JPWO2018146490A5 - - Google Patents

Description

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

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, gender, smoking history, history of PONV or motion sickness, length of surgery, use of volatile anesthetics, and use of opioid analgesics. In general, women are more prone to PONV than men, as are nonsmokers and those who have previously experienced PONV or motion sickness.

PONV is an important issue for patients and healthcare providers. Patients are often rated above postoperative pain as the most feared complication, which is a major factor in causing anxiety and patient distress. PONV may delay the discharge of a patient from a hospital or result in readmission after an inpatient procedure and may require admission of an outpatient. This has a great economic and social impact. As the infection rate of resistant bacteria in the hospital increases, it may affect the clinical outcome.

Numerous mechanisms have been implicated in PONV, most notably the release of serotonin from the intestinal wall and the activation of chemoreceptor trigger zones in the brain. Therefore, several different receptors appear to be involved in PONV, which represent effective targets for drug therapy. The most important are the serotonergic 5HT ₃ receptors and the dopaminergic D ₂ and possibly D ₃ receptors.

Despite the routine use of prophylactic antiemetics in moderate and high-risk patients, PONV is still about 30-40% of patients receiving current standard treatment with 5HT ₃ antagonists and corticosteroids. There is still a high need for effective and safe additional drugs, especially those with different mechanisms of action, which occur in cases.

The use of amisulpride as an antiemetic agent is described in WO 2011/110854, published September 15, 2011, claiming priority from the UK patent specification GB1004020.2 filed March 11, 2010. By clearly stating the source, the entire disclosure content is made part of the specification of the present application.

In a multicenter, double-blind, randomized, dose-range-finding Phase II study (conducted by the applicant), amisulpride 1 mg, 5 mg, and amisulpride were given to adult surgical patients at moderate to high risk of PONV (prevention). It was given intravenously at a dose of 20 mg and the fourth group was given placebo. Incidence of PONV was lower in all amisulpride groups, significantly lower at 1 mg (48%, p <0.05) and 5 mg (40%, p <0.01) compared to placebo (69%). This suggests that 5 mg is located at or near the bottom of the U-shaped dose-response curve when assessing the incidence of PONV.

Two multicenter, double-blind, randomized, placebo-controlled phase III clinical trials conducted by the applicant, including 626 evaluable adult surgical patients with moderate and high risk of PONV (prevention). In 5 mg of amisulpride, the incidence of PONV could be reduced to 48%, while placebo was 59% (p <0.01).

In a multicenter, double-blind, randomized, phase III study involving 1147 evaluable adult surgical patients at high risk of PONV (prevention) conducted by the applicant, amisulpride 5 mg and standard antiemetics The combination reduced the incidence of PONV to 42%, while the combination of placebo and standard antiemetics was 53% (p <0.001).

In another clinical trial conducted by the applicant, 5 mg and 10 mg doses of amisulpride were compared to placebo for the treatment of PONV in patients who did not receive prior prophylaxis. There is no difference in clinical efficacy between doses 5 mg and 10 mg, suggesting that both doses are in the flat area of the U-shaped dose-response curve. Both doses were significantly better than placebo in the treatment of PONV.

WO2011 / 110854

The present invention is at least partially based on the results of the applicant's study of amisulpride as a rescue treatment for PONV (ie, in patients who received prior prevention of PONV but subsequently presented with PONV). As expected, amisulpride was found to be effective as a rescue treatment for PONV (following vomiting and / or nausea episodes), but detailed analysis of the data surprised that amisulpride dose of 10 mg was PONV. It was found to be more effective as a rescue treatment than the amisulpride dose of 5 mg. This was quite unexpected, especially given the results of the clinical trials mentioned above (suggesting that there should be no difference between the two doses).

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

According to the second aspect, a method for treating postoperative nausea and / or vomiting of a patient is provided, comprising administering amisulpride to the patient, and the patient administering a prophylactic agent for postoperative nausea and / or vomiting. The dose of amisulpride is 7.5 to 15 mg.

Amisulpride has a single chiral center and there are two enantiomers, namely (S-) amisulpride and (R +) amisulpride. It may be preferable to use racemic or (S-) amisulpride, which is substantially free of (R +) enantiomers. Almost all therapeutic activity has been reported to be found in (S-) enantiomers, so the use of this enantiomer is 50% (eg, 50%, 60%, 70) dose compared to racemic. %, 80%, or 90%, or 50% to 60%, 60% to 70%, 70% to 80%, or 80 to 90%) can be reduced.

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

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

As used herein, the terms postoperative nausea and / or vomiting (PONV) have conventional meaning in the art. It is well understood in the art to imply the occurrence of one or more vomiting episodes (vomiting and / or vomiting) following a surgical procedure, or the desire for vomiting (nausea). Nausea involves the same physiological mechanisms as vomiting, but occurs in the closed glottis. PONV may be defined as nausea and / or vomiting that occurs within 48 hours of the completion of the surgical procedure. It may also be defined as nausea and / or vomiting that occurs within 24 hours of the end of the surgical procedure.

As used herein, "episode of vomiting" means the occurrence of vomiting and / or the occurrence of nausea.

As used herein, "episode of nausea" means the occurrence of nausea. This may be indicated by the patient reporting a desire for vomiting or requesting an antiemetic agent.

As used herein, "surgical procedure" has conventional meaning in the art. Preferably, it comprises the administration of general anesthesia, for example general inhalation anesthesia. Treatment can be elective surgery under general anesthesia (open surgery or laparoscopic surgery). It is preferable that it lasts for at least 1 hour from the induction of anesthesia to extubation. Prior to extubation, the wound closes.

As used herein, the term "end of surgical procedure" has conventional meaning in the art and is understood by those of skill in the art. It usually coincides with wound closure at the end of surgery.

As used herein, the term "about" or "abbreviation" is a number that, when used in conjunction with a number (eg, 5, 10%, 1/3), may be less than or greater than that number. Shows the range. For example, "about 5" is a range of numbers 10%, 5%, 2%, or 1% less than or greater than 5, for example, 4.5 to 5.5, or 4.75 to 5.25, or 4.9 to 5.1, or 4.95 to. The range of 5.05 is shown. In some examples, "about 5" indicates a range of numbers 2% or 1% less than or greater than 5, eg, 4.9 to 5.1, or 4.95 to 5.05.

In one embodiment of the invention, the dose of amisulpride is 7.5 mg to 15 mg. Preferably, the effective amount (ie, dose) of amisulpride comprises 8 to 15 mg of amisulpride, more preferably 8.5, 9, or 9.5 to 15 mg. The dose of amisulpride may be 7.5 to 14.5, 14, 13.5, 13, 12.5, 12, 11.5, 11, or 10.5. Any of the above range restrictions may be combined with each other. Preferably, the dose is 8-12 mg, more preferably 9-12 mg, most preferably about 10 mg amisulpride. The most preferred dose is 10 mg. Preferably, amisulpride is in the form of a racemic mixture.

Preferably, amisulpride is administered as a once-daily dose.

Preferably, amisulpride is administered as a racemate. When administered as S-enantiomer, the dose can be varied accordingly (eg, halved).

According to the present invention, amisulpride is used for "treatment" of PONV. This means that the patient is already PONV (defined above). Further, according to the present invention, the patient has already been administered a preventive drug for PONV. Therefore, of course, prevention of PONV has not been successful.

The "prevention" of PONV according to the present invention is administered prior to the treatment of PONV. "Preventive drug" means a drug administered with the intent / purpose of prevention of PONV. Suitable drugs will be known to those of skill in the art. An example is shown below.

It may be advantageous to administer amisulpride in combination with other antiemetics (ie, other than amisulpride). "Other antiemetics" are preferably other classes of antiemetics that can add additional efficacy benefits. Therefore, preferably, the different antiemetics are not D ₂ antagonists. These include, but are not limited to, steroids, most preferably dexamethasone, 5HT ₃ antagonists, including but not limited to ondansetron, granisetron, and palonosetron, and NK ₁ antagonists such as aprepitant, netupitant, or lorapitant. Is included. Amisulpride may be combined with metoclopramide, which has both D ₂ and 5HT ₃ properties. Preferably, the other antiemetic agent is ondansetron, granisetron, or dexamethasone. Amisulpride may be combined with one or more (eg, two or three) different antiemetics. Other classes of drugs may be administered via any suitable route of administration (eg, orally, intravenously, or intramuscularly, via a route of administration that is common to the drug). In some cases, other classes of drugs may be administered within 6 hours of the end of surgery. In another example, other classes of drugs may be administered 6 hours after the end of surgery.

Prophylactic agents are preferably administered prior to the end of surgery. In a preferred embodiment, prevention is applied from about 4 hours prior to the surgical procedure to the end of wound closure / surgery. It is preferably given by the end of wound closure / surgery, more preferably at the time of anesthesia (and more preferably at the time of induction of anesthesia).

There are numerous prophylactic agents suitable for use in the present invention, which are well known to those of skill in the art. Certain prophylactic agents may be selected based on a number of factors, such as age and weight, or, for example, being administered other specific medications. Preferably, the prophylactic agent is an antiemetic agent that is not amisulpride. More preferably, the prophylactic agent is not a dopamine-2 (D ₂ ) antagonist.

In some embodiments, the prophylactic agent is an antiemetic agent selected from 5HT ₃ antagonists, corticosteroids, antihistamines (H ₁ ), anticholinergic agents, H ₂ antagonists, or NK ₁ antagonists. The prophylactic agent can be selected from any of the above antiemetics (ie, combination therapy).

5HT ₃ antagonists can be ondansetron, granisetron, palonosetron, tropisetron, or dolasetron. Preferred is ondansetron, granisetron, or palonosetron. More preferably, it is ondansetron. Corticosteroids can be dexamethasone, hydrocortisone, betamethasone, methylprednisolone, or prednisolone. Dexamethasone is preferred. The antihistamine (H ₁ ) can be dimenhydrinate, hydroxyzine, diphenhydramine, promethazine, cyclizine, or meclizine. The anticholinergic agent can be scopolamine / hyostin. The H ₂ antagonist can be famotidine. NK ₁ antagonists can be aprepitants. The D ₂ antagonist can be haloperidol, droperidol, or domperidone when used as a prophylactic antiemetic.

Common doses of the various antiemetics described above are known to those of skill in the art. For example, ondansetron is typically in doses of 2 to 20 mg, or 2 to 15 mg, or about 10 mg, or about 4 mg. For granisetron, the dose is generally 1-3 mg, eg 1 mg. For dexamethasone, the typical dose is 4-20 mg, eg 4 mg.

The amisulpride used according to the present invention can be packaged for sale together with the attached instruction manual. The instructions for use (drug label) should indicate that the patient being treated should have undergone a surgical procedure and should be selected from a group of unsuccessful patients who received prior prophylaxis for PONV (ie, rescue treatment). ) It is preferable to clearly indicate that. It is also preferred to specify that the dose of amisulpride is 10 mg.

The amisulpride used in the present invention is preferably formulated as an intravenous preparation (and for intravenous administration). Amisulpride can be in the form of salts, hydrates, or solvates. The salt may be a pharmaceutically acceptable salt, such as an acid addition salt derived from an inorganic or organic acid, eg, a hydrochloride salt, a hydrobromide salt, a p-toluenesulfonate, a phosphate salt, a sulfate salt, etc. Perchlorate, acetate, trifluoroacetate, propionate, citrate, malonate, succinate, lactate, oxalate, tartrate, and benzoate.

The salt may be formed with a base. Examples of such salts include salts derived from inorganic or organic bases, for example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, morpholin salt, piperidine salt and dimethyl. Examples thereof include an amine salt and an organic amine salt such as a diethylamine salt.

The intravenous formulation of amisulpride used in the present invention may be in the form of an aqueous or non-aqueous (eg, oily) solution or suspension for sterile injection. The sterile injectable formulation can be a sterile injectable solution or suspension in a non-toxic parenteral acceptable diluent or solvent, eg, a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, phosphate buffer, Ringer's solution, and isotonic saline. In addition, sterile non-volatile oils can be used as solvents or suspension media. Any sterile non-volatile oil may be used for this purpose, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of the intravenous formulations of the present invention. Suspensions can be formulated according to known techniques using their appropriate dispersants or wetting and suspending agents.

Aqueous suspensions contain active ingredients mixed with excipients suitable for making aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacant rubber, and acacia rubber, dispersants or wetting agents, such as natural phosphatide, such as lecithin, or. Condensates of alkylene oxides and fatty acids, such as polyoxyethylene stearate, or condensates of ethylene oxide and long-chain fatty alcohols, such as heptadecaethyleneoxysetanol, or condensates of ethylene oxide and partial esters and hexitol derived from fatty acids. For example, a condensate of polyoxyethylene with a partial ester derived from a fatty acid and anhydrous hexitol, such as polyoxyethylene sorbitan monooleate. Aqueous suspensions are one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavorings, and one or more sweetnesses such as sucrose or saccharin. It may contain an agent.

Injectable compositions are generally aqueous and contain a buffer, such as a citrate buffer. Other ingredients may not be needed. The pH of such compositions can be, for example, 4 to 7, for example about 5.

Dispersible powders and granules suitable for the preparation of aqueous suspensions with the addition of water provide an active ingredient mixed with a dispersant or wetting agent, a suspending agent and one or more preservatives. Suitable dispersants or wetting and suspending agents are known.

The pharmaceutical composition of the present invention may be in the form of an oil-in-water emulsion. The oil phase can 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 are natural rubbers such as acacia rubber or tragacant rubber, natural phosphatides such as soybeans, lecithin, and esters or partial esters derived from fatty acids and anhydrous hexitols such as sorbitan monooleate and condensates of said partial esters with ethylene oxide. For example, it can be 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 can be in the form of a vial of active agent with a syringe and a needle, or in the form of a prefilled syringe / needle combination.

In some embodiments, amisulpride is included in the non-IV injectable formulation. It may be in the form of a solid or liquid formulation and may be formulated for oral administration. The solid formulation can be in the form of tablets or capsules, molten 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 in the form of syrups and packaged in vials.

Amisulpride can be in the form of a suppository for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that melts in the rectum and releases the drug as it is solid at room temperature but liquid at rectal temperature. Such materials include cocoa butter and polyethylene glycol.

For topical delivery, transdermal and transmucosal patches, creams, ointments, jellies, solutions, or suspensions may be used. For sublingual delivery, a fast-dissolving tablet formulation, as well as many of those described above, may be used. For oral administration, which is the preferred administration, amisulpride can be administered as tablets, capsules, or liquids.

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

The amisulpride preparation may contain any number of pharmaceutically acceptable excipients such as sweeteners and preservatives.

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

When the use or method of the present invention provides administration of two or more drugs, the drugs can be administered simultaneously, sequentially or individually. It is not necessary to pack the drugs together (although this is an embodiment of the invention). There is no need to administer the drug at the same time. As used herein, "individual" dosing means that the drug is administered as part of the same overall dosing regimen (which may include many days), but is preferably given on the same day. Means to be administered to. As used herein, "simultaneously" means that the drugs are taken together or formulated as a single composition. As used herein, "consecutively" means that the drugs are administered at about the same time, preferably within about 1 hour of each other.

Prophylactics should be given before vomiting occurs. Preferably, it is administered as a single prophylactic dose.

Preferably, amisulpride is administered by IV infusion (push), preferably over a period of about 20 seconds to 20 minutes. For example, if the patient feels pain during infusion, it may be preferable to increase the infusion time. In some embodiments, amisulpride is administered over a period of about 1-15, 1-10, 1-5, or 1 or 2 minutes. Amisulpride is preferably administered in a single dose.

Amisulpride should actually be administered as soon as possible following the first vomiting episode and / or the first nausea episode (eg, the first request for an antiemetic to treat nausea, or a report of vomiting desire). be. Preferably, amisulpride is administered within 1 hour of the first vomiting episode and / or within 1 hour of the first nausea episode. More preferably, it is administered within 30 minutes of the first vomiting episode and / or within 30 minutes of the first nausea episode. Even more preferably, it is administered within 15 minutes of the first emetic episode and / or within 15 minutes of the first nausea episode.

In some embodiments, no further dose of amisulpride is administered within 24 hours after the initial dosing. In some embodiments, after the initial dosing according to the invention, at least one additional dosing is given within about 24 hours, preferably within about 12 hours, from the first dosing.

In a preferred embodiment, the patient is a human.

The present invention will be described by the following studies.

Study 1

protocol

A randomized, double-blind, placebo-controlled trial of amisulpride for IV injection as a treatment for existing postoperative nausea and vomiting in pre-prevented patients was conducted. The main purpose of this study is to compare the efficacy of 5 mg and 10 mg of amisulpride with placebo as a treatment for existing PONV in patients who have been previously treated with PONV prophylaxis.

The study was conducted in adult patients (aged 18+) who had previously received PONV prevention and experienced PONV within 24 hours after surgery and had an expected duration of inhalation anesthesia of at least 1 hour.

A single dose of 5 mg or 10 mg dose of amisulpride or the corresponding placebo was administered at a low rate of IV over about 2 minutes.

The primary efficacy variable was a binary variable of success or failure of initial PONV treatment, with success being the absence of vomiting episodes (vomiting or nausea) 30 minutes to 24 hours after study drug administration and 24 hours after study drug administration. It was defined as the absence of antiemetic relief at any time during the period (“complete remission”).

Secondary validity variables include:
-Occurrence and severity of nausea (VRS score> 0) and severe nausea (VRS score ≥ 4). Includes measurements of nausea over time, such as the area under the nausea score curve for a period of up to 24 hours.
・ Occurrence of vomiting (including nausea) after administration of the study drug.
-Use of antiemetic relief drugs.
-Time to failure of initial PONV treatment.
Sub-analysis of successes and failures with various parameters, including PONV onset time and gender in relation to the end of surgery.

result

The complete remission (CR) rate was as follows.
Placebo (235 patients) 28.5%
Amisulpride 5 mg (237 patients) 33.8% (p = 0.109)
Amisulpride 10 mg (230 patients) 41.7%, (p = 0.003)

Conclusion

When used as a " rescue " treatment, i.e., when used to treat patients with PONV episodes when the pre-prevention received by the patient is unsuccessful, amisulpride at a dose of 10 mg is given (5 mg). There are advantages (compared to the dose of). In this situation, a dose of 10 mg of amisulpride proved to be particularly effective. This can be a very effective reduction in the length of stay in the recovery room after anesthesia and can benefit healthcare providers.