperative nausea and/or vomiting, and wherein the dose of amisulpride is from 7.5 to 15 mg.

12. A method according to claim 11 having any of the additional features of claims 1 to 10.