GB2602123A

GB2602123A - Composition for procedural sedation and use thereof

Info

Publication number: GB2602123A
Application number: GB2020153.9A
Authority: GB
Inventors: Julian De Silva Don; Du Plessis Andre; Botha Willem; Von Backstrom Andre
Original assignee: Centre London Ltd
Current assignee: Centre London Ltd
Priority date: 2020-12-18
Filing date: 2020-12-18
Publication date: 2022-06-22
Anticipated expiration: 2040-12-18
Also published as: GB202020153D0; GB2602123B

Abstract

A composition comprising: a first active compound which is midazolam or a pharmaceutically acceptable salt thereof; a second active compound which is propofol or pharmaceutically acceptable salt thereof; a third active compound which is ketamine or a pharmaceutically acceptable salt thereof; and a fourth active which is remifentanil or a pharmaceutically acceptable salt thereof, for use in procedural sedation of a patient, wherein the active compounds of the composition are to be administered simultaneously, separately or sequentially is provided. The composition may further comprise at least one further active compound selected from the group consisting of paracetamol, dexamethasone, parecoxib and pharmaceutically acceptable salts thereof. Preferably, the total dose of the first active compound is in the range 0.5 to 3mg, and preferably, the total dose of the third active compound is in the range 10 to 25mg. Preferably, at least one the first and third active compounds is administered as one or more bolus doses as an injection. Preferably, at least one of the second and fourth active compounds is administered by infusion. The composition is preferably for use in inducing and maintaining procedural sedation in a patient during a surgical procedure.

Description

Composition for procedural sedation and use thereof The present invention relates to compositions for use in procedural sedation of a patient, and in particular to compositions for use in inducing and maintaining procedural sedation in a patient during a surgical or medical procedure. The present invention further relates to use of such compositions for inducing and maintaining procedural sedation of a patient, in particular but not exclusively, during surgical procedures.

The use of anaesthesia during surgical, therapeutic and diagnostic procedures is well established.

There are three broad categories of anaesthesia, which may be used according to the specific requirements of the patient and the procedure being carried out.

Local and regional anaesthesia can be used to block pain in specific parts of the body. Whilst local or regional anaesthesia may be sufficient for a range of smaller procedures, the patient generally maintains consciousness and may retain some level of sensation. Accordingly, local or regional anaesthetic techniques alone are generally unsuitable for longer and/or more complicated procedures, or where it is required to provide some relief from anxiety in the patient, for example. Local or regional anaesthesia is particularly unsuitable where it is necessary to prevent or limit patient movement during the procedure.

General anaesthesia, in contrast, suppresses the central nervous system and results is complete loss of consciousness. Normally, the patient's ability to maintain a patent airway independently is lost or impaired and breathing intervention is therefore usually required. General anaesthesia benefits from a lack of patient movement, thus reducing the risk of accidental injury. However, a large number of side effects are associated with the use of general anaesthesia, contributing to long post-procedure recovery times.

Sedation suppresses the nervous system sufficiently to place the patient in a "sleep-like" state, thus providing simultaneous relaxation and pain relief. Sedation techniques can range from mild or minimal sedation, in which the patent remains awake, responsive to verbal commands, and capable of unassisted breathing, to deep sedation, in which patients are asleep but maintain some responsiveness to stimulation. Patients in deep sedation may require assistance in breathing.

Sedation avoids a number of side effects associated with general anaesthesia, such as injury to the teeth and/or oral cavity and sore throat (caused by the necessary insertion of a breathing tube), and in some rare but extreme cases, patient death. Furthermore, sedation recovery times are typically faster due to the relatively small amounts of medication required to induce sedation compared to general anaesthesia. At the same time, sedation provides a benefit over local or regional anaesthesia in inducing a relaxed state in the patient and preventing or limiting patient movement.

Despite the established benefits of sedation, side effects such as vomiting and nausea can still be common. In addition, recovery times can be longer than desired due to the use of high doses of medication, particularly following relatively long procedures where sedation is maintained for longer durations and/or where the patient shows resistance to the anaesthetic medication, thus requiring higher doses to be administered.

Accordingly, there remains a need for methods and compositions for inducing and maintaining sedation, which minimise the required dosages of medication and yield faster recovery times with reduced side effects.

The present invention seeks to provide an improved composition for inducing and maintaining sedation in a patient during a surgical procedure.

According to the present invention in a first aspect there is provided a composition comprising: a first active compound which is midazolam or a pharmaceutically acceptable salt thereof; a second active compound which is propofol or a pharmaceutically acceptable salt thereof; a third active compound which is ketamine or a pharmaceutically acceptable salt thereof; and a fourth active compound which is remifentanil or a pharmaceutically acceptable salt thereof, for use in procedural sedation of a patient, wherein the active compounds of the composition are to be administered simultaneously, separately or sequentially.

In the context of the present specification, including the appended claims, the term "procedural sedation" is to be interpreted as a sedation technique in which the patient remains conscious throughout the period of sedation, but which produces a state of depression of the central nervous system enabling treatment to be carried out. In procedural sedation, the nervous system is suppressed through the use of a combination of anaesthetic, sedative and/or analgesic drugs, without suppressing the level of consciousness to the point where the patient becomes completely unconscious.

Accordingly, the patient retains consciousness throughout the period of sedation. This is in contrast to general anaesthesia, in which the patient becomes completely unconscious. The term "procedural sedation" includes techniques ranging from mild or minimal sedation to deep sedation. The level of sedation can be optimised according to the particular procedure and patient.

In some preferred embodiments, the composition is provided for use in conscious sedation of a patient. In the context of the present specification, "conscious sedation" is to be interpreted as a relatively mild or minimal form of procedural sedation in which the patient remains conscious throughout the period of sedation, but which produces a state of depression of the central nervous system enabling treatment to be carried out, wherein verbal contact with the patient is maintained throughout the period of sedation and wherein the patient continues to show a purposeful response to light tactile stimulation throughout the period of sedation. Reflex withdrawal from a painful stimulus is not considered a purposeful response. Conscious sedation retains the patient's ability to maintain a patent airway independently and continuously.

In the context of the present specification, including the appended claims, the term "composition" is to be interpreted as a combined preparation or aggregate of active compounds, which active compounds may be administered to the patient simultaneously, separately or sequentially in any form.

In the composition of the present invention, the active compounds may be present in the form of pharmaceutically acceptable salts. A large variety of suitable pharmaceutically acceptable salts of the active compounds will be within the knowledge of the skilled person. Non-limiting examples of preferred salts include hydrochloride and maleate salts.

It has been found that the particular combination of active compounds in the present invention provides a composition which demonstrates surprisingly low levels of side effects, in particular nausea and vomiting, in the patients to whom the composition is administered, when compared to known anaesthetic compositions. Furthermore, the recovery time of patients to whom the composition is administered has been found to be surprisingly fast.

In particular, it has been found that by providing the first to fourth active compounds in combination, the amount of each active compound which is required to maintain the required level of consciousness is significantly reduced compared to other compositions which are known for use in sedation. Thus, by reducing the amount of each active compound, the side effects experienced by patients and the recovery time of patients are significantly reduced compared to known compositions.

More specifically, the present inventors have made the unexpected discovery that the specific combination of first, second, third and fourth active compounds in the composition of the present invention provides improved sedation On terms analgesic efficacy and recovery time) compared to the use of only some of the active compounds. Use of the first and second active compounds in combination (i.e. in the absence of the third and fourth active compounds) for procedural sedation during surgical procedures resulted in a proportion of patients experiencing breakthrough discomfort in some more sensitive areas of the body, such as the face. Use of the first, second and third active compounds in combination (i.e. in the absence of the fourth active compound) for the same purpose resulted in increased recovery times, whilst patients still experienced breakthrough discomfort in sensitive areas. By combining all four active compounds, it was found that the required level of sedation (i.e. consciousness) could be maintained, whilst preventing breakthrough discomfort in sensitive areas, with relatively small amounts of each of the active compounds being required. Accordingly, recovery time was also reduced.

The composition of the present invention may comprise at least one further active compound, which may be selected from the group consisting of paracetamol, dexamethasone, parecoxib, clonidine and pharmaceutically acceptable salts thereof. It will be appreciated that the composition may additionally comprise a number of additional active compounds appropriate for use during procedural sedation and/or surgical procedures, such appropriate active compounds being known to a person skilled in the art of anaesthesia.

In preferred embodiments, at least one of the first to fourth active compounds is administered parenterally, and most preferably intravenously. In a most preferred embodiment, each of the first to fourth active compounds is administered intravenously.

The composition of the present invention may be administered simultaneously, separately or sequentially. In some embodiments of the present invention, at least two of the first to fourth active compounds may be provided in a mixture and thus administered together. In one embodiment, all of the first to fourth active compounds may be provided in a mixture. This arrangement provides relatively facile administration of all active compounds together, such as by bolus dose or infusion.

In preferred embodiments of the present invention, at least two of the active compounds are administered separately. Accordingly, the administration of the individual active compounds can be tailored to the requirements of the patient and the procedure.

The total dose of each of the first to fourth active compounds required during any given administration will depend on several factors including, for example, patient metabolism (i.e. a particular patient's tolerance to any one or more of the active compounds) and the duration of the procedure being carried out (longer procedures will require higher total doses). A number of other factors may affect the required total dose, which will be known to the skilled person.

Preferably, the composition comprises a total dose of the first active compound of 3 mg or less. The composition may preferably comprise a total dose of the first active compound in the range 0.5 to 3 mg.

Preferably, the composition comprises a total dose of the third active compound of 50 mg or less and more preferably 25 mg or less. The composition may preferably comprise a total dose of the third active compound in the range 10 to 50 mg, more preferably in the range 10 to 25 mg, and most preferably in the range 10 to 20 mg.

In some embodiments, at least one of the first to fourth active compounds is arranged to be administered as one or more bolus doses. That is to say, at least one of the first to fourth active compounds is provided in the composition in the form of one or more bolus doses. In this context, the term bolus dose is to be understood as a discrete quantity of an active compound to be administered at a controlled, preferably rapid, rate. At least one of the first to fourth active compounds may be administered in the form of a loading dose and one or more optional maintenance doses. That it so say, at least one of the first to fourth active compounds may be present in the composition in the form of a loading dose and one or more optional maintenance doses. Said loading dose is a bolus dose administered at or towards the beginning of a sedation procedure as the first dose of a given active compound. Said one or more optional maintenance doses are bolus doses administered subsequently to the loading dose at appropriate time intervals, which time intervals may be predetermined or variable according to the requirements of the patient and the procedure. The one or more optional maintenance doses are administered if required, according to the needs of the patient and the duration of the procedure.

The or each bolus dose may preferably be in the form of an intravenous injection.

In some embodiments, at least one of the first and third compounds is administered as one or more bolus doses. That is to say, the composition may comprise one or more bolus doses of the first active compound and/or one or more bolus doses of the third active 25 compound.

In preferred embodiments, the first active compound is administered as one or more bolus doses. The first active compound may be provided as a loading dose and, optionally, one or more maintenance doses. The composition may preferably comprise a loading dose of the first active compound, which loading dose comprises the first active compound in an amount in the range 0.5 to 3 mg, more preferably in the range 1 to 2 mg and most preferably of approximately 1 mg. The composition may comprise one or more maintenance doses of the first active compound in addition to the loading dose of the first active compound, the or each optional maintenance dose comprising the first active compound in an amount in the range 0.25 to 0.5 mg. In a most preferred embodiment, the composition comprises a loading dose of the first active compound comprising approximately 1 mg of the first active compound, and one or more optional maintenance doses of the first active compound, each maintenance dose comprising 0.25 to 0.5 mg of the first active compound.

In a further preferred embodiment, the third active compound is administered as one or more bolus doses. The third active compound may preferably be provided as a loading dose and, optionally, one or more maintenance doses. The composition may preferably comprise a loading dose of the third active compound, which loading dose comprises the third active compound in an amount in the range 10 to 25 mg, and more preferably of approximately 10 mg. The composition may comprise one or more maintenance doses of the third active compound in addition to the loading dose of the third active compound, the or each optional maintenance dose comprising approximately 10 mg of the third active compound. In a most preferred embodiment, the composition comprises a loading dose of the third active compound comprising 10 mg of the third active compound, and one or more optional maintenance doses of the third active compound, each maintenance dose comprising 10 mg of the third active compound.

In some embodiments of the present invention, the composition may comprise a loading dose of the first active compound and a loading dose of the third active compound, wherein the loading dose of the third active compound is administered subsequently to the loading dose of the first active compound. Said loading doses of the first and third active compounds may be the only doses of the first and third active compounds, or alternatively the composition may further comprise one or more maintenance doses of the first and/or third active compounds, respectively.

In preferred embodiments of the present invention, at least one of the first to fourth active compounds is administered by infusion, and preferably as a target controlled infusion. Preferably, at least one of the second and fourth active compounds is administered by infusion, and more preferably both the second and fourth active compounds are administered by infusion. Most preferably, the second and fourth active compounds are administered simultaneously by infusion. The second and fourth active compounds may be administered separately and simultaneously by infusion, or may be administered as a mixture by infusion.

In preferred embodiments, the second active compound is administered as a target controlled infusion to achieve an effect site concentration of the second active compound in the range 0.8 to 4 mcg/ml.

In preferred embodiments, the fourth active compound is administered as a target controlled infusion to achieve an effect site concentration of the fourth active compound in the range 0.5 to 2 ng/ml.

According to the present invention in a second aspect, there is provided the use of a composition in accordance with the first aspect for inducing and maintaining procedural sedation in a patient. The use may preferably be for inducing and maintaining procedural sedation in a patient during a surgical procedure, which may in some embodiments be a cosmetic surgical procedure The following Examples provides a description of the safe administration of a composition in accordance with the present invention, which are given by way of example only. As will be readily appreciated by a person of ordinary skill in the art, variations of the composition and the administration thereof are possible, which fall within the scope of the appended claims. The following examples are thus not to be construed as limiting and are provided as illustrative examples only, enabling a person of ordinary skill in the art to carry out the present invention.

Examples

A sample of 192 patients undergoing cosmetic surgical procedures were administered with the composition of the present invention, in order to induce procedural sedation.

All of the first to fourth active compounds of the composition were administered intravenously. Appropriate stock solutions of the first to fourth active compounds were prepared or obtained at appropriate concentrations. Appropriate solutions and concentrations of the first to fourth active compounds will be known to a person skilled in the art of anaesthesia. Exemplary sources of the first to fourth active compounds are as follows: Midazolam: 10 mg/2m1solution, vial (obtained from F. Hoffmann-La Roche AG (Roche)); Propofol: 200 mg/20m1 solution, vial (obtained from Norameda UAB); Ketamine: 50 mg/ml solution, vial (obtained from Pfizer Inc, marketed as Ketalar); Remifentanil: 2 mg powder, vial (obtained from Wockhardt UK Limited).

Remifentanil in the form of a powder is diluted in 0.9% sodium chloride solution in water to form a solution with a remifentanil concentration of 20 mcg/ml.

The total amount of each of the first to fourth active compounds administered to each of the patients (i.e. the total amount of each of the first to fourth active compounds provided in the composition in each example) was determined according a number of variable factors in order to maintain the desired level of procedural sedation throughout the duration of the procedure. Such factors include, for example, the height, weight and age of the patient, the patient's observed tolerance to the composition and the duration of the procedure. Variation of the amount of each active compound in order to maintain the desired level of sedation throughout the procedure will be within the competence of a person skilled in the art of anaesthesia.

Midazolam was administered at the start of the procedure (0 minutes) as a loading dose by intravenous injection. Optionally, one or more maintenance doses of midazolam were administered during the procedure, as determined by the duration of the procedure and the observed needs of the patient. In all examples, the loading dose contained midazolam in an amount in the range 0.5 to 3 mg, and each maintenance dose (where used) contained midazolam in an amount in the range 0.25 to 0.5 mg. In all examples, the total amount of midazolam administered was in the range 0.5 to 3 mg. Midazolam was administered in the form of a hydrochloride salt.

Propofol was administered by infusion using a standard syringe pump. Propofol was administered at the start of the procedure (0 minutes) as a target controlled infusion to achieve an effect site concentration of 0.8 to 4 mcg/ml. Target controlled infusion of propofol was continued until completion of the procedure.

Remifentanil was administered by infusion using a standard syringe pump. Remifentanil was administered at the start of the procedure (0 minutes) as a target controlled infusion to achieve an effect site concentration in the range 0.5 to 2 ng/ml.

Target controlled infusion of remifentanil was continued until completion of the procedure. Remifentanil was administered in the form of a hydrochloride salt.

Ketamine was administered as a loading dose at approximately 3 minutes subsequent to the start of the procedure (that is, approximately 3 minutes after the administration of the loading dose of midazolam). Ketamine was administered as a loading dose by intravenous injection. Optionally, one or more maintenance doses of ketamine were administered during the procedure, as determined by the duration of the procedure and the observed needs of the patient. In all examples, the loading dose contained ketamine in an amount in the range 10 to 25 mg, and each maintenance dose (where used) contained approximately 10 mg of ketamine. In preferred methods of administration, each of the loading dose and maintenance doses (where used) contained approximately 10 mg of ketamine. In all examples, the total amount of ketamine administered was in the range 10 to 25 mg.

During the procedure, the patient was assessed according to the following criteria to ensure patient safety and efficacy of the sedation: 1. If appropriate and ordered by physician, the patient was placed on monitoring equipment with patient specific alarm mechanisms activated.

2. The patient was continuously monitored ECG status and oxygen saturation.

3. Blood pressure cuff readings (non-invasive blood pressure or manual) were carried out at 5 to 15 minute intervals.

4. The patient's responsiveness to verbal and physical stimuli was assessed 5 minutes after administration of any active compound and at intervals of 5 to 15 minutes thereafter.

5. An assessment of the patient's pain level was carried out at 5 to 15 minute intervals.

In the event that the patient's level of sedation appeared inadequate and/or the patient's level of pain appeared too high, administration of the composition was adjusted in an appropriate manner, as will be readily appreciated by a person skilled in the art of anaesthesia. For example, in some cases, one or more maintenance doses of ketamine, which provides both a sedative and analgesic effect, were administered. Similarly, in some cases, one or more maintenance doses of midazolam were administered, to increase and/or prolong sedation of the patient.

Once sedation was no longer required (i.e. once the surgical procedure has been completed), infusion of medications was stopped.

Results and Discussion Following the procedure, the 192 patients within the sample were surveyed to determine the general level of satisfaction with the sedation, side effects experienced and recovery time. The composition of the present invention was thus assessed according to the following measures: 1. Overall patient satisfaction with sedation, on a scale of 0 (unsatisfied) to 10 (satisfied).

2. Number of patients experiencing nausea before and after discharge.

3. Number of patients experiencing vomiting following the procedure (before or after discharge).

4. Patient pain level two hours after the procedure, on a scale of 0 (no pain) to 10 (severe pain).

5. Patient recovery time, determined by the time taken for the patient to be discharged according to the following discharge criteria: i) Patient is alert and oriented to time and place; ii) Patient is able to ambulate without dizziness; iii) Patient has stable vital signs (return to baseline); iv) Patient is able to take oral fluids with minimal nausea; v) Patient is able to maintain satisfactory verbal communication and vi) Patient is free from unusual pain, nausea or bleeding.

The results of the survey of 192 patients are provided in Table 1.

Table 1

Number of patients /192 Total patients surveyed 192 100 Happy with sedation (satisfaction 183 95 score 6 to 10) Not happy with sedation (satisfaction 3 2 score 0 to 5) Nausea before discharge 20 10 Nausea after discharge 24 13 Vomiting before or after discharge 6 3 Moderate pain (pain score 6 to 10) 21 11 Discharged same day 192 100 Discharged within 1 hour of surgery 182 95 As can be seen from the results above, the composition according to the present invention provides a combined preparation or aggregate for use in the procedural sedation of patients, which demonstrates high levels of patient satisfaction, relatively low levels of post-procedure nausea, vomiting and pain, and surprisingly fast recovery times.

Of the patients surveyed, a very large proportion (95 °/0) indicated general satisfaction with the procedure, with only a very small proportion (2 °/0) indicating any degree of dissatisfaction.

Side effects commonly experienced by patients following sedation using known techniques and compositions were found to be rare with the use of the composition of the present invention. The number of patients experiencing nausea before or after discharge was very low (11 % and 12 %, respectively) and the number of patients experiencing vomiting at any stage post-procedure was extremely low (3 °A). Furthermore, the number of patients experiencing moderate levels of pain more than two hours after the procedure was only 12 %.

A significant measure of the efficacy of a sedation technique and/or composition is the amount of time taken for the patient to recover to an extent sufficient to be discharged. According to the above discharge criteria, 100 % of patients administered with the composition of the present invention were discharged on the day of surgery. More than 90 % of patients were discharged within 1 hour of completion of the procedure. This is not only beneficial for the wellbeing of the patient, but also provides economic advantages to a clinic or treatment centre by significantly reducing the amount of time taken for patients to be discharged, and, in particular, obviating the need for patients to stay overnight. This increases the number of patients that can be treated in a day and reduces the costs of post-operative care.

Accordingly, it has been shown that the present invention provides a composition for use in the procedural sedation of a patient which demonstrates reduced levels of common side effects and results in fast recovery times.

The present invention further demonstrates significant benefits in comparison to the use of general anaesthesia, as indicated in Table 2.

Table 2

Complication General Anaesthesia Present invention (procedural sedation) Proportion of patients experiencing nausea 70 to 80 % 10 to 23 % Proportion of patients experiencing vomiting 20 to 30 % 3 To Proportion of patients 1 in 100 cases Nil experiencing physical injury to teeth (No airway tube inserted) Proportion of patients experiencing a sore throat 20 to 50 % <51% (Airway tube inserted) (No airway tube inserted) Proportion of patients experiencing nerve injury 1 in 500 cases Nil Proportion of patients experiencing blindness 1 in 250,000 cases Nil Proportion of patients experiencing deep vein thrombosis 0.5 to 1 per 1000 Nil Proportion of patients experiencing death 1 in 100,000 cases (Severe airway issue, atypical response) Nil (Patient remains conscious throughout procedure) Recovery time A proportion stay overnight in hospital All patients go home day of surgery (>90 % home within 1 hour) As can be seen from Table 2, the use of the composition of the present invention for procedural sedation offers significant advantages over general anaesthesia. The present invention eliminates common side effects associated with general anaesthesia, including physical injury to teeth, nerve injury, blindness, deep vein thrombosis and death. Further side effects including vomiting and sore throat are also significantly reduced. Moreover, the recovery time associated with the use of the composition of the present invention for procedural sedation is typically much faster than for general anaesthesia.

This provides improved patient wellbeing, as well as significant economic advantages as described above.

The invention has been described above with reference to specific embodiments, given by way of example only. It will be appreciated that different variations are possible, which fall within the scope of the appended claims.

Claims

Claims 1 A composition comprising: a first active compound which is midazolam or a pharmaceutically acceptable salt thereof; a second active compound which is propofol or a pharmaceutically acceptable salt thereof; a third active compound which is ketamine or a pharmaceutically acceptable salt thereof; and a fourth active compound which is remifentanil or a pharmaceutically acceptable salt thereof, for use in procedural sedation of a patient, wherein the active compounds of the composition are to be administered simultaneously, separately or sequentially.
2 A composition according to Claim 1, further comprising at least one further active compound selected from the group consisting of paracetamol, dexamethasone, parecoxib and pharmaceutically acceptable salts thereof.
3. A composition according to any preceding claim, wherein at least one of the active compounds of the composition is to be administered parenterally.
4. A composition according to Claim 3, where at least one of the active compounds of the composition is to be administered intravenously.
5. A composition according to any preceding claim, wherein at least two of the active compounds are provided in a mixture.
6. A composition according to any preceding claim, wherein at least two of the active compounds are administered separately.
7. A composition according to any preceding claim, comprising a total dose of the first active compound in the range 0.5 to 3 mg.
8. A composition according to any preceding claim, comprising a total dose of the third active compound in the range 10 to 25 mg.
9. A composition according to any preceding claim, wherein at least one of the first and third active compounds is administered as one or more bolus doses.
10. A composition according to claim 9, wherein the or each bolus dose is an injection.
11. A composition according to claim 9 or 10, comprising a loading dose of the first active compound, the loading dose of the first active compound comprising the first active compound in an amount in the range 0.5 to 3 mg.
12. A composition according to claim 11, wherein the loading dose of the first active compound comprises the first active compound in an amount in the range 1 to 2 mg.
13. A composition according to claim 11 or 12, further comprising one or more maintenance doses of the first active compound, the or each maintenance dose of the first active compound comprising the first active compound in an amount in the range 0.25 to 0.5 mg.
14. A composition according to any one of claims 9 to 13, comprising a loading dose of the third active compound, the loading dose of the third active compound comprising the third active compound in an amount in the range 10 to 25 mg
15. A composition according to claim 14, wherein the loading dose of the third active compound comprises the third active compound in an amount of approximately 10 mg.
16. A composition according to claim 1401 15, further comprising one or more maintenance doses of the third active compound, the or each maintenance dose of the third active compound comprising the third active compound in an amount of approximately 10 mg.
17. A composition according to any preceding claim, comprising a loading dose of the first active compound and a loading dose of the third active compound, wherein the loading dose of the third active compound is administered subsequently to the loading dose of the first active compound.
18. A composition according to any preceding claim, wherein at least one of the active compounds is administered by infusion.
19. A composition according to Claim 18, wherein at least one of the second and fourth active compounds is administered by infusion.
20. A composition according to Claim 19, wherein the second and fourth active compounds are administered simultaneously by infusion.
21. A composition according to Claim 19 or 20, wherein the second active compound is administered as a target controlled infusion to achieve an effect site concentration of the second active compound in the range 0.8 to 4 mcg/ml.
22. A composition according to any one of Claims 18 to 21, wherein the fourth active compound is administered as a target controlled infusion to achieve an effect site concentration of the fourth active compound in the range 0.5 to 2 ng/ml.
23. Use of a composition according to any one of the preceding claims for inducing and maintaining procedural sedation in a patient.
24. The use according to claim 23, for inducing and maintaining procedural sedation in a patient during a surgical procedure.