Treatment of postoperative emesis with amisulpride

Abstract

Amisulpride can be used to treat (especially prevent) postoperative vomiting in patients undergoing surgery, where postoperative vomiting could be potentially dangerous.

Description

[0001] This application is a divisional application of patent application 201780068552.8 entitled "Therapy for Postoperative Vomiting with Amisulpride", filed on November 1, 2017. Technical Field

[0002] This invention relates to a treatment for postoperative vomiting. Background Technology

[0003] Postoperative vomiting is a subtype of postoperative nausea and vomiting (PONV). PONV occurs in approximately 30% of all surgical patients and 70% of high-risk patients. Risk factors for PONV include: type of surgery, sex, smoking history, history of PONV or motion sickness, duration of surgery, use of volatile anesthetics, and use of opioid analgesics. Generally, women are more prone to PONV than men, as are non-smokers and women who have previously experienced PONV or motion sickness.

[0004] PONV is a significant issue for both patients and healthcare providers. It is often considered one of the most feared complications by patients, even more so than postoperative pain, and is therefore a major cause of anxiety and patient suffering. PONV can delay patient discharge from the hospital or lead to readmission after inpatient surgery, and may also require outpatient admission. This has significant economic and social implications. With increasing rates of hospital-acquired drug-resistant infections, it may also translate into impacts on clinical outcomes.

[0005] PONV involves many mechanisms, most notably the release of serotonin from the intestinal wall and the activation of chemical receptor triggering areas in the brain. Therefore, several different receptors appear to be involved in PONV and represent potential targets for drug therapy. Among the most important are the serotonergic 5HT3 and dopaminergic D2 receptors, and possibly the D3 receptor.

[0006] Despite the routine use of prophylactic antiemetics in intermediate and high-risk patients, PONV still occurs in approximately 30% of cases, even in patients receiving the latest medications, and there remains a great need for additional medications, especially those with different mechanisms of action.

[0007] The use of amisulpride as an antiemetic is described in WO2011 / 110854, published on September 15, 2011, which claims priority to UK patent application GB 1004020.2, filed on March 11, 2010. The entire contents of both documents are incorporated herein by reference.

[0008] In a multicenter, double-blind, randomized, placebo-controlled phase II clinical trial in adult surgical patients (conducted by the applicant), the incidence of PONV associated with amisulpride at 5 mg was 40% compared with a placebo incidence of 69% (p < 0.01). There was no difference between amisulpride and placebo in the nature, incidence, or severity of adverse events, or laboratory or ECG abnormalities.

[0009] In two multicenter, double-blind, randomized, placebo-controlled phase III clinical trials (re-initiated by the applicant) involving 626 evaluable adult surgical patients, the incidence of PONV associated with amisulpride at 5 mg was 48%, compared to 59% with placebo (p < 0.01). There was no significant difference in safety between amisulpride and placebo, except that a transient increase in serum prolactin levels was more common with amisulpride.

[0010] Postoperative vomiting is particularly problematic in certain patient groups. This is because it increases the risk of pulmonary aspiration and is associated with suture dehiscence, esophageal rupture, subcutaneous emphysema, and bilateral pneumothorax. Postoperative vomiting can also lead to venous hypertension, increased intracranial pressure (ICP), and hematoma. Therefore, there are certain surgical procedures in which postoperative vomiting poses a significant potential risk to patients. Summary of the Invention

[0011] This invention is based on the results of a Phase III study conducted by the applicant, in which amisulpride was used to prevent postoperative vomiting (PONV) in high-risk patients. As expected, amisulpride was found to be effective in treating PONV; however, after detailed analysis of the data (particularly the secondary efficacy analysis), it was unexpectedly found that the relative risk reduction (RRR) for the incidence of vomiting was much higher than expected (e.g., compared to the RRR of the overall risk of PONV). Therefore, amisulpride is particularly effective in preventing postoperative vomiting.

[0012] There is a subgroup of patients with particularly problematic postoperative vomiting, and in some embodiments, the present invention recognizes that the use of amisulpride in this patient subgroup is particularly beneficial. In some cases, amisulpride is particularly effective in the treatment of postoperative vomiting in patients who have at least three risk factors for postoperative vomiting, wherein said risk factors are selected from a history of postoperative nausea and vomiting and / or motion sickness; habitual non-smoking; being female; or anticipated use of postoperative opioid analgesics.

[0013] According to a first aspect, the present invention relates to amisulpride, which is used as a treatment for postoperative vomiting in patients. Patients may be selected from a group of patients undergoing surgery, where postoperative vomiting is potentially dangerous.

[0014] According to the second aspect, a method for treating or preventing postoperative vomiting in a patient—who is undergoing surgery—involves administering an effective amount of amisulpride to the patient and optionally pre-selecting patients from a group of patients undergoing surgery for treatment or prevention, wherein postoperative vomiting is potentially dangerous to the patient. Detailed Implementation

[0015] Amisulpride has one chiral center and exists in two enantiomers, namely ( S- )-Ammoniasulfamethoxazole and ( R+ )-Amisulpride. Racemic or ( S- )-Amisulpride, which is basically free of ( R+ - Enantiomers. It has been reported that, ( S- Almost all therapeutic activity has been found in the enantiomer, so using this enantiomer means that the dose can be reduced by 50% (e.g., 50%, 60%, 70%, 80% or 90%, or 50%-60%, 60%-70%, 70%-80% or 80-90%) compared to the racemic version.

[0016] A racemic mixture or racemate of amisulpride means that amisulpride contains ( S- )-Ammoniasulfamethoxazole and ( R + - Both enantiomers. For example, a racemic mixture may contain 40% to 60% (enantiomers). S- )-Amisulpride and 60% to 40% ( R+ )-Enantiomers. In some embodiments, the racemic mixture may contain about 50% ( S- )- Amisulpride and about 50% ( R+ )-Enantiomers.

[0017] Basically does not contain ( R+ -Enantiomers ( S- Amisulpride contains less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of ( R+ )-Enantiomers. For example, essentially free of ( R+ -Enantiomers ( S- Amisulpride contains less than 2% or less than 1% ( R+ )-Enantiomers.

[0018] As used in this article, the term postoperative vomiting refers to one or more episodes of vomiting (vomiting and / or retching). Regurgitation involves the same physiological mechanisms as vomiting, but occurs at the closed glottis.

[0019] As used herein, when used with numerical values ​​(e.g., 5, 10%, 1 / 3), the term “about” or “approximately” refers to a range of values ​​that may be less than or greater than that number. For example, “about 5” refers to a range of values ​​that are 10%, 5%, 2%, or 1% smaller 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 cases, “about 5” refers to a range of values ​​that are 2% or 1% smaller or greater than 5, such as 4.9 to 5.1 or 4.95 to 5.05.

[0020] Preferably, the effective amount (i.e., dosage) of amisulpride comprises 1 to 40 mg of amisulpride, more preferably 1 to 20 mg or 2.5 to 20 mg, more preferably 5 to 10 mg, and most preferably about 5 mg of amisulpride. The effective amount of amisulpride may also comprise 2.5 to 5 mg, 2.5 to 10 mg, 2.5 to 40 mg, 5 to 20 mg, 5 to 40 mg, 1 to 5 mg, or 1 to 10 mg of amisulpride. Preferably, amisulpride is in the form of a racemic mixture.

[0021] Preferably, the effective amount (i.e., dosage) of amisulpride comprises 1 to 20 mg of amisulpride, more preferably 1 to 10 mg, even more preferably 2.5 to 5 mg, and most preferably about 2.5 mg of amisulpride. The effective amount of amisulpride may also comprise 1 to 2.5 mg, 1 to 5 mg, 1 to 20 mg, 2.5 to 10 mg, or 2.5 to 20 mg of amisulpride. Preferably, amisulpride is (… S- It is in the form of )-amysulpiride and is essentially free of ( R+ )-Enantiomers.

[0022] Preferably, amisulpride is administered in a single daily dose. More preferably, it is administered in a single dose.

[0023] Combining amisulpride with other classes of drugs that may increase additional efficacy benefits may be advantageous. Preferably, the other classes of drugs are different antiemetics (i.e., antiemetics that are not amisulpride). More preferably, the different antiemetics are not D2 antagonists. These include, but are not limited to, steroids, most preferably dexamethasone; 5HT3 antagonists (including, but not limited to, ondansetron, granisetron, and palonosetron); and NK1 antagonists such as aprepitant, netupitant, or rolapitant. Preferably, the other antiemetic is ondansetron, granisetron, or dexamethasone. The other classes of drugs can be administered via any suitable route of administration (e.g., via the typical route of administration of the drug, such as oral, intravenous, or intramuscular). In some cases, the other classes of drugs may be administered within 6 hours after the end of surgery. In other cases, the other classes of drugs may be administered 6 hours after the end of surgery.

[0024] The typical dosages of the different antiemetics listed above are known to those skilled in the art. For example, the dosage of ondansetron is typically 2 to 20 mg, or 2 to 15 mg, or about 10 mg or about 4 mg. For granisetron, the dosage is typically 1-3 mg, such as 1 mg. For dexamethasone, the typical dosage is 4-20 mg, such as 4 mg.

[0025] The amisulpride used according to the present invention may be packaged and sold together with the accompanying instructions for use. The instructions for use (drug label) preferably specifies in the list of indications that the drug may be used for patients undergoing surgery where postoperative vomiting may be potentially dangerous. It may specify the surgical procedures as defined herein (e.g., as in the claims).

[0026] Amisulpride used in this invention is preferably formulated as an intravenous preparation (and for intravenous administration). Amisulpride can be in the form of a salt, hydrate, or solvate. Salts include pharmaceutically acceptable salts, such as acid addition salts derived from inorganic or organic acids, such as hydrochloride, hydrobromide, p-toluenesulfonate, phosphate, sulfate, perchlorate, acetate, trifluoroacetate, propionate, citrate, malonate, succinate, lactate, oxalate, tartrate, and benzoate.

[0027] Salts can also be formed from bases. Such salts include those derived from inorganic or organic bases, such as alkali metal salts like sodium and potassium salts and alkaline earth metal salts like magnesium and calcium salts, as well as organic amine salts like morpholine, piperidine, dimethylamine, and diethylamine salts.

[0028] The intravenous formulation of amisulpride used in this invention can be in the form of a sterile, injectable aqueous or non-aqueous (e.g., oily) solution or suspension. The sterile injectable formulation can also be a sterile injectable solution or suspension in a non-toxic, parenteral-acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable carriers and solvents that can be used include water, phosphate buffer solutions, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile, non-volatile oils can be used as solvents or suspension media. For this purpose, any mild, non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid can be used to prepare the intravenous formulation of this invention. Suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques.

[0029] Aqueous suspensions contain an active ingredient and excipients suitable for their preparation. Such excipients are suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic; dispersants or wetting agents such as naturally occurring phospholipids, such as lecithin, or condensation products of alkyl esters and fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide and long-chain aliphatic alcohols, such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxide and esters derived from fatty acids and hexitols, such as polyoxyethylene and esters derived from fatty acids and hexitol anhydrides, such as polyoxyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as ethylparaben or n-propylparaben, one or more colorants, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin.

[0030] Compositions for injection are typically aqueous and contain a buffer, such as citrate buffer. No other components are required. The pH of such compositions can be, for example, 4 to 7, such as about 5.

[0031] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water provide active ingredients along with dispersants or wetting agents, suspending agents, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are known.

[0032] The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil; or a mineral oil, such as liquid paraffin; or a mixture thereof. Suitable emulsifiers may be naturally occurring gums, such as gum arabic or gum tragali; naturally occurring phospholipids, such as soybean or lecithin; and esters or metaesters derived from fatty acids and hexitan anhydrides, such as sorbitan monooleate, and the condensation product of said metaester with ethylene oxide, such as polyoxyethylene sorbitan monooleate.

[0033] The intravenous unit dose of amisulpride suitable for use in this invention is preferably a single-dose injection containing amisulpride. In a preferred embodiment, this may be in the form of a vial of active agent combined with a syringe and needle or a pre-filled syringe / needle combination.

[0034] In some implementations, amisulpride is a non-IV injectable formulation. It can be in the form of a solid or liquid formulation and can be formulated for oral administration. Solid formulations can be in the form of tablets or capsules, molten tablets, or dispersible powders or granules (which may require addition to water). Liquid formulations can be in the form of aqueous or oily suspensions or syrups, and they can be packaged in vials.

[0035] Amisulpride can be in suppository form for rectal administration. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thus melting in the rectum to release the drug. Such substances include cocoa butter and polyethylene glycol.

[0036] For local delivery, transdermal and transmucosal patches, creams, ointments, gels, solutions, or suspensions can be used. For sublingual delivery, rapidly dissolving tablet formulations, as well as some of the above-mentioned forms, can be used. For oral administration, amisulpride is preferably administered in tablet, capsule, or liquid form.

[0037] 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 supplied in blister packs.

[0038] Amisulpride preparations may contain any number of pharmaceutically acceptable excipients, such as sweeteners and preservatives.

[0039] Formulations of amisulpride suitable for use in this invention are described in WO2011 / 110854.

[0040] When the use or method of the present invention provides administration of more than one drug, they may be administered simultaneously, sequentially, or separately. They need not be packaged together (but this is one embodiment of the invention). They also need not be administered simultaneously. As used herein, “separately” 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 approximately the same time, preferably with an interval of about 1 hour between each other.

[0041] As used herein, "therapy" means treatment or prevention. Preferably, the ammoniasulfonamide used in this invention is for the prevention of postoperative vomiting.

[0042] In some embodiments, amisulpride according to the invention can be used in patients undergoing surgery where postoperative vomiting is potentially dangerous. For example, vomiting in these patients may lead to medical complications that could be fatal, such as suture rupture causing bleeding or serious infection.

[0043] Other examples of dangerous / harmful medical complications caused by postoperative vomiting include aspiration into the lungs, suture dehiscence, esophageal rupture, subcutaneous emphysema, bilateral pneumothorax, venous hypertension, increased intracranial pressure, or hematomas such as those under surgical flaps, vascular anastomoses, and aneurysm clips.

[0044] Technicians are aware of surgeries where postoperative vomiting can be problematic (or lead to the aforementioned complications). Examples of such surgeries include oral surgeries (such as suture jaw surgery or dental surgery), ear, nose, or throat (ENT) surgeries (such as tonsillectomy or thyroidectomy), head or face surgeries (such as craniotomy, hemorrhagic stroke surgery, ischemic stroke surgery, rhinoplasty, cosmetic surgery of the face or eyes), gastrointestinal (GI) surgeries (such as paraesophageal surgery, antireflux surgery, bariatric surgery, gastrectomy, gastric bypass surgery, or gastric sleeve surgery), lung surgeries (such as surgical lung biopsy, lobectomy, or wedge resection), abdominal surgeries (such as surgical hernia repair, abdominal hysterectomy, abdominoplasty, laparotomy, any surgery involving a large abdominal incision, or open abdominal aortic aneurysm repair), or intestinal surgeries.

[0045] Preferably, the surgical procedure according to the invention involves administering general anesthesia, such as general inhalation anesthesia. The procedure can be an elective procedure under general anesthesia (open or laparoscopic technique). It is preferred that the period from induction of anesthesia to extubation lasts at least one hour. The wound will be closed before extubation.

[0046] As used in this article, “undergoing surgery” refers to the period from about 2 hours before surgery to about 24 hours after surgery when vomiting occurs (during which treatment is no longer considered prevention).

[0047] Ammonia-sulfamethoxazole is preferred for the prevention of postoperative vomiting, i.e., administered as described above, but before the onset of vomiting. It is preferably administered as a single preventative dose.

[0048] In a preferred embodiment, amisulpride is administered up to 4 hours prior to surgery. It is preferably administered no later than wound closure / end of surgery, more preferably during anesthesia (more preferably during induction of anesthesia).

[0049] Preferably, amisulpride is administered via IV infusion (bolus), preferably over a period of about 20 seconds to 1 or 2 minutes. In some embodiments, this period can be up to 10 minutes, for example, if the patient experiences pain during injection or if a higher dose (e.g., 20 mg) is administered. In a preferred embodiment, amisulpride is administered over about 1 to 2 minutes, or within 1 or 2 minutes. Amisulpride is preferably administered as a single dose.

[0050] Preferably, the patient has at least three risk factors for postoperative vomiting, wherein said risk factors are selected from a history of postoperative nausea and vomiting and / or motion sickness; habitual non-smoking status; being female; and anticipated use of postoperative opioid analgesics. More preferably, the patient has all four risk factors. These risk factors can define a patient group in which amisulpride is particularly useful in the treatment of postoperative vomiting.

[0051] In a particularly preferred embodiment of the invention, amisulpride at a dose of 5 mg can be used to prevent postoperative vomiting in patients, preferably in patients undergoing surgery where postoperative vomiting may be potentially dangerous to the patient, and where the patient has at least three risk factors for postoperative vomiting, said risk factors being selected from a history of postoperative nausea and vomiting and / or motion sickness; habitual non-smoking status; being female; or anticipated use of postoperative opioid analgesics.

[0052] The following research illustrates the present invention.

[0053] Study 1 plan A randomized, double-blind, placebo-controlled phase III study was conducted to investigate the combined prevention of postoperative nausea and vomiting (PONV) with amisulpride in high-risk patients. The primary objective of the study was to evaluate the efficacy of amisulpride at 5 mg in preventing PONV in adult surgical patients at high risk of PONV. Amisulpride was administered in combination with a standard antiemetic.

[0054] The study included 1204 randomized adult patients (≥18 years old) at high risk of PONV who underwent elective outpatient (day-case) or inpatient surgery under general inhalation anesthesia, with the general inhalation anesthesia expected to last at least one hour from induction to extubation. Of the 1204 randomized patients, 1147 were on medication and eligible.

[0055] High risk of PONV is defined as having at least three of the following risk factors: - History of PONV / or motion sickness - Habitual non-smoking status - women - Expected use of postoperative opioid analgesics 5 mg of amisulpride is administered intravenously (IV) over one minute as a single, slow bolus during induction of anesthesia, in combination with a standard antiemetic. Examples of standard antiemetics used include ondansetron, granisetron, and dexamethasone.

[0056] The two groups in the study are as follows: Group 1: 5 mg of amisulpride IV in combination with a standard antiemetic that is not a dopamine D2-antagonist (e.g., 4 mg ondansetron IV, 1 mg granisetron IV, or 4 mg dexamethasone IV). Group 2 (Control): Amisulpride IV placebo combined with a standard antiemetic as defined above. The primary efficacy variable was the presence or absence of PONV during the 24-hour postoperative period, where PONV was defined as the occurrence of one or more episodes of vomiting (vomiting and / or dry heaving) or the administration of one or more doses of emergency antiemetic medication. By this definition, the absence of PONV was referred to as a “complete response” (CR). Several secondary variables were assessed, including the occurrence of vomiting (vomiting and / or dry heaving).

[0057] Analysis of main efficacy The incidence of complete remission (CR) within 0–24 hours post-operation was compared between the amisulpride group and the placebo group using the Pearson χ² test and Yates continuity correction at a 2.5% one-sided significance level. The primary efficacy analysis population was the modified intention-to-treat (mITT) population.

[0058] Secondary efficacy analysis The Pearson χ² test was used to compare secondary power variables assessed by incidence (e.g., vomiting) between groups.

[0059] Results (excerpt) The data upon which this invention is based is summarized below: Table 1: PONV Incidence Rate within 24 Hours – RRR (Relative Risk Reduction)

[0060] *Complete response **Examples of standard antinausea medications listed above** Table 2: Incidence of postoperative vomiting (vomiting and / or dry heaving) – RRR

[0061] in conclusion Compared with placebo plus standard antiemetic, amisulpride plus standard antiemetic improved the CR rate by 11.08% in the mITT (modified intention-to-treat) population, which was statistically significant (p < 0.001), equivalent to a relative risk reduction (RRR) of 20.8% in PONV rate.

[0062] Compared with placebo, the incidence of vomiting (vomiting and / or dry heaving) in the amisulpride group was statistically significantly lower (p = 0.003), with a surprisingly high RRR of 31% compared with the total PONV RRR.

Claims

1. Use of amisulpride in combination with a 5HT3 antagonist, NK1 antagonist, or steroid in the preparation of a medicament for the prevention of postoperative vomiting in patients with a history of postoperative nausea and vomiting and / or motion sickness, wherein the amount of amisulpride is 5 mg; and The patients mentioned also had the following risk factors for postoperative vomiting: habitual non-smoker status; being female; and expected use of postoperative opioid analgesics.

2. The use according to claim 1, wherein the patient is undergoing surgery, and postoperative vomiting is potentially dangerous to the patient.

3. The use according to claim 1 or 2, wherein postoperative vomiting would expose the patient to the following risks: aspiration into the lungs, suture dehiscence, esophageal rupture, subcutaneous emphysema, bilateral pneumothorax, venous hypertension, increased intracranial pressure, or hematoma such as hematoma under surgical flaps, vascular anastomoses, and aneurysm clips.

4. The use according to any one of claims 1 to 3, wherein the surgical procedure is selected from oral surgery, ear, nose or throat (ENT) surgery, head or face surgery, gastrointestinal (GI) surgery, lung surgery, abdominal surgery and intestinal surgery.

5. According to the use of claim 4, wherein the oral surgery is a suture jaw surgery or dental surgery, and the ENT surgery is a tonsillectomy or thyroidectomy; the head or facial surgery is a craniotomy, hemorrhagic stroke surgery, ischemic stroke surgery, rhinoplasty, or cosmetic surgery of the face or eyes; the GI tract surgery is a paraesophageal surgery, antireflux surgery, bariatric surgery, gastrectomy, gastric bypass surgery, or gastric sleeve surgery; the lung surgery is a surgical lung biopsy, lobectomy, or wedge resection; and the abdominal surgery is a surgical hernia repair, abdominal hysterectomy, abdominoplasty, laparotomy, any surgery involving a large abdominal incision, or open abdominal aortic aneurysm repair.

6. The use according to any one of claims 1 to 4, wherein another antiemetic is dexamethasone, ondansetron, granisetron, palonosetron, aprepitant, netupitant, or lorapitant.

7. The use according to any one of claims 1 to 6, wherein amisulpride is substantially in the racemic form, or amisulpride is in the form of (S-)-amisulpride, which is substantially free of the (R+)-enantiomer.

8. The use according to any one of claims 1 to 7, wherein the drug is administered via an intravenous route.

9. The use according to claim 8, wherein the drug is administered by infusion over about 1 to 2 minutes.

10. The use according to any one of claims 1 to 9, wherein the drug is administered in a single dose.

11. The use according to any one of claims 1 to 10, wherein the drug is administered during the induction of anesthesia.

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