WO2016102463A1 - Combination of remifentanil and propofol - Google Patents

Combination of remifentanil and propofol Download PDF

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Publication number
WO2016102463A1
WO2016102463A1 PCT/EP2015/080788 EP2015080788W WO2016102463A1 WO 2016102463 A1 WO2016102463 A1 WO 2016102463A1 EP 2015080788 W EP2015080788 W EP 2015080788W WO 2016102463 A1 WO2016102463 A1 WO 2016102463A1
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Prior art keywords
propofol
remifentanil
patient
product
administered
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PCT/EP2015/080788
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French (fr)
Inventor
Arnaud BOSTEELS
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Bosteels Arnaud
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Application filed by Bosteels Arnaud filed Critical Bosteels Arnaud
Priority to EP15828336.6A priority Critical patent/EP3236956A1/en
Publication of WO2016102463A1 publication Critical patent/WO2016102463A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives

Definitions

  • the technical fields of the invention are anesthetics, in particular remifentanil and propofol, and target controlled infusion systems.
  • Anesthesia is a temporary state of sedation and inducted sleep in which the patient becomes unconscious and experiences loss of memory. In addition to anesthesia stricto sensu, the patient experiments analgesia or pain relief. Both sedation, asleep, and analgesia lead to stress reduction, preserving thereby physiological homeostasis, and muscle relaxation, in particular, relaxation of the skeletal muscle. Sedation is defined as the inducement of a state of calm, analgesia is defined as the insensitivity to pain, and physiological homeostasis is basically measured as maintenance of normal blood pressure and heart rate levels during surgery.
  • Remifentanil is a potent, ultra-short acting ⁇ -opioid synthetic analgesic agonist, chemically designated as a 3-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1 - piperidine]propanoic acid methyl ester.
  • a commercially available formulation of remifentanil hydrochloride is Ultiva®, which is a white to off-white lyophilized powder for intravenous (IV) administration after reconstitution and dilution.
  • the commercially available Ultiva® vial formulations contain 1 , 2, or 5 mg of remifentanil base; 15 mg glycine; and hydrochloric acid.
  • the Ultiva® remifentanil hydrochloride formulation is indicated for IV administration: 1 ) as an analgesic agent for use during the induction and maintenance of general anesthesia for inpatient and outpatient procedures; 2) for continuation as an analgesic into the immediate postoperative period in adult patients under the direct supervision of an anesthesia practitioner in a postoperative anesthesia care unit or intensive care setting; and 3) as an analgesic component of monitored anesthesia care in adult patients.
  • Propofol is a short-acting hypnotic and amnestic agent, indicated for IV administration.
  • the uses of propofol include general anesthesia and sedation for inpatient and outpatient procedures.
  • Propofol is chemically described as 2,6-diisopropylphenol.
  • a commercially available formulation of propofol is the injectable emulsion Diprivan®, a sterile, aqueous, non-pyrogenic oil-in-water emulsion containing 10 mg/mL or 20 mg/ml of propofol suitable for intravenous administration.
  • the 10 mg/mL formulation also contains soybean oil (100 mg/mL), glycerol (22.5 mg/mL), egg lecithin (12 mg/mL); and disodium edetate (0.005%); with sodium hydroxide to adjust pH.
  • the Diprivan® Injectable Emulsion is isotonic and has a pH of 7 to 8.5.
  • Other commercially available formulation of propofol are Propofol-®Lipuro 10 mg/ml (1 %) and Propofol-®Lipuro 20 mg/ml (2%).
  • Propofol is an IV sedative-hypnotic agent that can be used in adult patients for 1 ) initiation and maintenance of Monitored Anesthesia Care (MAC) sedation; 2) combined sedation and regional anesthesia; and 3) Intensive Care Unit (ICU) sedation of intubated, mechanically ventilated patients. It can be used for patients of 3 years of age or older for Induction of General Anesthesia. It can be further used for patients of 2 months of age or older for Maintenance of General Anesthesia. Propofol has progressively replaced sodium thiopental in anesthesia procedures, because it offers a more rapid recovery than the latter and it gives less nausea and vomiting.
  • MAC Monitored Anesthesia Care
  • ICU Intensive Care Unit
  • Propofol is administered at a dose of 2 to 2.5 mg/Kg during the induction to general anesthesia.
  • the induction phase terminates with intubation of the patient to support his respiratory functions.
  • maintenance rates of general anesthesia are in the order of 100 to 200 g/kg/min for adult patients (Diprivan FDA NDA-19-627/S-045, page 23).
  • overdosing patients undergoing anesthesia may result in a drop of blood's pressure, respiratory arrest, cardiac arrest, and death.
  • WO2007147505A2 discloses a mixture of drugs containing remifentanil and propofol in a ratio meant to achieve a steady state concentration ratio in plasma or at the effect site, for the use in anaesthesia, between 0.0015:1 and 0.0035:1 , or, for the use in sedation, between 0.0002:1 and 0.0008:1 , especially to be used in connection with a system for controlling administration of a mixture of drugs.
  • US20060093785A1 discloses a prepackaged combination drug for infusion into a patient having a need for pain and anxiety control during a medical procedure without general anesthesia; said drug comprising: a combination drug of remifentanil and propofol in which the ratio of propofol to remifentanil is more than about 500 ⁇ g to 1 ⁇ g so as to provide adequate pain management and anxiety control without suppressing the ventilation of said patient.
  • WO2007035573A2 discloses a product for efficiently facilitating the induction of general anesthesia and intubation, said product comprising: a) a package containing a combination of drugs; b) said combination of drugs in said package comprising remifentanil and propofol in a ratio effective to induce general anesthesia so as to permit intubation of said patient without stress, increased heart rate and/or increased blood pressure, in which said package comprises two vials, one of which contains a lyophilic powder of remifentanil and the other contains an emulsion of propofol in a ratio of about 2 ⁇ g of remifentanil to 1 mg of propofol.
  • Diprifusor® obtainable from the company AstraZeneca, is a target controlled infusion (TCI) system for the administration of propofol.
  • TCI target controlled infusion
  • a preferred set of pharmacokinetic parameters for propofol is selected using computer simulation of a known infusion scheme with pharmacokinetic parameters described in published literature.
  • the selected model is included in a module that is interfaced with, and later incorporated into, a computer- compatible infusion pump.
  • the TCI software consists of a particular arrangement of infusion control algorithms linked to a pharmacokinetic simulation program ( ⁇ University of Glasgow).
  • the program includes a three-compartment pharmacokinetic model and incorporates the 'Marsh' pharmacokinetic parameters.
  • US5609575A (Graseby Medical Limited) describes a TCI system in which the dose- concentration routine uses the body weight index as the only patient parameter in the system and only achieves a rough simulation of the concentration.
  • US8038645B2 (Bayer Technology Services GmbH) relates to a device for the time-controlled intravenous administering of the anesthetic propofol by means of a method used for determining an adequate dosage profile and adequately controlling an infusion pump as a metering apparatus, and which would permit exact time-controlled administration of propofol taking into account individual physiological, anatomical, biochemical, and genetic factors of the patient. Summary of the invention
  • TOE trans-esophageal ultrasound
  • This invention aims to providing to a patient undergoing a medical or surgical procedure, with a safe and effective anesthesia.
  • the present invention provides a combination of at least two drugs working in synergy, propofol and remifentanil, and employing safer and more effective doses.
  • the present invention integrates these two drugs in an electronically managed decision-making software, which monitors the amount of drugs to be delivered to the patient according to his body parameters and following a selected pharmacokinetic model, thereby further increasing the safety of the anesthetic procedure.
  • propofol is combined with remifentanil, less propofol is needed to place and maintain the patient under general anesthesia. Less propofol is thus accumulated in the body over the course of the infusion.
  • the present invention relates to a product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in inducing general anesthesia, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 , characterized in that the product is administered during 40 to 90 seconds at a target effect-site concentration of 4 ⁇ g/mL; and in the case the dose ratio of remifentanil to propofol (w/w) is from 0.0020:1 to 0.0029:1 , the product is further administered during additional 45 to 90 seconds at a second target effect-site concentration of 5 or 6 ⁇ g/mL.
  • the present invention relates to a product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in inducing general anesthesia, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 , characterized in that the product is administered during 45 to 90 seconds at a target effect-site concentration of 5 or 6 ⁇ g/mL.
  • the present invention relates to a product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in inducing general anesthesia, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 , characterized in that the product is administered during less than 40 seconds at a first target effect-site concentration of 2 ⁇ g/mL, and during additional 40 to 90 seconds at a second target effect-site concentration of 4 ⁇ g/mL; and in the case the dose ratio of remifentanil to propofol (w/w) is from 0.0020:1 to 0.0029:1 , the product is further administered during additional 45 to 90 seconds at a third target effect-site concentration of 5 or 6 ⁇ g/mL.
  • the present invention relates to a product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in inducing general anesthesia, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 , characterized in that the product is administered to adult patients.
  • the present invention relates to a product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in maintaining general anesthesia in patients, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 , characterized in that the administration rate of propofol is between 50 and less than 100 ⁇ g/Kg/min.
  • the present invention relates to a product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in inducing or maintaining general anesthesia, characterized in that the dose ratio (w/w) of remifentanil to propofol is from 0.0025:1 to 0.0039:1 , preferably from 0.0026:1 to 0.0034:1 , preferably from 0.0027:1 to 0.0033:1 , more preferably from 0.0028:1 to 0.0032:1 , even more preferably 0.0030:1.
  • the present invention relates to a kit for preparing a product according to any one of the embodiments presented herein, the kit comprising a first container comprising remifentanil or the pharmaceutically acceptable salt thereof, a second container comprising propofol or the pharmaceutically acceptable salt thereof, and instructions for mixing the remifentanil and propofol to obtain said dose ratio (w/w).
  • the present invention relates to a pharmaceutical composition consisting of remifentanil or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the content of remifentanil base is of 1.25 or 1 .5 mg.
  • the present invention relates to an infusion system for time-controlled administration to a patient of the product according to any one of the embodiments presented herein, said infusion system comprising:
  • an infusion pump adapted to deliver the fluid product from the supply to the patient at a controlled infusion rate(s);
  • control device operatively connected to the infusion pump and provided with a control algorithm for controlling the infusion rate, said control algorithm comprising steps for setting i) during an induction phase of the administration process one or more target plasma or effect-site concentration(s) of the product, ii) during a maintenance phase of the administration process one or more target plasma or effect-site concentration(s) of the product, and iii) during the termination phase of the administration process one or more target plasma or effect-site concentration(s) of the product.
  • the present invention relates to a method of inducing general anesthesia in a patient comprising administering to said patient an effective amount of a pharmaceutical composition comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 ; characterized in that the pharmaceutical composition is administered during 40 to 90 seconds at a target effect-site concentration of 4 ⁇ g/mL; and in the case the dose ratio of remifentanil to propofol (w/w) is from 0.0020:1 to 0.0029:1 , the product is further administered during additional 45 to 90 seconds at a second target effect- site concentration of 5 or 6 ⁇ g/mL.
  • the present invention relates to a method of inducing general anesthesia in a patient comprising administering to said patient an effective amount of a pharmaceutical composition comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 ; characterized in that the pharmaceutical composition is administered during 45 to 90 seconds at a target effect-site concentration of 5 or 6 ⁇ g/mL.
  • the present invention relates to a method of inducing general anesthesia in a patient comprising administering to said patient an effective amount of a pharmaceutical composition comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 ; characterized in that the pharmaceutical composition is administered during less than 40 seconds at a first target effect-site concentration of 2 ⁇ g/mL, and during additional 40 to 90 seconds at a second target effect-site concentration of 4 ⁇ g/mL; and in the case the dose ratio of remifentanil to propofol (w/w) is from 0.0020:1 to 0.0029:1 , the pharmaceutical composition is further administered during additional 45 to 90 seconds at a third target effect-site concentration of 5 or 6 ⁇ g/mL.
  • the present invention relates to a method of inducing general anesthesia in an adult patient comprising administering to said adult patient an effective amount of a pharmaceutical composition comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 .
  • the present invention relates to a method of maintaining general anesthesia in a patient comprising administering to said patient an effective amount of a pharmaceutical composition comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 , characterized in that the administration rate of propofol is between 50 and less than 100 ⁇ g/Kg/min.
  • the present invention relates to a method of inducing or maintaining general anesthesia in a patient comprising administering to said patient an effective amount of a pharmaceutical composition comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, characterized in that the dose ratio (w/w) of remifentanil to propofol is from 0.0025:1 to 0.0039:1 , preferably from 0.0026:1 to 0.0034:1 , preferably from 0.0027:1 to 0.0033:1 , more preferably from 0.0028:1 to 0.0032:1 , even more preferably 0.0030:1 .
  • the dose ratio (w/w) of remifentanil to propofol is from 0.0025:1 to 0.0039:1 , preferably from 0.0026:1 to 0.0034:1 , preferably from 0.0027:1 to 0.0033:1 , more preferably from 0.0028:1 to 0.0032:1
  • FIG. 1 shows a schematic representation of how a medical practitioner would make use of the target controlled infusion system on a patient. Obviously, the whole content of the figure, amongst which the intervention on a human body, is not claimed.
  • An intravenous line 3 is connected to an intravenous drip 2, containing a normal sterile saline solution, to a cannula 4 that is inserted through the skin in a vein of the patient 1.
  • a syringe 6, containing a combination of remifentanil and propofol, is placed in a syringe driver 5 and connected to the intravenous line 3 via an extension tubing 7.
  • the extension tubing 7 is connected to the intravenous line 3 using a three-way tap 8.
  • the syringe driver 5 is controlled by the apparatus 9 comprising the software according to the invention.
  • the present invention relates to a product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in inducing general anesthesia, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 , characterized in that the product is administered during 40 to 90 seconds at a target effect-site concentration of 4 ⁇ g/mL; and in the case the dose ratio of remifentanil to propofol (w/w) is from 0.0020:1 to 0.0029:1 , the product is further administered during additional 45 to 90 seconds at a second target effect-site concentration of 5 or 6 ⁇ g/mL.
  • the present invention relates to a product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in inducing general anesthesia, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 , characterized in that the product is administered during 45 to 90 seconds at a target effect-site concentration of 5 or 6 ⁇ g/mL.
  • the present invention relates to a product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in inducing general anesthesia, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 , characterized in that the product is administered during less than 40 seconds at a first target effect-site concentration of 2 ⁇ g/mL, and during additional 40 to 90 seconds at a second target effect-site concentration of 4 ⁇ g/mL; and in the case the dose ratio of remifentanil to propofol (w/w) is from 0.0020:1 to 0.0029:1 , the product is further administered during additional 45 to 90 seconds at a third target effect-site concentration of 5 or 6 ⁇ g/mL.
  • the present invention relates to a product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in inducing general anesthesia, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 , characterized in that the product is administered to adult patients.
  • the present invention relates to a method of inducing general anesthesia in a patient comprising administering to said patient an effective amount of a pharmaceutical composition comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 ; characterized in that the pharmaceutical composition is administered during 40 to 90 seconds at a target effect-site concentration of 4 ⁇ g/mL; and in the case the dose ratio of remifentanil to propofol (w/w) is from 0.0020:1 to 0.0029:1 , the product is further administered during additional 45 to 90 seconds at a second target effect- site concentration of 5 or 6 ⁇ g/mL.
  • the present invention relates to a method of inducing general anesthesia in a patient comprising administering to said patient an effective amount of a pharmaceutical composition comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 ; characterized in that the pharmaceutical composition is administered during 45 to 90 seconds at a target effect-site concentration of 5 or 6 ⁇ g/mL.
  • the present invention relates to a method of inducing general anesthesia in a patient comprising administering to said patient an effective amount of a pharmaceutical composition comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 ; characterized in that the pharmaceutical composition is administered during less than 40 seconds at a first target effect-site concentration of 2 ⁇ g/mL, and during additional 40 to 90 seconds at a second target effect-site concentration of 4 ⁇ g/mL; and in the case the dose ratio of remifentanil to propofol (w/w) is from 0.0020:1 to 0.0029:1 , the pharmaceutical composition is further administered during additional 45 to 90 seconds at a third target effect-site concentration of 5 or 6 ⁇ g/mL.
  • the present invention relates to a method of inducing general anesthesia in an adult patient comprising administering to said adult patient an effective amount of a pharmaceutical composition comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 .
  • the dose of propofol during induction is between 0.5 and less than 2 mg/Kg.
  • the present invention relates to a product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in maintaining general anesthesia in patients, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 , characterized in that the administration rate of propofol is between 50 and less than 100 ⁇ g/Kg/min.
  • the present invention also relates to a method of maintaining general anesthesia in a patient comprising administering to said patient an effective amount of a pharmaceutical composition comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 , characterized in that the administration rate of propofol is between 50 and less than 100 ⁇ g/Kg/min.
  • the present invention also relates to a product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in inducing or maintaining general anesthesia, characterized in that the dose ratio (w/w) of remifentanil to propofol is from 0.0025:1 to 0.0039:1 , preferably from 0.0026:1 to
  • 0.0034:1 preferably from 0.0027:1 to 0.0033:1 , more preferably from 0.0028:1 to
  • the present invention also relates to a method of inducing or maintaining general anesthesia in a patient comprising administering to said patient an effective amount of a pharmaceutical composition comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, characterized in that the dose ratio (w/w) of remifentanil to propofol is from 0.0025:1 to 0.0039:1 , preferably from 0.0026:1 to 0.0034:1 , preferably from 0.0027:1 to 0.0033:1 , more preferably from 0.0028:1 to 0.0032:1 , even more preferably 0.0030:1 .
  • the present invention further relates to a product comprising remifentanil, propofol, and a muscle relaxant, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous, separate, or sequential use in inducing general anesthesia, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0017:1 to 0.0023:1 , preferably from 0.0018:1 to 0.0022:1 , more preferably from 0.0019:1 to 0.0021 :1 , or 0.0020:1 , characterized in that the product comprising remifentanil, propofol, and a muscle relaxant, is administered at a target effect-site concentration of 4 ⁇ g/mL. In one embodiment, the referred product is administered during 40 to 90 seconds at a target effect- site concentration of 4 ⁇ g/mL.
  • muscle relaxant refers to, without being limited to, rocuronium, cisatracurium, atracurium, vecuronium, and succinylcholine.
  • the combination of propofol and remifentanil may comprise any one of these drugs in the form of a pharmaceutically acceptable salt.
  • salts comprised in the combination according to the present invention are those wherein the counter-ion is pharmaceutically acceptable, which salts can be referred to as pharmaceutically acceptable acid and base addition salts.
  • salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are included within the ambit of the present invention.
  • the pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms that remifentanil or propofol are able to form.
  • the pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid in an anion form.
  • Appropriate anions comprise, for example, trifluoroacetate, acetate, benzenesulfonate , benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsyiate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate/diphosphate,
  • the remifentanil salt is remifentanil hydrochloride.
  • remifentanil or the pharmaceutically acceptable salt thereof is formulated with a pharmaceutically acceptable carrier as a powder, wherein the amount of remifentanil base in the powder is 1 , 1.25, 1 .5, 2, or 5 mg.
  • remifentanil is provided in vial formulations containing, 1 , 1 .25, 1.5, 2, or 5 mg of remifentanil base; 15 mg of glycine; hydrochloric acid, and any other suitable ingredient.
  • propofol is formulated as an emulsion at a concentration of 10 mg/mL, or 20 mg/mL.
  • the emulsion of propofol contains 50 ml_.
  • 1 mg to 2 mg, more preferably 1.25 mg, even more preferably 1 .5 mg of remifentanil are present in the combination with 50 ml. of the emulsion of propofol at 10 mg/mL.
  • the composition containing the active ingredient propofol also may contain as pharmaceutically acceptable carrier, soybean oil, glycerol, egg lecithin; and edetate, preferably disodium edetate; with sodium hydroxide to adjust pH.
  • propofol can be formulated as an oil-in-water emulsion using oil
  • Remifentanil can be formulated as a lyophilized preparation using caking agents such as mannitol or dextrose. Agents to modify the pH of the final formulation can also be added including citric acid or sodium citrate, acetic acid or sodium acetate, sodium hydroxide, or hydrochloric acid.
  • the propofol can be packaged in a pre-filled syringe and the remifentanil in a single-dose vial. The propofol emulsion can then be used to re-constitute the vial of remifentanil at the time of use to provide the final formulation.
  • the two drugs of the present invention can also be mixed together in formulation with other preservative compounds to provide adequate shelf life as a mixture.
  • a stable co- formulation of propofol and remifentanil may be achieved by one of several methods. For example, use of organic co-solvents, ethanol, glycerol, and propylene glycol alone or in combination in mixtures with water (water for injection, USP) may be used to co-formulate propofol and remifentanil hydrochloride. Ethanol may be used at concentrations up to 20%, glycerol may be used in concentrations up to 50%, and propylene glycol may be used at concentrations up to 30% in the final dosage form. The final dosage form may contain ratios up to 50% organic ingredients. The propofol would be dissolved in the required amount of the organic solvent, the remifentanil hydrochloride would be dissolved in the required amount of water. The two solutions would then be combined to produce the final formulation.
  • organic carriers may be used to solubilize the propofol in aqueous media including small organic molecules such as sugars (sucrose, dextrose, lactose, trehalose, and mannitol) or polymers such as povidone (polyvinylpyrrolidone) or polyethylene glycol (PEG).
  • Sugars may be used in concentrations up to about 5% w/w of the final formulation (to be isotonic for example).
  • the povidone may be used in concentrations of 10 to 25% w/w of the final formulation.
  • the polyethylene glycol (PEG 300 or PEG 400) may be used in concentrations up to 30% v/v of the final formulation.
  • the carrier would be dissolved in water followed by the remifentanil and then the propofol to produce the final formulation.
  • Another category of carriers are those that form host-guest complexes. These include alfa and beta-cyclodextrin, sulfobutyl-ether beta cyclodextrin, and hydroxypropyl beta cyclodextrin.
  • the cyclodextrins are typically used at concentrations of 10 to 30% w/w of the final formulation.
  • the remifentanil would be dissolved in water.
  • the propofol would be blended with the cyclodextrin.
  • the aqueous solution would then be added slowly and with vigorous mixing to the propofol-cyclodextrin blend and mixing continued until a solution was achieved.
  • Various agents typically used in pharmaceutical preparations, could then be added to modify the pH of the formulation.
  • the free-base form of remifentanil may be prepared and incorporated into the oil-phase of the propofol oil-in-water emulsion.
  • remifentanil may be dissolved in water and treated with ammonium hydroxide which will induce the precipitation of the remifentanil free-base.
  • the remifentanil free-base may be isolated by filtration and dried.
  • the propofol and remifentanil may then be dissolved in the oil and glycerol and mixed until dissolved.
  • the lecithin is suspended in water and blended.
  • the oil solution is then added to the water lecithin suspension and homogenized until the proper particle size distribution is achieved (typically below 1 ⁇ ).
  • Various agents, typically used in pharmaceutical preparations, could then be added to modify the pH of the solution.
  • the product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use is a pharmaceutical composition comprising said drugs intimately mixed.
  • said product or pharmaceutical composition comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, is present in a container, preferably a syringe, which container is marked to indicate that it contains opioids, preferably with two transversal red stripes indicating that it contains opioids.
  • said product is administered intravenously as a bolus injection, as a continuous infusion, or a combination thereof.
  • continuous infusion refers to intravascular infusions, and the like methods of providing a continuous drug dosage over a period of time.
  • a continuous infusion of the product according to any one of the embodiments presented herein is administered during and optionally some time after the surgical operation.
  • Another embodiment relates to the product according to any one of the embodiments presented herein, for use in the prevention of muscle rigidity during anesthesia.
  • general anesthesia refers to the conventional meaning in the art, and differs from “local anesthesia”, which is anesthesia of a small part of the body such as a tooth or an area of skin.
  • patient includes patients undergoing general anesthesia including adult patients, patients from 10 to 16 years old, elderly patients, debilitated patients, neurosurgical patients, and patients undergoing cardiac surgery. Due to different reasons, like traumatic circumstances, consumption of illegal drugs, side-effects of drugs, or any effect caused by an illness, to name a few, the patient may be already in an unconscious state, or numbed, or paralyzed, or under physiological stress, before administering the anesthetics of the present invention.
  • adult when referring to a patient, refers to those patients older than 16 years old and younger than 55 years old.
  • the combination of remifentanil and propofol according to the present invention may be used for all kinds of operations requiring anesthesia.
  • surgical procedures refer to invasive discomfort-producing medical procedures. Included are such procedures as endoscopy, angiography, dental work, such as tooth extractions, as well as what is traditionally thought of a surgery, for example appendectomies and the like.
  • Surgeries include, without being limited to, general surgery, including cardiothoracic surgery, breast surgery, colorectal surgery, endocrine surgery, oncological surgery, plastic surgery, skin surgery, transplant surgery, trauma surgery, vascular surgery, craniofacial surgery, dental surgery, gynecology surgery, neurosurgery, ophthalmic surgery, oral and maxillofacial surgery, orthopaedic surgery, otolaryngology, podiatric surgery, urologic surgery, knee arthroscopy, varices, pulmonary vein isolation (PVI), laparoscopic surgery (LAPS), myomectomy, hysteroscopy, cervical arthrodesis, abdominoplasty, mammoplasty, gastric bypass, endoprosthesis, thyroidectomy, stomatology, and the like, and any surgery indicated in the 'Examples' chapter below. Diagnoses and treatments that involve the use of invasive methods - such as catheterization (especially cardiac catheterization) and endoscopy - and which are in need of anesthetics
  • the invention further relates to a kit for preparing a product according to any one of the embodiments presented herein, the kit comprising a first container comprising remifentanil or the pharmaceutically acceptable salt thereof, a second container comprising propofol or the pharmaceutically acceptable salt thereof, and instructions for mixing the remifentanil and propofol to obtain said dose ratio (w/w).
  • the invention also relates to a pharmaceutical composition consisting of remifentanil or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the content of remifentanil base is of 1 .25 or 1.5 mg.
  • the pharmaceutical composition consisting of remifentanil or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and having a content of remifentanil base of 1 .25 or 1 .5 mg, is in powder form.
  • the pharmaceutical composition consisting of remifentanil or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and having a content of remifentanil base of 1.25 or 1.5 mg, is present in a sealed container.
  • the product according to any one of the embodiments presented herein may be infused into the blood stream of the patient optionally together with a normal saline solution.
  • a normal saline solution is defined as a sterile solution of sodium chloride.
  • the product according to any one of the embodiments presented herein is injected into the blood stream of the patient via an intravenous line coupled to an intravenous drip comprising a normal sterile saline solution, or any other acceptable isotonic intravenous solution, e.g. Sterofundin® ISO (B.Braun), Ringerfundin® (B.Braun), Plasma-Lyte® A (Baxter), glucose or dextrose 5%, Ringers lactate solution, and the like.
  • the content of two containers a first container being a vial containing remifentanil in powder form and a second container being a syringe containing propofol, are mixed.
  • each container -preferably a vial or a syringe- can be made of plastic or glass, and the top of each container will function as an external screw thread and will be covered by a membrane.
  • a centerpiece may be used to connect both containers.
  • the centerpiece is made of plastic and consists of a hollow cylindrical structure with a hollow needle fixed in the middle. This needle may be long enough to pierce through both membranes on the top of the containers.
  • At each end of the centerpiece there may be a short internal screw thread, to screw both containers onto the centerpiece, allowing an easy handling of the whole structure.
  • the propofol or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier is contained in a syringe, to which remifentanil or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, has been added.
  • the user may inject some of the propofol through the hollow needle into the first container to dilute the remifentanil and aspirate part of or everything back into the originally propofol-comprising container.
  • the invention further relates to an infusion system for time-controlled administration to a patient of the product or pharmaceutical composition according to any one of the embodiments presented herein, said infusion system comprising:
  • an infusion pump adapted to deliver the fluid product from the supply to the patient at a controlled infusion rate(s);
  • control device operatively connected to the infusion pump and provided with a control algorithm for controlling the infusion rate, said control algorithm comprising steps for setting i) during an induction phase of the administration process one or more target plasma or effect-site concentration(s) of the product, ii) during a maintenance phase of the administration process one or more target plasma or effect-site concentration(s) of the product, and iii) during the termination phase of the administration process one or more target plasma or effect-site concentration(s) of the product.
  • the infusion system further comprises an intravenous line and connectors.
  • the connectors may be a tubing coming from the syringe and a 3-way tap.
  • the infusion system delivers the fluid product from the supply to the intravenous line and to the patient.
  • the one or more target plasma or effect-site concentration(s) of the product, during the induction, maintenance, or termination phase are one, two, three, or four target plasma or effect-site concentration(s) of the product or pharmaceutical composition.
  • the infusion system further comprises a user interface for input of the patient data, and optionally for input of the target plasma or effect-site concentration(s) of the product during the induction, maintenance, or termination phases of the administration process, wherein the target plasma or effect-site concentration(s) may be modified by the user during the administration process.
  • the patient data is selected from body weight, age, gender, length, body-mass index (BMI), lean body mass (LBM), ASA (American Society of Anesthesiologists) status, blood pressure, heart rate, cardiac output, volumes and composition (proportion of water, fat and protein) of individual organs, euroSCORE 2 test, BNP (brain natriuretic peptide) test, and gene expression data for metabolically active enzymes, active transporters, opioid receptors, and GABA receptors.
  • BMI body-mass index
  • LBM lean body mass
  • ASA American Society of Anesthesiologists
  • the infusion rate(s) is calculated to achieve the required target plasma or effect-site concentration(s) of the product during the induction, maintenance, and termination phases of the administration process; and wherein said infusion rate(s) is calculated based on a pharmacokinetic model selected from, and without being limited to, Schnider et al., Lewitt et al., Tackley et al., Marsh et al., Dyck & Shafer, Adam et al., Gepts et al., Minto et al., and PK-Sim®.
  • the supply of the product according to any one of the embodiments presented herein, in fluid form is a container comprising a mixture of remifentanil and propofol.
  • the administration rate of propofol during the maintenance phase is between 50 and less than 100 ⁇ g/Kg/min.
  • the first target plasma or effect-site concentration of the product during the induction phase of the administration process is 2, 4, 5, or 6 ⁇ g/mL.
  • the second target plasma or effect-site concentration of the product during the induction phase of the administration process is 4, 5, or 6 ⁇ g/mL.
  • the third target plasma or effect-site concentration of the product during the induction phase of the administration process is 5 or 6 ⁇ g/mL.
  • the target plasma or effect-site concentration of the product during the maintenance phase of the administration process is between 1.2 and 2.8 ⁇ g/mL, preferably between 1 .5 and 2.5 ⁇ g/mL, more preferably between 1.8 and 2.2 ⁇ g/mL.
  • the supply of the product is contained in a syringe connected to a syringe driver.
  • control algorithm calculates the dose of the product to be administered into the patient's blood.
  • control algorithm calculates the dose of the drug to be administered based on the amount of propofol only.
  • the pharmacokinetic model may be a new one calculated for the combination of propofol and remifentanil.
  • the pharmacokinetic models already available and calculated for propofol may be used for the administration of the two drugs of the present invention. It has been found that such pharmacokinetic models are safe and effective for the two drugs. Examples of these pharmacokinetic models include, without being limited to, Schnider et al., Lewitt et al., Tackley et al., Adam et al., Gepts et al., Marsh et al., Minto et al., and PK-Sim®.
  • Schnider et al. factor the influence of age on the pharmacodynamics of propofol, and characterize the relation between plasma concentration and the time course of drug effect (Schnider, TW, Minto CF, Shafer SL, Gambus PL, Andresen C, Goodale DB, Youngs E, The Influence of Age on Propofol Pharmacodynamics, Anesthesiology, June 1999 - Volume 90 - Issue 6 - pp 1502-1516).
  • the Schnider model relies on four parameters : the patient's age, gender, weight and length.
  • Lewitt et al. describes a physiology-based pharmacokinetic model for the simulation of plasma pharmacokinetics of propofol after intravenous administration (Levitt D G, Schnider T w., Human physiologically based pharmacokinetic model for propofol. BMC Anesthesiol. 2005 Apr. 22; 5(1 ):4).
  • Tackley et al. describe the delivery of propofol using a computer controlled infusion pump designed to achieve and maintain a blood concentration of 3 ⁇ g/mL of propofol as rapidly as possible, based on their pharmacokinetic model (Tackley RM, Lewis GTR, Prys- Roberts C, Coates D, Monk CR, Faroqui MH, Computer controlled infusion of propofol, British Journal of Anaesthesia, 1989, vol 62, pages 46-53).
  • Gepts et al. describe the disposition of intravenous anesthetic propofol administered as a constant rate infusion (Gepts E, Camu F, Cockshott ID, Douglas EJ, Disposition od propofol administered as constant rate infusions in humans, Anaesthesia and analgesia 1987, vol 66, pages 1256-63). In this model, there is a large amount of drug eliminated during distribution).
  • Marsh et al. describe a computer controlled infusion device for propofol for the induction and maintenance of general anesthesia in patients undergoing surgical procedures (Marsh B, White M, Morton N, Kenny GNC, Pharmacokinetics model driven infusion of propofol in children, British Journal of Anaesthesia 1991 , vol 67, pages 41-8).
  • the Marsh model is based on the Gepts model.
  • Minto et al. describe the influence of age and gender on the pharmacokinetics and pharmacodynamics of the new short-acting opioid remifentanil (Minto CF, Schnider TW, Egan TD, Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil, Model development, Anesthesiology 1997;86:10-21 ).
  • PK- Sim® www.PK-Sim.com
  • S. Willmann, J. Lippert, M. Sevestre, J. Solodenko, F. Fois, W. Schmitt "PK-Sim®: a physiologically based pharmacokinetic 'whole-body' model", Biosilico 1 , 121 -124 (2003)).
  • This simulation procedure takes into account the influence of individual physiological and anatomical parameters such as organ size and composition, blood flow rates, etc. on the pharmacokinetic behavior of medicinal products as a function of time.
  • DE-A-10345837 has also described how biochemical and genetic information, e.g. expression data on metabolically active enzymes or active transporters, can be used to determine a dose individually tailored to the patient.
  • the pharmacokinetic models mentioned above achieve a certain target concentration in the patient's effect site, i.e. the brain, or plasma.
  • the ultimate goal when administering a particular dose of a drug is to obtain the desired clinical effect, for which a specific therapeutic concentration of the drug at the site of action, or receptor, is necessary.
  • the aim of TCI techniques is to use pharmacokinetic modeling to calculate the infusion rates required to achieve a desired plasma concentration.
  • the user instead of specifying an infusion rate, the user specifies a target concentration based on clinical judgment.
  • the effect-site is not the plasma but the brain.
  • concentrations cannot be directly measured in the brain.
  • the first TCI models were plasma- targeted because it was considered that blood-brain equilibration was virtually instantaneous, but over the time, TCI models evolved into a quantitative approach of determining the effect- site concentration of drug effect. Either way, both target plasma or effect-site concentration(s) of the product are contemplated in the scope of the present invention.
  • the infusion rate of remifentanil and propofol may be expressed as the sum of remifentanil (R) and propofol (P), in micrograms, per kilogram of body weight per minute of infusion ( ⁇ gF ⁇ gP)/Kg/min).
  • the infusion may be expressed as the sum of remifentanil and propofol, in milligrams, per kilogram of body weight per hour of infusion ((mgR+mgP)/Kg/h). It can further be expressed in the sum of remifentanil and propofol in milliliters, per hour of infusion.
  • the infusion rate is indicated for propofol only and may be expressed as the quantity of propofol (P), in micrograms, per kilogram of body weight per minute of infusion ⁇ gP/Kg/min).
  • the infusion may be expressed as the amount of propofol, in milligrams, per kilogram of body weight per hour of infusion ((mgP)/Kg/h). It can further be expressed as the amount of propofol in milliliters, per hour of infusion.
  • the target plasma concentration and/or the effect-site concentration may be expressed as the sum of remifentanil and propofol, expressed in micrograms, per milliliter of blood plasma (( ⁇ gR+ ⁇ gP)/mL).
  • the target plasma concentration and/or the effect-site concentration is expressed for the product of the invention as the amount of propofol only, expressed in micrograms, per milliliter of blood plasma ⁇ gP/mL).
  • the administration of an effective amount of the product or pharmaceutical composition comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, said administration is performed with the infusion system according to any one of the embodiments presented herein.
  • Example 1 Preparation of a combination of propofol and remifentanil with a 30 uq/ml remifentanil concentration
  • a mixture of propofol and remifentanil was prepared according to the following protocol. 2 ml. of a syringe containing 10 mg/mL propofol solution of 50 ml_, obtained from the company B.Braun, were drawn and injected into a 2 ml. vial of Ultiva®, obtained from the company GlaxoSmithKline containing 2 mg of base powder remifentanil. 1 .5 ml. of the solution remifentanil / propofol was then aspirated from the Ultiva® vial and injected into the propofol syringe. A 49.50 ml. solution (thus approx. 50 ml.
  • An extension tubing was attached at one end to the syringe tip.
  • the extension tubing was fixed at the other end to the IV line of the patient.
  • the syringe was put into a syringe driver device in full control of the plunger of the syringe, which injected the remifentanil / propofol mixture into the IV line by means of a pump guided by a software.
  • the Schnider model was chosen amongst other pharmacokinetic models, such as Marsh and Minto. Then, parameters of age, gender, length and weight of the patient that was to be treated were entered. The software then calculated the amount of propofol that was injected, such as to stay in the appropriate therapeutic window.
  • Patient 1 was injected during the induction phase a total of 8,96 ml. of the combination of propofol and remifentanil prepared as indicated above. At the moment the effect-site concentration was of 4 ⁇ g/mL and the TCI system was not pumping any more volume (display showed 0.00 mL/h), then the patient was checked for pain stimuli reaction. If the patient did not react, then he was intubated with a laryngoscope.
  • Patient 2 was injected during the induction phase a total of 8,91 mL of the combination of propofol and remifentanil prepared as indicated above. At the moment the effect-site concentration was of 4 ⁇ 9/ ⁇ _ and the TCI system was not pumping any more volume (display showed 0.00 mL/h), then the patient was checked for pain stimuli reaction. If the patient did not react, then he was intubated with a laryngoscope.
  • Patient 3 was injected during the induction phase a total of 8,21 mL of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of midazolam and 7.5 mg of sufentanil were also administered to the patient. At the moment the effect-site concentration was of 4 ⁇ g/mL and the TCI system was not pumping any more volume, then the patient was checked for pain stimuli reaction. As the patient did not react, he was then intubated with a laryngoscope.
  • TAP block refers to transverse abdominis plane block, a peripheral nerve block, designed to anesthetize the nerves supplying the anterior abdominal wall.
  • the effect-site concentration was of 4 ⁇ g/mL and the TCI system was not pumping any more volume, then the patient was checked for pain stimuli reaction. As the patient did not react, he was then intubated with a laryngoscope.
  • Patient 5 was injected a total of 10,29 mL of the combination of propofol and remifentanil prepared as indicated above. At the moment the effect-site concentration was of 4 ⁇ / ⁇ . and the TCI system was not pumping any more volume, then the patient was checked for pain stimuli reaction. As the patient did not react, he was then intubated with a laryngoscope.
  • PECS Pectoral Nerve block and it is a technique to block the nerves of the pectoral (thorax) region, to decrease post-operative pain.
  • the effect-site concentration was of 4 ⁇ g/mL and the TCI system was not pumping any more volume, then the patient was checked for pain stimuli reaction. As the patient did not react, she was then intubated with a laryngoscope.
  • Patient 7 was injected a total of 9 mL of the combination of propofol and remifentanil prepared as indicated above. At the moment the effect-site concentration was of 4 ⁇ / ⁇ . and the TCI system was not pumping any more volume, then the patient was checked for pain stimuli reaction. As the patient did not react, he was then intubated with a laryngoscope.
  • Patient 8 was injected a total of 9.85 ml. of the combination of propofol and remifentanil prepared as indicated above. TAP blocks and PECS procedures were performed to the patient. At the moment the effect-site concentration was of 4 ⁇ / ⁇ . and the TCI system was not pumping any more volume, then the patient was checked for pain stimuli reaction. As the patient did not react, he was then intubated with a laryngoscope.
  • Patient 9 was injected a total of 7.8 ml. of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of the benzodiazepine midazolam were administered to the patient at the beginning of induction just before the administration of the remifentanil-propofol mixture. The induction phase started and at the moment the effect-site concentration was of 4 ⁇ g/mL and the TCI system was not pumping any more volume, then the patient was checked for pain stimuli reaction. As the patient did not react, he was then intubated with a laryngoscope.
  • Patient 10 was injected a total of 7.26 ml. of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of the benzodiazepine midazolam were administered to the patient at the beginning of induction just before the administration of the remifentanil-propofol mixture. The induction phase started and at the moment the effect-site concentration was of 4 ⁇ g/mL and the TCI system was not pumping any more volume, then the patient was checked for pain stimuli reaction. As the patient did not react, he was then intubated with a laryngoscope.
  • Patient 1 1 was injected a total of 10.60 mL of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of the benzodiazepine midazolam and 90 ⁇ g of clonidine for blood pressure control, were administered to the patient at the beginning of induction just before the administration of the remifentanil-propofol mixture. The induction phase started and at the moment the effect-site concentration was of 6 ⁇ g/mL and the TCI system was not pumping any more volume, then the patient was checked for negative pain stimuli reaction. The patient was intubated with a laryngoscope. Later, 6 mg cisatracurium were administered for patient positioning purposes.
  • Patient 12 was injected a total of 1 1.67 mL of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of the benzodiazepine midazolam were administered to the patient at the beginning of induction just before the administration of the remifentanil-propofol mixture. The induction phase started and at the moment the effect-site concentration was of 4 ⁇ g/mL and the TCI system was not pumping any more volume, then the patient was checked for negative pain stimuli reaction. He was then intubated with a laryngoscope. Later, 4 mg cisatracurium were administered to the patient for patient positioning purposes.
  • Patient 13 was injected a total of 7.36 mL of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of the benzodiazepine midazolam were administered to the patient at the beginning of induction just before the administration of the remifentanil-propofol mixture. The induction phase started and at the moment the effect-site concentration was of 4 ⁇ g/mL and the TCI system was not pumping any more volume, then the patient was checked for negative pain stimuli reaction. Because of a difficult airway situation in the patient, the intubation was performed with Airtraq®, a fibreoptic intubation device used for indirect (video or optic assisted) tracheal intubation.
  • Airtraq® a fibreoptic intubation device used for indirect (video or optic assisted) tracheal intubation.
  • Patient 15 was injected a total of 13,89 ml. of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of the benzodiazepine midazolam were administered to the patient at the beginning of induction just before the administration of the remifentanil-propofol mixture. The induction phase started and at the moment the effect-site concentration was of 6 ⁇ g/mL and the TCI system was not pumping any more volume, the patient was checked for negative pain stimuli reaction and he was intubated with a laryngoscope. Later, 6 mg of the benzoisoquinoline cisatracurium were administered to the patient.
  • Patient 36 was injected a total of 10.00 ml. of the combination of propofol and remifentanil prepared as indicated above. 1.7 mg of the benzodiazepine midazolam and 60 mg lidocaine were administered to the patient at the beginning of induction just before the administration of the remifentanil-propofol mixture. The induction phase started and at the moment the effect-site concentration was of 4 ⁇ g/mL and the TCI system was not pumping any more volume, then the patient was checked for negative pain stimuli reaction. The patient was then intubated with a laryngoscope. Target effect- Cumulative Period of time Cumulative dose
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table.
  • a pulmonary recruitment manoeuvre was performed by inflating an important volume of oxygen into the lungs of the patient and for which a bolus of 100 mg propofol was injected. Afterwards, continuous infusion was stopped and the patient opened his eyes, 1 1 minutes and 20 seconds later.
  • Patient 38 was injected a total of 5.31 mL of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of the benzodiazepine midazolam and 50 mg of lidocaine were administered to the patient at the beginning of induction just before the administration of the remifentanil-propofol mixture. The induction phase started and at the moment the effect-site concentration was of 4 ⁇ g/mL and the TCI system was not pumping any more volume, then the patient was checked for negative pain stimuli reaction. The patient was then intubated with a laryngoscope.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened her eyes, 9 minutes and 45 seconds later.
  • Patient 39 was injected a total of 13.55 mL of the combination of propofol and remifentanil prepared as indicated above. Prior to the administration of the combination of propofol-remifentanil, 2.0 mg of the benzodiazepine midazolam and 60 mg of lidocaine were administered to the patient. The induction phase started and at the moment the effect-site concentration was of 4 ⁇ g/mL and the TCI system was not pumping any more volume, then the patient was checked for negative pain stimuli reaction. The patient was then intubated with a laryngoscope.
  • Patient 41 was injected a total of 7.72 ml. of the combination of propofol and remifentanil prepared as indicated above. Prior to the administration of the combination of propofol-remifentanil, 1.5 mg of the benzodiazepine midazolam and 50 mg of lidocaine were administered to the patient. The induction phase started and at the moment the effect-site concentration was of 4 ⁇ g/mL and the TCI system was not pumping any more volume, then the patient was checked for negative pain stimuli reaction. The patient was then intubated with a laryngoscope.
  • Patient 44 was injected a total of 7.82 mL of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of the benzodiazepine midazolam and 50 mg of lidocaine were administered to the patient prior to the administration of the combination of propofol-remifentanil.
  • the induction phase started and at the moment the effect-site concentration was of 4 ⁇ g/mL and the TCI system was not pumping any more volume, then the patient was checked for negative pain stimuli reaction. The patient was then intubated with a laryngeal mask.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened her eyes, 4 minutes later.
  • Patient 45 was injected a total of 9.50 ml. of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of the benzodiazepine midazolam and 50 mg of lidocaine were administered to the patient prior to the administration of the combination of propofol-remifentanil.
  • the induction phase started and at the moment the effect-site concentration was of 4 ⁇ g/mL and the TCI system was not pumping any more volume, then the patient was checked for negative pain stimuli reaction. The patient was then intubated.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 5 minutes 10 seconds later.
  • Patient 48 was injected a total of 8.26 mL of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of the benzodiazepine midazolam and 50 mg of lidocaine were administered to the patient at the beginning of induction just before the administration of the remifentanil-propofol mixture. The induction phase started and at the moment the effect-site concentration was of 4 ⁇ / ⁇ . and the TCI system was not pumping any more volume, then the patient was checked for negative pain stimuli reaction. Because of a difficult airway situation in the patient, the intubation was performed with the use of Airtraq®. Later, cisatracurium was administered.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened her eyes, 4 minutes and 10 seconds later.
  • Patient 49 was injected a total of 9.16 mL of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of the benzodiazepine midazolam and 50 mg of lidocaine were administered to the patient prior to the injection of propofol-remifentanil. The induction phase started and at the moment the effect-site concentration was of 4 ⁇ g/mL and the TCI system was not pumping any more volume, then the patient was checked for negative pain stimuli reaction. The patient was then intubated.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. 1 mg of atropine and 7.5 mg of ephedrine were also injected during the maintenance phase at about 40 minutes from start of the anesthetic procedure. At the end of the procedure, infusion was stopped and the patient opened her eyes, 7 minutes and 30 seconds later.
  • Patient 60 was injected a total of 8.19 ml. of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of the benzodiazepine midazolam and 50 mg of lidocaine were administered to the patient prior to the injection of propofol-remifentanil.
  • the induction phase started and at the moment the effect-site concentration was of 4 ⁇ g/mL and the TCI system was not pumping any more volume, then the patient was checked for negative pain stimuli reaction. The patient was then intubated.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 6 minutes and 35 seconds later. Maintenance phase
  • Patient 64 was injected a total of 13.26 ml. of the combination of propofol and remifentanil prepared as indicated above. 1 .5 mg of the benzodiazepine midazolam, 50 mg of lidocaine were administered prior to the injection of propofol and remifentanil. A TAP block was performed. The induction phase started and at the moment the effect-site concentration was of 4 ⁇ g/mL and the TCI system was not pumping any more volume, then the patient was checked for negative pain stimuli reaction. The patient was intubated. Cisatracurium was administered around 10 minutes after intubation for patient positioning.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened her eyes, 6 minutes and 35 seconds later. Target effect-site
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened her eyes, 6 minutes and 10 seconds later.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened her eyes, 7 minutes and 20 seconds later.
  • the doses administered were averaged and the relevant measured clinical parameters are displayed in the table below.
  • Example 2 Preparation of a combination of propofol and remifentanil with a 20uq/ml remifentanil concentration
  • a mixture of propofol and remifentanil was prepared according to the following protocol. 1 ml. of a syringe containing 10 mg/mL propofol solution of 50 ml. propofol from B.Braun, was drawn and injected into a vial of Ultiva®, obtained from the company GlaxoSmithKline containing 1 mg of base powder remifentanil. The entire 1 mL-solution remifentanil / propofol was then aspirated from the Ultiva® vial and injected into the propofol syringe. A 50 ml.
  • An extension tubing was attached at one end to the syringe tip.
  • the extension tubing was fixed at the other end to the IV line of the patient.
  • the syringe was put into a syringe driver device in full control of the plunger of the syringe, which injected the remifentanil / propofol mixture into the IV line by means of a pump guided by a software.
  • the Schnider model was chosen amongst other pharmacokinetic models, such as Marsh and Minto. Then, parameters of age, gender, length and weight of the patient that was to be treated were entered. The software then calculated the amount of propofol that was injected, such as to stay in the appropriate therapeutic window.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, some minutes later.
  • 1.5 mg of the benzodiazepine midazolam were administered to the patient 17 followed by injection of a total of 12.33 mL of the combination of propofol and remifentanil prepared as indicated above, at the beginning of induction just before the administration of the remifentanil-propofol mixture.
  • the induction phase started and at the moment the effect- site concentration was of 6 ⁇ g/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 6 minutes and 23 seconds later.
  • 1.5 mg of the benzodiazepine midazolam and 30 mg of lidocaine were administered to patient 18 followed by injection of a total of 9,51 mL of the combination of propofol and remifentanil prepared as indicated above.
  • the induction phase started and at the moment the effect-site concentration was of 6 ⁇ g/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. 6 mg of cisatracurium were administered to the patient during surgery. Infusion was stopped and the patient opened his eyes, 5 minutes and 50 seconds later.
  • benzodiazepine midazolam and 30 mg of lidocaine were administered to patient 19 followed by injection of a total of 12.22 mL of the combination of propofol and remifentanil prepared as indicated above.
  • the induction phase started and at the moment the effect-site concentration was of 6 ⁇ g/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. 4 mg of cisatracurium were administered to the patient during surgery. Infusion was stopped and the patient opened his eyes, 9 minutes and 20 seconds later.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 8 minutes and 40 seconds later.
  • Patient 22 was injected a total of 9,71 mL of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of the benzodiazepine midazolam and 30 mg of lidocaine were administered to the patient at the beginning of induction just before the administration of the remifentanil-propofol mixture. The induction phase started and at the moment the effect-site concentration was of 6 ⁇ g/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 10 minutes later.
  • Patient 24 was injected a total of 10,22 ml. of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of the benzodiazepine midazolam and 40 mg of lidocaine were administered to the patient at the beginning of induction just before the administration of the remifentanil-propofol mixture. The induction phase started and at the moment the effect-site concentration was of 6 ⁇ g/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 6 minutes and 55 seconds later.
  • Patient 25 was injected a total of 9,99 ml. of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of the benzodiazepine midazolam and 40 mg of lidocaine were administered to the patient at the beginning of induction just before the administration of the remifentanil-propofol mixture. The induction phase started and at the moment the effect-site concentration was of 6 ⁇ g/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 6 minutes and 27 seconds later.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 10 minutes later.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 10 minutes later.
  • benzodiazepine midazolam and 40 mg of lidocaine were administered to patient 31 , which was further injected a total of 10.05 mL of the combination of propofol and remifentanil prepared as indicated above. Isuprel was administered to the patient during the procedure, for cardiac rhythm testing purposes. The induction phase started and at the moment the effect-site concentration was of 5 ⁇ g/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 5 minutes and 30 seconds later.
  • benzodiazepine midazolam and 40 mg of lidocaine were administered to patient 32, who was further injected a total of 7.00 mL of the combination of propofol and remifentanil prepared as indicated above.
  • the induction phase started and at the moment the effect-site concentration was of 5 ⁇ / ⁇ . and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 10 minutes later.
  • Patient 33 1.5 mg of the benzodiazepine midazolam and 40 mg of lidocaine were administered to patient 33, who was further injected a total of 9.27 mL of the combination of propofol and remifentanil prepared as indicated above.
  • the induction phase started and at the moment the effect-site concentration was of 5 ⁇ g/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, some minutes later.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 5 minutes and 25 seconds later.
  • benzodiazepine midazolam and 50 mg of lidocaine were administered to patient 43, who was further injected a total of 1 1.10 mL of the combination of propofol and remifentanil prepared as indicated above.
  • the induction phase started and at the moment the effect-site concentration was of 5 ⁇ g/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 9 minutes and 25 seconds later.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, more than 10 minutes later.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 3 minutes and 30 seconds later.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 8 minutes and 30 seconds later.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 6 minutes and 15 seconds later.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 5 minutes later.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 4 minutes later.
  • induction rate pressure (Mg/ml) (Mg/kg) ⁇ g/kg/min) ⁇ g/kg/min)
  • Example 3 Preparation of a combination of propofol and remifentanil with a 25 uq/ml remifentanil concentration
  • a mixture of propofol and remifentanil was prepared according to the following protocol. 2 mL of a syringe containing 10 mg/mL propofol solution of 50 mL propofol from B.Braun, were drawn and injected into a 2 mL vial of Ultiva®, obtained from the company GlaxoSmithKline containing 2 mg of base powder remifentanil. 1 .25 mL of the solution remifentanil / propofol was then aspirated from the Ultiva® vial and injected into the propofol syringe.
  • a 50 mL (49.25 mL) solution was obtained containing 1.25 mg remifentanil and about 500 mg of propofol, thus achieving a final concentration of 25 ⁇ g/mL of remifentanil and approximately 10 mg/mL of propofol, which may also be expressed as the dose ratio (w/w) of remifentanil to propofol of 0.0025:1 .
  • An extension tubing was attached at one end to the syringe tip.
  • the extension tubing was fixed at the other end to the IV line of the patient.
  • the syringe was put into a syringe driver device in full control of the plunger of the syringe, which injected the remifentanil / propofol mixture into the IV line by means of a pump guided by a software.
  • the Schnider model was chosen amongst other pharmacokinetic models, such as Marsh and Minto. Then, parameters of age, gender, length and weight of the patient that was to be treated were entered. The software then calculated the amount of propofol that was injected, such as to stay in the appropriate therapeutic window.
  • benzodiazepine midazolam and 20 mg of lidocaine were administered to patient 52, who was further injected a total of 10.35 mL of the combination of propofol and remifentanil prepared as indicated above.
  • the induction phase started and at the moment the effect-site concentration was of 4 ⁇ g/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated. 8 mg of cisatracurium was administered during surgery.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 3 minutes and 30 seconds later.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 7 minutes and 15 seconds later.
  • 1.5 mg of the benzodiazepine midazolam and 50 mg of lidocaine were administered to the patient 54, who was further injected a total of 9.05 mL of the combination of propofol and remifentanil prepared as indicated above.
  • the induction phase started and at the moment the effect-site concentration was of 4 ⁇ g/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 6 minutes later.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 9 minutes and 30 seconds later.
  • Example 4 Preparation of a combination of propofol and remifentanil with a 40 uq/ml remifentanil concentration
  • a mixture of propofol and remifentanil was prepared according to the following protocol. 2 mL of a syringe containing 10 mg/mL propofol solution of 50 mL propofol from B.Braun, were drawn and injected into a 2 mL vial of Ultiva®, obtained from the company GlaxoSmithKline containing 2 mg of base powder remifentanil. The whole 2 mL of the solution remifentanil / propofol was then aspirated from the Ultiva® vial and injected into the propofol syringe.
  • a 50 mL solution was obtained containing 2 mg remifentanil and 500 mg of propofol, thus achieving a final concentration of 40 ⁇ g/mL of remifentanil and approximately 10 mg/mL of propofol, which may also be expressed as the dose ratio (w/w) of remifentanil to propofol of 0.0040:1 .
  • An extension tubing was attached at one end to the syringe tip.
  • the extension tubing was fixed at the other end to the IV line of the patient.
  • the syringe was put into a syringe driver device in full control of the plunger of the syringe, which injected the remifentanil / propofol mixture into the IV line by means of a pump guided by a software.
  • the Schnider model was chosen amongst other pharmacokinetic models, such as Marsh and Minto. Then, parameters of age, gender, length and weight of the patient that was to be treated were entered. The software then calculated the amount of propofol that was injected, such as to stay in the appropriate therapeutic window.
  • 1.5 mg of the benzodiazepine midazolam were administered to patient 16, who was further injected a total of 13.73 mL of the combination of propofol and remifentanil prepared as indicated above.
  • the induction phase started and at the moment the effect-site concentration was of 4 ⁇ g/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated. 6 mg of cisatracurium were administered to the patient during surgery.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, some minutes later.
  • benzodiazepine midazolam and 30 mg of lidocaine were administered to patient 20, who was further injected a total of 1 1.23 mL of the combination of propofol and remifentanil prepared as indicated above.
  • the induction phase started and at the moment the effect-site concentration was of 4 ⁇ g/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 6 minutes later.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 10 minutes 10 seconds later.
  • the maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 6 minutes later.
  • the doses administered were averaged and the relevant clinical parameters measured and displayed in the table below.

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Abstract

The invention relates to a product or pharmaceutical composition comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in inducing and maintaining general anesthesia, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1.

Description

COMBINATION OF REMIFENTANIL AND PROPOFOL
Technical field of the invention
The technical fields of the invention are anesthetics, in particular remifentanil and propofol, and target controlled infusion systems.
Background of the invention
Anesthesia is a temporary state of sedation and inducted sleep in which the patient becomes unconscious and experiences loss of memory. In addition to anesthesia stricto sensu, the patient experiments analgesia or pain relief. Both sedation, asleep, and analgesia lead to stress reduction, preserving thereby physiological homeostasis, and muscle relaxation, in particular, relaxation of the skeletal muscle. Sedation is defined as the inducement of a state of calm, analgesia is defined as the insensitivity to pain, and physiological homeostasis is basically measured as maintenance of normal blood pressure and heart rate levels during surgery.
At the present time, no single agent provides adequate levels of each and all of these effects, so combinations of drugs must be used in cases like surgery.
Remifentanil is a potent, ultra-short acting μ-opioid synthetic analgesic agonist, chemically designated as a 3-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1 - piperidine]propanoic acid methyl ester. A commercially available formulation of remifentanil hydrochloride is Ultiva®, which is a white to off-white lyophilized powder for intravenous (IV) administration after reconstitution and dilution. The commercially available Ultiva® vial formulations contain 1 , 2, or 5 mg of remifentanil base; 15 mg glycine; and hydrochloric acid. The Ultiva® remifentanil hydrochloride formulation is indicated for IV administration: 1 ) as an analgesic agent for use during the induction and maintenance of general anesthesia for inpatient and outpatient procedures; 2) for continuation as an analgesic into the immediate postoperative period in adult patients under the direct supervision of an anesthesia practitioner in a postoperative anesthesia care unit or intensive care setting; and 3) as an analgesic component of monitored anesthesia care in adult patients.
Propofol is a short-acting hypnotic and amnestic agent, indicated for IV administration. The uses of propofol include general anesthesia and sedation for inpatient and outpatient procedures. Propofol is chemically described as 2,6-diisopropylphenol. A commercially available formulation of propofol is the injectable emulsion Diprivan®, a sterile, aqueous, non-pyrogenic oil-in-water emulsion containing 10 mg/mL or 20 mg/ml of propofol suitable for intravenous administration. In addition to the active component, propofol, the 10 mg/mL formulation also contains soybean oil (100 mg/mL), glycerol (22.5 mg/mL), egg lecithin (12 mg/mL); and disodium edetate (0.005%); with sodium hydroxide to adjust pH. The Diprivan® Injectable Emulsion is isotonic and has a pH of 7 to 8.5. Other commercially available formulation of propofol are Propofol-®Lipuro 10 mg/ml (1 %) and Propofol-®Lipuro 20 mg/ml (2%). Propofol is an IV sedative-hypnotic agent that can be used in adult patients for 1 ) initiation and maintenance of Monitored Anesthesia Care (MAC) sedation; 2) combined sedation and regional anesthesia; and 3) Intensive Care Unit (ICU) sedation of intubated, mechanically ventilated patients. It can be used for patients of 3 years of age or older for Induction of General Anesthesia. It can be further used for patients of 2 months of age or older for Maintenance of General Anesthesia. Propofol has progressively replaced sodium thiopental in anesthesia procedures, because it offers a more rapid recovery than the latter and it gives less nausea and vomiting.
Propofol is administered at a dose of 2 to 2.5 mg/Kg during the induction to general anesthesia. The induction phase terminates with intubation of the patient to support his respiratory functions. Following the induction dose, maintenance rates of general anesthesia are in the order of 100 to 200 g/kg/min for adult patients (Diprivan FDA NDA-19-627/S-045, page 23). However, due to propofol's narrow therapeutic window, overdosing patients undergoing anesthesia may result in a drop of blood's pressure, respiratory arrest, cardiac arrest, and death. There are indicia supporting that comedian Joan Rivers died from a propofol's overdose during an anesthetic procedure.
WO2007147505A2 (Universitat Bern) discloses a mixture of drugs containing remifentanil and propofol in a ratio meant to achieve a steady state concentration ratio in plasma or at the effect site, for the use in anaesthesia, between 0.0015:1 and 0.0035:1 , or, for the use in sedation, between 0.0002:1 and 0.0008:1 , especially to be used in connection with a system for controlling administration of a mixture of drugs.
US20060093785A1 (Hickle) discloses a prepackaged combination drug for infusion into a patient having a need for pain and anxiety control during a medical procedure without general anesthesia; said drug comprising: a combination drug of remifentanil and propofol in which the ratio of propofol to remifentanil is more than about 500 μg to 1 μg so as to provide adequate pain management and anxiety control without suppressing the ventilation of said patient.
WO2007035573A2 (Scott Laboratories) discloses a product for efficiently facilitating the induction of general anesthesia and intubation, said product comprising: a) a package containing a combination of drugs; b) said combination of drugs in said package comprising remifentanil and propofol in a ratio effective to induce general anesthesia so as to permit intubation of said patient without stress, increased heart rate and/or increased blood pressure, in which said package comprises two vials, one of which contains a lyophilic powder of remifentanil and the other contains an emulsion of propofol in a ratio of about 2 μg of remifentanil to 1 mg of propofol. Diprifusor®, obtainable from the company AstraZeneca, is a target controlled infusion (TCI) system for the administration of propofol. A preferred set of pharmacokinetic parameters for propofol is selected using computer simulation of a known infusion scheme with pharmacokinetic parameters described in published literature. The selected model is included in a module that is interfaced with, and later incorporated into, a computer- compatible infusion pump. The TCI software consists of a particular arrangement of infusion control algorithms linked to a pharmacokinetic simulation program (© University of Glasgow). The program includes a three-compartment pharmacokinetic model and incorporates the 'Marsh' pharmacokinetic parameters.
US5609575A (Graseby Medical Limited) describes a TCI system in which the dose- concentration routine uses the body weight index as the only patient parameter in the system and only achieves a rough simulation of the concentration.
US8038645B2 (Bayer Technology Services GmbH) relates to a device for the time- controlled intravenous administering of the anesthetic propofol by means of a method used for determining an adequate dosage profile and adequately controlling an infusion pump as a metering apparatus, and which would permit exact time-controlled administration of propofol taking into account individual physiological, anatomical, biochemical, and genetic factors of the patient. Summary of the invention
It is an objective of the present invention to provide safer and effective pharmaceutical formulations for inducing and maintaining general anesthesia.
It is an objective of the present invention to provide different doses with improved clinical benefits when administering remifentanil in combination with propofol when inducing or maintaining anesthesia.
It is an objective of the present invention to provide administration regimens with improved clinical benefits when administering remifentanil in combination with propofol when inducing or maintaining anesthesia.
It is an objective of the present invention to provide cohorts of patients which can clinically benefit from specific combinations of remifentanil and propofol when inducing or maintaining anesthesia.
It is a further objective of the present invention to provide adequate sedation and analgesia during anesthesia to the patient.
It is an objective of the present invention to provide a combination drug for inducing general anesthesia that will minimize a patient's stress response to painful stimuli, including among others, tracheal intubation and surgical incision, and provide a quiet surgical field. It is an objective of the present invention to provide a method of inducing general anesthesia and intubating a patient while minimizing the patient's pain, anxiety and/or physiological stress.
It is a further objective of the present invention to provide a new combination drug for efficiently inducing and maintaining general anesthesia that provides fast onset of the state of general anesthesia as well as fast recovery of full consciousness, so as to enable the patient to be timely discharged.
It is a further objective of the present invention to minimize drug-induced adverse effects.
It is a further objective of the present invention to avoid muscle rigidity and/or chest rigidity during anesthesia.
It is a further objective of the present invention to avoid the use of curares and similar muscular relaxant drugs during induction of anesthesia
It is a further objective of the present invention to avoid the use of curares and similar muscular relaxant drugs during anesthesia for laparoscopic surgery.
It is a further objective of the present invention to avoid the use of curares and similar muscular relaxant drugs during the introduction of a trans-esophageal ultrasound (TOE) probe during anesthesia, specifically in cardiac surgery and cardiac catheterization.
It is a further objective of the present invention to avoid the use of barbiturates during anesthesia.
It is a further objective of the present invention to provide an anesthetic drug for patients for which muscle relaxants are contra-indicated, like patients with myasthenia gravis.
It is a further objective of the present invention to provide an anesthetic drug for patients for which volatile anesthetic agents and succinylcholine are contra-indicated, like patients with malignant hyperthermia.
It is a further objective of the present invention to provide an anesthesia assuring an easy and fast induction phase, stable hemodynamics and a dynamic balance between analgesia, hypnosis and amnesia during the course of the surgery, and a rapid and comfortable recovery from narcosis.
It is a further objective of the present invention to provide an anesthesia assuring an easy and fast induction phase and a rapid and comfortable recovery from narcosis for patients who need a caesarean section under general anesthesia.
It is a further objective of the present invention to intubate the patient more rapidly after the injection of the induction bolus.
It is a further objective of the present invention to minimize a drop in the patient's mean arterial pressure at induction of the drug. It is a further objective of the present invention to minimize a drop in the patient's heart rate at induction of the drug.
It is a further objective of the present invention to eliminate or substantially decrease the risks of increased heart rate and blood pressures and myocardial ischemia and/or infarction and hemorrhagic strokes during anesthesia.
It is a further objective of the present invention to reduce the occupational stress of anesthesiologists.
It is a further objective of the present invention to reduce the clinical costs.
It is a further objective of the present invention to provide a pre-packaged combination of two properly proportioned drugs in a single, two-compartment syringe or vial, to facilitate mixing and infusion into a patient, or alternatively, to provide a combination drug in a solution for efficient induction and/or maintenance of general anesthesia of a patient.
It is a further objective of the present invention to provide a combination drug in a single container that can be used in conjunction with a programmable infusion pump to induce and to maintain a patient in the state of general anesthesia.
It is an objective of the present invention to provide a TCI system for the simultaneous administration of remifentanil and propofol.
It is a further objective of the present invention to provide a TCI system that is less time-consuming, less labor intensive and less vulnerable to human errors, when compared to exclusively human directed systems.
It is a further objective of the present invention to let the anesthesiologist focus on surveillance of the patient instead of on the monitoring of the infusion.
It is an objective of the present invention to provide a drug administration profile that is tailored to the patient.
It is a further objective of the present invention to provide doses of remifentanil in combination with propofol that are adapted to the patient's morphological characteristics, age and gender.
It is a further objective of the present invention to provide a system using retrievable and reliable pharmacokinetic models.
It is a further objective of the present invention to provide a software ensuring safe, cost-effective and optimized drug delivery to the patient, thereby electronically monitoring his physiological condition.
It is a further objective of the present invention to provide a system to simplify an anesthesia procedure by using a single pharmaceutical composition, a single calculation of the dosage, and a single injection.
These objectives can be met either individually or in any combination, by the products, compositions, uses, and methods of the present invention. This invention aims to providing to a patient undergoing a medical or surgical procedure, with a safe and effective anesthesia.
To do so, the present invention provides a combination of at least two drugs working in synergy, propofol and remifentanil, and employing safer and more effective doses. In addition, the present invention integrates these two drugs in an electronically managed decision-making software, which monitors the amount of drugs to be delivered to the patient according to his body parameters and following a selected pharmacokinetic model, thereby further increasing the safety of the anesthetic procedure. When propofol is combined with remifentanil, less propofol is needed to place and maintain the patient under general anesthesia. Less propofol is thus accumulated in the body over the course of the infusion.
The present invention relates to a product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in inducing general anesthesia, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 , characterized in that the product is administered during 40 to 90 seconds at a target effect-site concentration of 4 μg/mL; and in the case the dose ratio of remifentanil to propofol (w/w) is from 0.0020:1 to 0.0029:1 , the product is further administered during additional 45 to 90 seconds at a second target effect-site concentration of 5 or 6 μg/mL.
The present invention relates to a product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in inducing general anesthesia, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 , characterized in that the product is administered during 45 to 90 seconds at a target effect-site concentration of 5 or 6 μg/mL.
The present invention relates to a product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in inducing general anesthesia, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 , characterized in that the product is administered during less than 40 seconds at a first target effect-site concentration of 2 μg/mL, and during additional 40 to 90 seconds at a second target effect-site concentration of 4 μg/mL; and in the case the dose ratio of remifentanil to propofol (w/w) is from 0.0020:1 to 0.0029:1 , the product is further administered during additional 45 to 90 seconds at a third target effect-site concentration of 5 or 6 μg/mL.
The present invention relates to a product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in inducing general anesthesia, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 , characterized in that the product is administered to adult patients. The present invention relates to a product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in maintaining general anesthesia in patients, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 , characterized in that the administration rate of propofol is between 50 and less than 100 μg/Kg/min.
The present invention relates to a product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in inducing or maintaining general anesthesia, characterized in that the dose ratio (w/w) of remifentanil to propofol is from 0.0025:1 to 0.0039:1 , preferably from 0.0026:1 to 0.0034:1 , preferably from 0.0027:1 to 0.0033:1 , more preferably from 0.0028:1 to 0.0032:1 , even more preferably 0.0030:1.
The present invention relates to a kit for preparing a product according to any one of the embodiments presented herein, the kit comprising a first container comprising remifentanil or the pharmaceutically acceptable salt thereof, a second container comprising propofol or the pharmaceutically acceptable salt thereof, and instructions for mixing the remifentanil and propofol to obtain said dose ratio (w/w).
The present invention relates to a pharmaceutical composition consisting of remifentanil or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the content of remifentanil base is of 1.25 or 1 .5 mg.
The present invention relates to an infusion system for time-controlled administration to a patient of the product according to any one of the embodiments presented herein, said infusion system comprising:
a) a supply of the product according to any one of the embodiments presented herein, in fluid form;
b) an infusion pump adapted to deliver the fluid product from the supply to the patient at a controlled infusion rate(s); and
c) a control device, operatively connected to the infusion pump and provided with a control algorithm for controlling the infusion rate, said control algorithm comprising steps for setting i) during an induction phase of the administration process one or more target plasma or effect-site concentration(s) of the product, ii) during a maintenance phase of the administration process one or more target plasma or effect-site concentration(s) of the product, and iii) during the termination phase of the administration process one or more target plasma or effect-site concentration(s) of the product.
The present invention relates to a method of inducing general anesthesia in a patient comprising administering to said patient an effective amount of a pharmaceutical composition comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 ; characterized in that the pharmaceutical composition is administered during 40 to 90 seconds at a target effect-site concentration of 4 μg/mL; and in the case the dose ratio of remifentanil to propofol (w/w) is from 0.0020:1 to 0.0029:1 , the product is further administered during additional 45 to 90 seconds at a second target effect- site concentration of 5 or 6 μg/mL.
The present invention relates to a method of inducing general anesthesia in a patient comprising administering to said patient an effective amount of a pharmaceutical composition comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 ; characterized in that the pharmaceutical composition is administered during 45 to 90 seconds at a target effect-site concentration of 5 or 6 μg/mL.
The present invention relates to a method of inducing general anesthesia in a patient comprising administering to said patient an effective amount of a pharmaceutical composition comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 ; characterized in that the pharmaceutical composition is administered during less than 40 seconds at a first target effect-site concentration of 2 μg/mL, and during additional 40 to 90 seconds at a second target effect-site concentration of 4 μg/mL; and in the case the dose ratio of remifentanil to propofol (w/w) is from 0.0020:1 to 0.0029:1 , the pharmaceutical composition is further administered during additional 45 to 90 seconds at a third target effect-site concentration of 5 or 6 μg/mL.
The present invention relates to a method of inducing general anesthesia in an adult patient comprising administering to said adult patient an effective amount of a pharmaceutical composition comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 .
The present invention relates to a method of maintaining general anesthesia in a patient comprising administering to said patient an effective amount of a pharmaceutical composition comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 , characterized in that the administration rate of propofol is between 50 and less than 100 μg/Kg/min.
The present invention relates to a method of inducing or maintaining general anesthesia in a patient comprising administering to said patient an effective amount of a pharmaceutical composition comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, characterized in that the dose ratio (w/w) of remifentanil to propofol is from 0.0025:1 to 0.0039:1 , preferably from 0.0026:1 to 0.0034:1 , preferably from 0.0027:1 to 0.0033:1 , more preferably from 0.0028:1 to 0.0032:1 , even more preferably 0.0030:1 . Brief description of the figures
Figure 1 shows a schematic representation of how a medical practitioner would make use of the target controlled infusion system on a patient. Obviously, the whole content of the figure, amongst which the intervention on a human body, is not claimed. An intravenous line 3 is connected to an intravenous drip 2, containing a normal sterile saline solution, to a cannula 4 that is inserted through the skin in a vein of the patient 1. A syringe 6, containing a combination of remifentanil and propofol, is placed in a syringe driver 5 and connected to the intravenous line 3 via an extension tubing 7. The extension tubing 7 is connected to the intravenous line 3 using a three-way tap 8. The syringe driver 5 is controlled by the apparatus 9 comprising the software according to the invention.
Detailed description of the invention
The present invention relates to a product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in inducing general anesthesia, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 , characterized in that the product is administered during 40 to 90 seconds at a target effect-site concentration of 4 μg/mL; and in the case the dose ratio of remifentanil to propofol (w/w) is from 0.0020:1 to 0.0029:1 , the product is further administered during additional 45 to 90 seconds at a second target effect-site concentration of 5 or 6 μg/mL.
The present invention relates to a product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in inducing general anesthesia, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 , characterized in that the product is administered during 45 to 90 seconds at a target effect-site concentration of 5 or 6 μg/mL.
The present invention relates to a product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in inducing general anesthesia, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 , characterized in that the product is administered during less than 40 seconds at a first target effect-site concentration of 2 μg/mL, and during additional 40 to 90 seconds at a second target effect-site concentration of 4 μg/mL; and in the case the dose ratio of remifentanil to propofol (w/w) is from 0.0020:1 to 0.0029:1 , the product is further administered during additional 45 to 90 seconds at a third target effect-site concentration of 5 or 6 μg/mL.
The present invention relates to a product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in inducing general anesthesia, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 , characterized in that the product is administered to adult patients.
The present invention relates to a method of inducing general anesthesia in a patient comprising administering to said patient an effective amount of a pharmaceutical composition comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 ; characterized in that the pharmaceutical composition is administered during 40 to 90 seconds at a target effect-site concentration of 4 μg/mL; and in the case the dose ratio of remifentanil to propofol (w/w) is from 0.0020:1 to 0.0029:1 , the product is further administered during additional 45 to 90 seconds at a second target effect- site concentration of 5 or 6 μg/mL.
The present invention relates to a method of inducing general anesthesia in a patient comprising administering to said patient an effective amount of a pharmaceutical composition comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 ; characterized in that the pharmaceutical composition is administered during 45 to 90 seconds at a target effect-site concentration of 5 or 6 μg/mL.
The present invention relates to a method of inducing general anesthesia in a patient comprising administering to said patient an effective amount of a pharmaceutical composition comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 ; characterized in that the pharmaceutical composition is administered during less than 40 seconds at a first target effect-site concentration of 2 μg/mL, and during additional 40 to 90 seconds at a second target effect-site concentration of 4 μg/mL; and in the case the dose ratio of remifentanil to propofol (w/w) is from 0.0020:1 to 0.0029:1 , the pharmaceutical composition is further administered during additional 45 to 90 seconds at a third target effect-site concentration of 5 or 6 μg/mL.
The present invention relates to a method of inducing general anesthesia in an adult patient comprising administering to said adult patient an effective amount of a pharmaceutical composition comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 . In one embodiment, the dose of propofol during induction is between 0.5 and less than 2 mg/Kg.
The present invention relates to a product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in maintaining general anesthesia in patients, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 , characterized in that the administration rate of propofol is between 50 and less than 100 μg/Kg/min.
The present invention also relates to a method of maintaining general anesthesia in a patient comprising administering to said patient an effective amount of a pharmaceutical composition comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 , characterized in that the administration rate of propofol is between 50 and less than 100 μg/Kg/min.
The present invention also relates to a product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in inducing or maintaining general anesthesia, characterized in that the dose ratio (w/w) of remifentanil to propofol is from 0.0025:1 to 0.0039:1 , preferably from 0.0026:1 to
0.0034:1 , preferably from 0.0027:1 to 0.0033:1 , more preferably from 0.0028:1 to
0.0032:1 , even more preferably 0.0030:1.
The present invention also relates to a method of inducing or maintaining general anesthesia in a patient comprising administering to said patient an effective amount of a pharmaceutical composition comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, characterized in that the dose ratio (w/w) of remifentanil to propofol is from 0.0025:1 to 0.0039:1 , preferably from 0.0026:1 to 0.0034:1 , preferably from 0.0027:1 to 0.0033:1 , more preferably from 0.0028:1 to 0.0032:1 , even more preferably 0.0030:1 .
The present invention further relates to a product comprising remifentanil, propofol, and a muscle relaxant, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous, separate, or sequential use in inducing general anesthesia, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0017:1 to 0.0023:1 , preferably from 0.0018:1 to 0.0022:1 , more preferably from 0.0019:1 to 0.0021 :1 , or 0.0020:1 , characterized in that the product comprising remifentanil, propofol, and a muscle relaxant, is administered at a target effect-site concentration of 4 μg/mL. In one embodiment, the referred product is administered during 40 to 90 seconds at a target effect- site concentration of 4 μg/mL.
The term muscle relaxant refers to, without being limited to, rocuronium, cisatracurium, atracurium, vecuronium, and succinylcholine. In a preferred embodiment of the present invention, the combination of propofol and remifentanil may comprise any one of these drugs in the form of a pharmaceutically acceptable salt. For therapeutic use, salts comprised in the combination according to the present invention are those wherein the counter-ion is pharmaceutically acceptable, which salts can be referred to as pharmaceutically acceptable acid and base addition salts. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are included within the ambit of the present invention.
The pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms that remifentanil or propofol are able to form. The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid in an anion form. Appropriate anions comprise, for example, trifluoroacetate, acetate, benzenesulfonate , benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsyiate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, triethiodide, and the like. The counterion of choice can be introduced using ion exchange resins. Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.
In one embodiment, for the product or pharmaceutical composition according to any one of the embodiments presented herein, the remifentanil salt is remifentanil hydrochloride.
In one embodiment, for the product or pharmaceutical composition according to any one of the embodiments presented herein, remifentanil or the pharmaceutically acceptable salt thereof is formulated with a pharmaceutically acceptable carrier as a powder, wherein the amount of remifentanil base in the powder is 1 , 1.25, 1 .5, 2, or 5 mg.
In another preferred embodiment of the present invention, remifentanil is provided in vial formulations containing, 1 , 1 .25, 1.5, 2, or 5 mg of remifentanil base; 15 mg of glycine; hydrochloric acid, and any other suitable ingredient.
In one embodiment, for the product according to any one of the embodiments presented herein, propofol is formulated as an emulsion at a concentration of 10 mg/mL, or 20 mg/mL. According to an embodiment of the present invention, the emulsion of propofol contains 50 ml_.
According to an embodiment of the present invention, 1 mg to 2 mg, more preferably 1.25 mg, even more preferably 1 .5 mg of remifentanil are present in the combination with 50 ml. of the emulsion of propofol at 10 mg/mL.
In a preferred embodiment of the present invention, the composition containing the active ingredient propofol also may contain as pharmaceutically acceptable carrier, soybean oil, glycerol, egg lecithin; and edetate, preferably disodium edetate; with sodium hydroxide to adjust pH.
In one embodiment, propofol can be formulated as an oil-in-water emulsion using oil
(soy bean or sesame oil), propylene glycol, and a lecithin (egg or soy lecithin) and water. Remifentanil can be formulated as a lyophilized preparation using caking agents such as mannitol or dextrose. Agents to modify the pH of the final formulation can also be added including citric acid or sodium citrate, acetic acid or sodium acetate, sodium hydroxide, or hydrochloric acid. The propofol can be packaged in a pre-filled syringe and the remifentanil in a single-dose vial. The propofol emulsion can then be used to re-constitute the vial of remifentanil at the time of use to provide the final formulation.
The two drugs of the present invention can also be mixed together in formulation with other preservative compounds to provide adequate shelf life as a mixture. A stable co- formulation of propofol and remifentanil may be achieved by one of several methods. For example, use of organic co-solvents, ethanol, glycerol, and propylene glycol alone or in combination in mixtures with water (water for injection, USP) may be used to co-formulate propofol and remifentanil hydrochloride. Ethanol may be used at concentrations up to 20%, glycerol may be used in concentrations up to 50%, and propylene glycol may be used at concentrations up to 30% in the final dosage form. The final dosage form may contain ratios up to 50% organic ingredients. The propofol would be dissolved in the required amount of the organic solvent, the remifentanil hydrochloride would be dissolved in the required amount of water. The two solutions would then be combined to produce the final formulation.
Other organic carriers may be used to solubilize the propofol in aqueous media including small organic molecules such as sugars (sucrose, dextrose, lactose, trehalose, and mannitol) or polymers such as povidone (polyvinylpyrrolidone) or polyethylene glycol (PEG). Sugars may be used in concentrations up to about 5% w/w of the final formulation (to be isotonic for example). The povidone may be used in concentrations of 10 to 25% w/w of the final formulation. The polyethylene glycol (PEG 300 or PEG 400) may be used in concentrations up to 30% v/v of the final formulation. To co-formulate propofol and remifentanil, the carrier would be dissolved in water followed by the remifentanil and then the propofol to produce the final formulation. Another category of carriers are those that form host-guest complexes. These include alfa and beta-cyclodextrin, sulfobutyl-ether beta cyclodextrin, and hydroxypropyl beta cyclodextrin. The cyclodextrins are typically used at concentrations of 10 to 30% w/w of the final formulation. The remifentanil would be dissolved in water. The propofol would be blended with the cyclodextrin. The aqueous solution would then be added slowly and with vigorous mixing to the propofol-cyclodextrin blend and mixing continued until a solution was achieved. Various agents, typically used in pharmaceutical preparations, could then be added to modify the pH of the formulation.
Alternatively, the free-base form of remifentanil may be prepared and incorporated into the oil-phase of the propofol oil-in-water emulsion. For example, remifentanil may be dissolved in water and treated with ammonium hydroxide which will induce the precipitation of the remifentanil free-base. The remifentanil free-base may be isolated by filtration and dried. The propofol and remifentanil may then be dissolved in the oil and glycerol and mixed until dissolved. The lecithin is suspended in water and blended. The oil solution is then added to the water lecithin suspension and homogenized until the proper particle size distribution is achieved (typically below 1 μηη). Various agents, typically used in pharmaceutical preparations, could then be added to modify the pH of the solution.
In one embodiment of the present invention, the product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use, is a pharmaceutical composition comprising said drugs intimately mixed.
In one embodiment of the present invention, said product or pharmaceutical composition comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, is present in a container, preferably a syringe, which container is marked to indicate that it contains opioids, preferably with two transversal red stripes indicating that it contains opioids.
In one embodiment, for the product according to any one of the embodiments presented herein, said product is administered intravenously as a bolus injection, as a continuous infusion, or a combination thereof.
The term "continuous infusion" refers to intravascular infusions, and the like methods of providing a continuous drug dosage over a period of time.
According to an embodiment of the present invention, a continuous infusion of the product according to any one of the embodiments presented herein, is administered during and optionally some time after the surgical operation.
Another embodiment relates to the product according to any one of the embodiments presented herein, for use in the prevention of muscle rigidity during anesthesia.
The term "product" is synonym to "pharmaceutical composition". The term "general anesthesia" refers to the conventional meaning in the art, and differs from "local anesthesia", which is anesthesia of a small part of the body such as a tooth or an area of skin.
The term "patient" includes patients undergoing general anesthesia including adult patients, patients from 10 to 16 years old, elderly patients, debilitated patients, neurosurgical patients, and patients undergoing cardiac surgery. Due to different reasons, like traumatic circumstances, consumption of illegal drugs, side-effects of drugs, or any effect caused by an illness, to name a few, the patient may be already in an unconscious state, or numbed, or paralyzed, or under physiological stress, before administering the anesthetics of the present invention.
The term "adult", when referring to a patient, refers to those patients older than 16 years old and younger than 55 years old.
According to an embodiment of the present invention, the combination of remifentanil and propofol according to the present invention may be used for all kinds of operations requiring anesthesia.
The term "surgery" and "surgical procedures" refer to invasive discomfort-producing medical procedures. Included are such procedures as endoscopy, angiography, dental work, such as tooth extractions, as well as what is traditionally thought of a surgery, for example appendectomies and the like. Surgeries include, without being limited to, general surgery, including cardiothoracic surgery, breast surgery, colorectal surgery, endocrine surgery, oncological surgery, plastic surgery, skin surgery, transplant surgery, trauma surgery, vascular surgery, craniofacial surgery, dental surgery, gynecology surgery, neurosurgery, ophthalmic surgery, oral and maxillofacial surgery, orthopaedic surgery, otolaryngology, podiatric surgery, urologic surgery, knee arthroscopy, varices, pulmonary vein isolation (PVI), laparoscopic surgery (LAPS), myomectomy, hysteroscopy, cervical arthrodesis, abdominoplasty, mammoplasty, gastric bypass, endoprosthesis, thyroidectomy, stomatology, and the like, and any surgery indicated in the 'Examples' chapter below. Diagnoses and treatments that involve the use of invasive methods - such as catheterization (especially cardiac catheterization) and endoscopy - and which are in need of anesthetics, are also considered "surgery" according to the invention.
The invention further relates to a kit for preparing a product according to any one of the embodiments presented herein, the kit comprising a first container comprising remifentanil or the pharmaceutically acceptable salt thereof, a second container comprising propofol or the pharmaceutically acceptable salt thereof, and instructions for mixing the remifentanil and propofol to obtain said dose ratio (w/w). The invention also relates to a pharmaceutical composition consisting of remifentanil or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the content of remifentanil base is of 1 .25 or 1.5 mg.
In one embodiment, the pharmaceutical composition consisting of remifentanil or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and having a content of remifentanil base of 1 .25 or 1 .5 mg, is in powder form.
In one embodiment, the pharmaceutical composition consisting of remifentanil or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and having a content of remifentanil base of 1.25 or 1.5 mg, is present in a sealed container.
In one embodiment, the product according to any one of the embodiments presented herein may be infused into the blood stream of the patient optionally together with a normal saline solution. A normal saline solution is defined as a sterile solution of sodium chloride. In a preferred embodiment of the present invention, the product according to any one of the embodiments presented herein, is injected into the blood stream of the patient via an intravenous line coupled to an intravenous drip comprising a normal sterile saline solution, or any other acceptable isotonic intravenous solution, e.g. Sterofundin® ISO (B.Braun), Ringerfundin® (B.Braun), Plasma-Lyte® A (Baxter), glucose or dextrose 5%, Ringers lactate solution, and the like.
According to an embodiment of the present invention, the content of two containers, a first container being a vial containing remifentanil in powder form and a second container being a syringe containing propofol, are mixed.
According to one embodiment of the present invention, each container -preferably a vial or a syringe- can be made of plastic or glass, and the top of each container will function as an external screw thread and will be covered by a membrane. A centerpiece may be used to connect both containers. The centerpiece is made of plastic and consists of a hollow cylindrical structure with a hollow needle fixed in the middle. This needle may be long enough to pierce through both membranes on the top of the containers. At each end of the centerpiece, there may be a short internal screw thread, to screw both containers onto the centerpiece, allowing an easy handling of the whole structure.
In one embodiment of the present invention, the propofol or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, is contained in a syringe, to which remifentanil or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, has been added.
In a preferred embodiment, once the membranes of both containers attached to the centerpiece have been pierced, the user may inject some of the propofol through the hollow needle into the first container to dilute the remifentanil and aspirate part of or everything back into the originally propofol-comprising container. The invention further relates to an infusion system for time-controlled administration to a patient of the product or pharmaceutical composition according to any one of the embodiments presented herein, said infusion system comprising:
a) a supply of the product or pharmaceutical composition according to any one of the embodiments presented herein, in fluid form;
b) an infusion pump adapted to deliver the fluid product from the supply to the patient at a controlled infusion rate(s); and
c) a control device, operatively connected to the infusion pump and provided with a control algorithm for controlling the infusion rate, said control algorithm comprising steps for setting i) during an induction phase of the administration process one or more target plasma or effect-site concentration(s) of the product, ii) during a maintenance phase of the administration process one or more target plasma or effect-site concentration(s) of the product, and iii) during the termination phase of the administration process one or more target plasma or effect-site concentration(s) of the product.
In one embodiment, the infusion system further comprises an intravenous line and connectors. The connectors may be a tubing coming from the syringe and a 3-way tap.
In one embodiment, the infusion system delivers the fluid product from the supply to the intravenous line and to the patient.
In one embodiment, the one or more target plasma or effect-site concentration(s) of the product, during the induction, maintenance, or termination phase, are one, two, three, or four target plasma or effect-site concentration(s) of the product or pharmaceutical composition.
In one embodiment, the infusion system according to the invention, further comprises a user interface for input of the patient data, and optionally for input of the target plasma or effect-site concentration(s) of the product during the induction, maintenance, or termination phases of the administration process, wherein the target plasma or effect-site concentration(s) may be modified by the user during the administration process.
In one embodiment, in the infusion system according to the invention, the patient data is selected from body weight, age, gender, length, body-mass index (BMI), lean body mass (LBM), ASA (American Society of Anesthesiologists) status, blood pressure, heart rate, cardiac output, volumes and composition (proportion of water, fat and protein) of individual organs, euroSCORE 2 test, BNP (brain natriuretic peptide) test, and gene expression data for metabolically active enzymes, active transporters, opioid receptors, and GABA receptors.
In one embodiment, in the infusion system according to the invention, the infusion rate(s) is calculated to achieve the required target plasma or effect-site concentration(s) of the product during the induction, maintenance, and termination phases of the administration process; and wherein said infusion rate(s) is calculated based on a pharmacokinetic model selected from, and without being limited to, Schnider et al., Lewitt et al., Tackley et al., Marsh et al., Dyck & Shafer, Adam et al., Gepts et al., Minto et al., and PK-Sim®.
In one embodiment, in the infusion system according to any one of the embodiments presented herein, the supply of the product according to any one of the embodiments presented herein, in fluid form, is a container comprising a mixture of remifentanil and propofol.
In one embodiment, in the infusion system according to any one of the embodiments presented herein, the administration rate of propofol during the maintenance phase is between 50 and less than 100 μg/Kg/min.
In one embodiment, in the infusion system according to any one of the embodiments presented herein, the first target plasma or effect-site concentration of the product during the induction phase of the administration process is 2, 4, 5, or 6 μg/mL.
In one embodiment, in the infusion system according to any one of the embodiments presented herein, the second target plasma or effect-site concentration of the product during the induction phase of the administration process is 4, 5, or 6 μg/mL.
In one embodiment, in the infusion system according to any one of the embodiments presented herein, the third target plasma or effect-site concentration of the product during the induction phase of the administration process is 5 or 6 μg/mL.
In one embodiment, in the infusion system according to any one of the embodiments presented herein, the target plasma or effect-site concentration of the product during the maintenance phase of the administration process is between 1.2 and 2.8 μg/mL, preferably between 1 .5 and 2.5 μg/mL, more preferably between 1.8 and 2.2 μg/mL.
In an embodiment, the supply of the product is contained in a syringe connected to a syringe driver.
According to an embodiment of the present invention, the control algorithm calculates the dose of the product to be administered into the patient's blood.
According to an embodiment of the present invention, the control algorithm calculates the dose of the drug to be administered based on the amount of propofol only.
In one embodiment, the pharmacokinetic model may be a new one calculated for the combination of propofol and remifentanil.
Alternatively, the pharmacokinetic models already available and calculated for propofol, may be used for the administration of the two drugs of the present invention. It has been found that such pharmacokinetic models are safe and effective for the two drugs. Examples of these pharmacokinetic models include, without being limited to, Schnider et al., Lewitt et al., Tackley et al., Adam et al., Gepts et al., Marsh et al., Minto et al., and PK-Sim®.
Schnider et al. factor the influence of age on the pharmacodynamics of propofol, and characterize the relation between plasma concentration and the time course of drug effect (Schnider, TW, Minto CF, Shafer SL, Gambus PL, Andresen C, Goodale DB, Youngs E, The Influence of Age on Propofol Pharmacodynamics, Anesthesiology, June 1999 - Volume 90 - Issue 6 - pp 1502-1516). The Schnider model relies on four parameters : the patient's age, gender, weight and length.
Lewitt et al. describes a physiology-based pharmacokinetic model for the simulation of plasma pharmacokinetics of propofol after intravenous administration (Levitt D G, Schnider T w., Human physiologically based pharmacokinetic model for propofol. BMC Anesthesiol. 2005 Apr. 22; 5(1 ):4).
Tackley et al. describe the delivery of propofol using a computer controlled infusion pump designed to achieve and maintain a blood concentration of 3 μg/mL of propofol as rapidly as possible, based on their pharmacokinetic model (Tackley RM, Lewis GTR, Prys- Roberts C, Coates D, Monk CR, Faroqui MH, Computer controlled infusion of propofol, British Journal of Anaesthesia, 1989, vol 62, pages 46-53).
Adam et al. describe a pharmacokinetic model wherein pharmacokinetic indices derived from blood concentrations of ICI 35868 are independent of the speed of injection (Adam HK, Briggs LP, Bahar M, Douglas EJ, Dundee JW, Pharmacokinetic evaluation of ICI 35868 in man, Single induction doses with different rates of injection, British Journal of Anaesthesia 1983; vol 55, pages 97-103).
Gepts et al. describe the disposition of intravenous anesthetic propofol administered as a constant rate infusion (Gepts E, Camu F, Cockshott ID, Douglas EJ, Disposition od propofol administered as constant rate infusions in humans, Anaesthesia and analgesia 1987, vol 66, pages 1256-63). In this model, there is a large amount of drug eliminated during distribution).
Marsh et al. describe a computer controlled infusion device for propofol for the induction and maintenance of general anesthesia in patients undergoing surgical procedures (Marsh B, White M, Morton N, Kenny GNC, Pharmacokinetics model driven infusion of propofol in children, British Journal of Anaesthesia 1991 , vol 67, pages 41-8). The Marsh model is based on the Gepts model.
Minto et al. describe the influence of age and gender on the pharmacokinetics and pharmacodynamics of the new short-acting opioid remifentanil (Minto CF, Schnider TW, Egan TD, Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil, Model development, Anesthesiology 1997;86:10-21 ).
The procedures claimed in DE-A-10160270 and DE-A-10345836 and corresponding physiology-based PK/PD models are also suitable for the present invention (marketed as PK- Sim® (www.PK-Sim.com); S. Willmann, J. Lippert, M. Sevestre, J. Solodenko, F. Fois, W. Schmitt: "PK-Sim®: a physiologically based pharmacokinetic 'whole-body' model", Biosilico 1 , 121 -124 (2003)). This simulation procedure takes into account the influence of individual physiological and anatomical parameters such as organ size and composition, blood flow rates, etc. on the pharmacokinetic behavior of medicinal products as a function of time. These physiological and anatomical parameters can be derived from a few easily measured parameters such as body weight and body mass index. In addition, these parameters are age-, sex-, and sometimes race-dependent. DE-A-10345837 has also described how biochemical and genetic information, e.g. expression data on metabolically active enzymes or active transporters, can be used to determine a dose individually tailored to the patient.
The pharmacokinetic models mentioned above achieve a certain target concentration in the patient's effect site, i.e. the brain, or plasma. There is a relation between the administered dose and plasma concentration, and a relation between effect organ concentration (brain) and clinical effect. The ultimate goal when administering a particular dose of a drug is to obtain the desired clinical effect, for which a specific therapeutic concentration of the drug at the site of action, or receptor, is necessary. The aim of TCI techniques is to use pharmacokinetic modeling to calculate the infusion rates required to achieve a desired plasma concentration. Thus, instead of specifying an infusion rate, the user specifies a target concentration based on clinical judgment.
For anesthesiologists, the effect-site is not the plasma but the brain. However, concentrations cannot be directly measured in the brain. The first TCI models were plasma- targeted because it was considered that blood-brain equilibration was virtually instantaneous, but over the time, TCI models evolved into a quantitative approach of determining the effect- site concentration of drug effect. Either way, both target plasma or effect-site concentration(s) of the product are contemplated in the scope of the present invention.
In an embodiment of the present invention, the infusion rate of remifentanil and propofol may be expressed as the sum of remifentanil (R) and propofol (P), in micrograms, per kilogram of body weight per minute of infusion (^gF^gP)/Kg/min). Alternatively, the infusion may be expressed as the sum of remifentanil and propofol, in milligrams, per kilogram of body weight per hour of infusion ((mgR+mgP)/Kg/h). It can further be expressed in the sum of remifentanil and propofol in milliliters, per hour of infusion.
In an embodiment of the present invention, the infusion rate is indicated for propofol only and may be expressed as the quantity of propofol (P), in micrograms, per kilogram of body weight per minute of infusion ^gP/Kg/min). Alternatively, the infusion may be expressed as the amount of propofol, in milligrams, per kilogram of body weight per hour of infusion ((mgP)/Kg/h). It can further be expressed as the amount of propofol in milliliters, per hour of infusion.
In an embodiment of the present invention, the target plasma concentration and/or the effect-site concentration may be expressed as the sum of remifentanil and propofol, expressed in micrograms, per milliliter of blood plasma ((μgR+μgP)/mL). In an embodiment of the present invention, the target plasma concentration and/or the effect-site concentration is expressed for the product of the invention as the amount of propofol only, expressed in micrograms, per milliliter of blood plasma ^gP/mL).
In one embodiment, the administration of an effective amount of the product or pharmaceutical composition comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, said administration is performed with the infusion system according to any one of the embodiments presented herein.
Examples
Example 1 : Preparation of a combination of propofol and remifentanil with a 30 uq/ml remifentanil concentration
A mixture of propofol and remifentanil was prepared according to the following protocol. 2 ml. of a syringe containing 10 mg/mL propofol solution of 50 ml_, obtained from the company B.Braun, were drawn and injected into a 2 ml. vial of Ultiva®, obtained from the company GlaxoSmithKline containing 2 mg of base powder remifentanil. 1 .5 ml. of the solution remifentanil / propofol was then aspirated from the Ultiva® vial and injected into the propofol syringe. A 49.50 ml. solution (thus approx. 50 ml. for calculation purposes) was obtained containing 1.5 mg remifentanil and 500 mg of propofol (actually 495 mg), thus achieving a final concentration of 30 μg/mL of remifentanil and approximately 10 mg/mL of propofol, which may also be expressed as the dose ratio (w/w) of remifentanil to propofol of 0.003:1. The 2 mL vial of Ultiva®, containing 2 mg of remifentanil, was not used in its entirety, only 75% of it. If it was, the final concentration of remifentanil in propofol would have been of 40 μg/mL.
An extension tubing was attached at one end to the syringe tip. The extension tubing was fixed at the other end to the IV line of the patient. The syringe was put into a syringe driver device in full control of the plunger of the syringe, which injected the remifentanil / propofol mixture into the IV line by means of a pump guided by a software.
The Schnider model was chosen amongst other pharmacokinetic models, such as Marsh and Minto. Then, parameters of age, gender, length and weight of the patient that was to be treated were entered. The software then calculated the amount of propofol that was injected, such as to stay in the appropriate therapeutic window.
Data was collected from patients undergoing general anesthesia before surgery. The patient data and type of surgery which each patient underwent is listed below.
Patient Gender (M/F) Age (years) Length (cm) Weight (kg) Type of surgery
1 F 29 168 64 data not provided
2 M 34 180 87 data not provided 3 M 44 167 87 data not provided
4 F 31 175 87 Abdominoplasty
Pulmonary vein
5 F 64 167 100
isolation
6 F 50 162 81 Mammoplasty
Pulmonary vein
7 M 45 188 100
isolation
Mammoplasty and
8 F 30 172 76
abdominoplasty
Pulmonary vein
9 F 66 164 74
isolation
Removal of
10 M 54 180 80
carcinoma
1 1 M 53 170 75 Surrenalectomy
Thyroid Lobectomy
12 F 43 163 96
retrosternal
13 F 41 155 55 Not provided
15 F 55 157 85 Gastric bypass
36 M 57 174 1 16 Gastric Bypass
38 F 78 155 50 Thyroidectomie
39 F 18 160 100 Gastric Banding
Liposuction lower
41 F 47 160 65
limb
44 F 41 160 61 Varices
45 M 34 180 96 Wisdom teeth
48 M 55 184 100 Hernia Umbilicalis
49 F 63 157 89 Coelioscopy
60 M 40 178 81 Gynaecomastie
Circular
64 M 33 183 127
abdominoplasty
67 F 60 153 71 Mastectomy
Tumorectomy (left
68 F 57 170 53
breast)
During the anesthesia procedure there was an initial induction phase which normally took up to about 2 minutes, at which moment intubation of the patient was performed to support his respiratory functions. The patient was checked for unconsciousness and reaction to pain. Following intubation, the maintenance phase was initiated, in which maintenance phase surgery took place. Following surgery or just before surgery was finished, the termination phase of anesthesia was initialized. Patient 1
Patient 1 was injected during the induction phase a total of 8,96 ml. of the combination of propofol and remifentanil prepared as indicated above. At the moment the effect-site concentration was of 4 μg/mL and the TCI system was not pumping any more volume (display showed 0.00 mL/h), then the patient was checked for pain stimuli reaction. If the patient did not react, then he was intubated with a laryngoscope.
Figure imgf000024_0001
When the maintenance phase started, surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. When infusion was stopped, the patient opened her eyes, 6 minutes later.
Figure imgf000024_0002
Patient 2
Patient 2 was injected during the induction phase a total of 8,91 mL of the combination of propofol and remifentanil prepared as indicated above. At the moment the effect-site concentration was of 4 μ9/ΓηΙ_ and the TCI system was not pumping any more volume (display showed 0.00 mL/h), then the patient was checked for pain stimuli reaction. If the patient did not react, then he was intubated with a laryngoscope.
Figure imgf000025_0001
When the maintenance phase started, surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table.
Figure imgf000025_0002
Patient 3
Patient 3 was injected during the induction phase a total of 8,21 mL of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of midazolam and 7.5 mg of sufentanil were also administered to the patient. At the moment the effect-site concentration was of 4 μg/mL and the TCI system was not pumping any more volume, then the patient was checked for pain stimuli reaction. As the patient did not react, he was then intubated with a laryngoscope.
Induction phase
Target effect- Cumulative Period of time Cumulative dose
Cumulative dose site cone, administered volume at these of administered
of administered setting for the (mL) of the solution conditions remifentanil
propofol (mg/kg) TCI Pump remifentanil /propofol (sec.) ( g kg)
2 Mg ml 4,00 22.60 1.38 0.46 4 μς/ιηΙ 8,21 50.20 2.83 0.94
When the maintenance phase started, surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. When infusion was stopped, the patient opened his eyes, 8 minutes later.
Figure imgf000026_0001
Patient 4
Patient 4 was injected during the induction phase a total of 10,92 ml. of the combination of propofol and remifentanil prepared as indicated above. 500 mg of atropine were also administered to the patient. A TAP block was performed. TAP block refers to transverse abdominis plane block, a peripheral nerve block, designed to anesthetize the nerves supplying the anterior abdominal wall. At the moment the effect-site concentration was of 4 μg/mL and the TCI system was not pumping any more volume, then the patient was checked for pain stimuli reaction. As the patient did not react, he was then intubated with a laryngoscope.
Figure imgf000026_0002
When the maintenance phase started, surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. When infusion was stopped, the patient opened her eyes, 3 minutes 21 seconds later. Maintenance phase
Target effect-site
Time cone, setting for the Administration rate of Administration rate of Propofol (min) TCI Pump remifentanil ^g/kg/min) ^g/kg/min)
(Mg/mL) (ml_/h)
15 2.0 0 0 0
30 2.4 49.8 0.286 95.4
45 2.2 42.4 0.244 81.23
60 2.2 41.9 0.241 80.27
90 2.3 43.6 0.251 83.52
120 2.1 37.8 0.217 72.41
150 2.2 38.9 0.224 74.52
180 2.8 50.4 0.290 96.55
210 2.4 40.7 0.234 77.97
240 2.1 34.5 0.198 66.09
270 2.0 32.5 0.187 62.26
Average 0.216 71.84
Patient 5
Patient 5 was injected a total of 10,29 mL of the combination of propofol and remifentanil prepared as indicated above. At the moment the effect-site concentration was of 4 μς/ΓηΙ. and the TCI system was not pumping any more volume, then the patient was checked for pain stimuli reaction. As the patient did not react, he was then intubated with a laryngoscope.
Figure imgf000027_0001
When the maintenance phase started, surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. When infusion was stopped, the patient opened her eyes, 9 minutes 30 seconds later.
Maintenance phase
Time Target effect-site Administration rate of Administration rate of
points cone, setting for the Remifentanil ^g/kg/min) Propofol (min) TCI Pump ^g/kg/min)
(Mg/mL) (rnL/h)
15 1.8 42.0 0.210 70.00
30 1 .8 41.3 0.207 68.83
45 1 .6 35.4 0.177 59.00
60 1 .6 35.3 0.177 58.83
90 1 .6 34.8 0.174 58.00
120 1.6 34.2 0.171 57.00
150 1 .6 33.8 0.169 56.33
180 1 .6 33.4 0.167 55.67
210 1 .6 32.3 0.162 53.83
240 1 .6 31.9 0.160 53.17
Average 0.177 59.07
Patient 6
Patient 6 was injected a total of 8.87 ml. of the combination of propofol and remifentanil prepared as indicated above. PECS were performed to the patient. PECS refers to Pectoral Nerve block and it is a technique to block the nerves of the pectoral (thorax) region, to decrease post-operative pain. At the moment the effect-site concentration was of 4 μg/mL and the TCI system was not pumping any more volume, then the patient was checked for pain stimuli reaction. As the patient did not react, she was then intubated with a laryngoscope.
Figure imgf000028_0001
When the maintenance phase started, surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. When infusion was stopped, the patient opened her eyes, 3 minutes later.
Maintenance phase
Time Target effect-site Administration rate of
Administration rate of
points cone, setting for the Propofol
Remifentanil ^g/kg/min)
(min) TCI Pump ^g/kg/min) (Mg/mL) (rnL/h)
15 2.0 39.2 0.242 80.66
30 1 .8 32.4 0.200 66.67
45 1 .8 31.2 0.193 64.20
60 1 .8 31.9 0.197 65.64
90 2.0 0 0 0
120 2.5 43.8 0.270 90.12
150 2.3 38.4 0.237 79.01
180 2.2 36.6 0.226 75.31
210 2.5 43.2 0.267 88.89
240 2.2 44.4 0.274 91.36
270 2.0 36.0 0.222 74.07
Average 0.21 1 70.54
Patient 7
Patient 7 was injected a total of 9 mL of the combination of propofol and remifentanil prepared as indicated above. At the moment the effect-site concentration was of 4 μς/ΓηΙ. and the TCI system was not pumping any more volume, then the patient was checked for pain stimuli reaction. As the patient did not react, he was then intubated with a laryngoscope.
Figure imgf000029_0001
When the maintenance phase started, surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. When infusion was stopped, the patient opened his eyes, 14 minutes later.
Maintenance phase
Target effect-site
Time cone, setting for the Administration rate of
Administration rate of
points TCI Pump Propofol
Remifentanil ^g/kg/min)
(min) ^g/kg/min)
( g mL) (mL/h)
15 1 .8 35.6 0.178 59.33
30 1 .6 28.4 0.142 47.33 45 1 .5 25.4 0.127 42.33
60 1 .8 31.1 0.156 51.83
90 1 .8 30.8 0.154 51.33
120 1 .7 28.4 0.142 47.33
150 1 .7 28.2 0.141 47.00
180 1 .7 28.2 0.141 47.00
210 2.0 31.7 0.159 52.83
240 2.0 31.6 0.158 52.67
Average 0.150 49.90
Patient 8
Patient 8 was injected a total of 9.85 ml. of the combination of propofol and remifentanil prepared as indicated above. TAP blocks and PECS procedures were performed to the patient. At the moment the effect-site concentration was of 4 μς/ΓηΙ. and the TCI system was not pumping any more volume, then the patient was checked for pain stimuli reaction. As the patient did not react, he was then intubated with a laryngoscope.
Figure imgf000030_0001
When the maintenance phase started, surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. When infusion was stopped, the patient opened her eyes, 4 minutes 35 seconds later.
Maintenance phase
Target effect-site
Time cone, setting for the Administration rate of
Administration rate of
points TCI Pump Propofol
Remifentanil ^g/kg/min)
(min) ^g/kg/min)
( g mL) (rnL/h)
15 2.0 40.4 0.266 88.60
30 2.0 35.7 0.235 78.29
45 1 .8 29.7 0.195 65.13
60 1 .8 29.9 0.197 65.57
90 2.0 33.5 0.220 73.46
120 2.0 33.0 0.217 72.37 150 2.0 32.2 0.212 70.61
180 1 .9 29.0 0.191 63.60
210 2.0 31.0 0.204 67.98
240 2.0 30.4 0.200 66.67
Average 0.214 71.23
Patient 9
Patient 9 was injected a total of 7.8 ml. of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of the benzodiazepine midazolam were administered to the patient at the beginning of induction just before the administration of the remifentanil-propofol mixture. The induction phase started and at the moment the effect-site concentration was of 4 μg/mL and the TCI system was not pumping any more volume, then the patient was checked for pain stimuli reaction. As the patient did not react, he was then intubated with a laryngoscope.
Figure imgf000031_0001
When the maintenance phase started, surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. When infusion was stopped, the patient opened her eyes, 8 minutes later.
Figure imgf000031_0002
Patient 10 Patient 10 was injected a total of 7.26 ml. of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of the benzodiazepine midazolam were administered to the patient at the beginning of induction just before the administration of the remifentanil-propofol mixture. The induction phase started and at the moment the effect-site concentration was of 4 μg/mL and the TCI system was not pumping any more volume, then the patient was checked for pain stimuli reaction. As the patient did not react, he was then intubated with a laryngoscope.
Figure imgf000032_0001
When the maintenance phase started, surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. When infusion was stopped, the patient opened his eyes, 13 minutes later.
Figure imgf000032_0002
Patient 1 1
Patient 1 1 was injected a total of 10.60 mL of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of the benzodiazepine midazolam and 90 μg of clonidine for blood pressure control, were administered to the patient at the beginning of induction just before the administration of the remifentanil-propofol mixture. The induction phase started and at the moment the effect-site concentration was of 6 μg/mL and the TCI system was not pumping any more volume, then the patient was checked for negative pain stimuli reaction. The patient was intubated with a laryngoscope. Later, 6 mg cisatracurium were administered for patient positioning purposes.
Figure imgf000033_0002
When the maintenance phase started, surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. When infusion was stopped, the patient opened his eyes some minutes later.
Figure imgf000033_0003
Patient 12
Patient 12 was injected a total of 1 1.67 mL of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of the benzodiazepine midazolam were administered to the patient at the beginning of induction just before the administration of the remifentanil-propofol mixture. The induction phase started and at the moment the effect-site concentration was of 4 μg/mL and the TCI system was not pumping any more volume, then the patient was checked for negative pain stimuli reaction. He was then intubated with a laryngoscope. Later, 4 mg cisatracurium were administered to the patient for patient positioning purposes.
Figure imgf000033_0001
site cone, administered volume at these of administered of administered setting for the (mL) of the solution conditions remifentanil propofol (mg/kg) TCI Pump remifentanil /propofol (sec.) (MQ/kg)
2 Mg/ml 5.80 22.00 1.81 0.60
4 g/ml 1 1.67 47.00 3.65 1.22
When the maintenance phase started, surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. When infusion was stopped, the patient opened her eyes some minutes later.
Figure imgf000034_0001
Patient 13
Patient 13 was injected a total of 7.36 mL of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of the benzodiazepine midazolam were administered to the patient at the beginning of induction just before the administration of the remifentanil-propofol mixture. The induction phase started and at the moment the effect-site concentration was of 4 μg/mL and the TCI system was not pumping any more volume, then the patient was checked for negative pain stimuli reaction. Because of a difficult airway situation in the patient, the intubation was performed with Airtraq®, a fibreoptic intubation device used for indirect (video or optic assisted) tracheal intubation.
Induction phase
Target effect- Cumulative Period of time Cumulative dose
Cumulative dose site cone, administered volume at these of administered
of administered setting for the (mL) of the solution conditions remifentanil
propofol (mg/kg) TCI Pump remifentanil /propofol (sec.) ( g kg)
2 μg/ml 3.60 30.00 1.96 0.65 4 μς/ιηΙ 7.36 60.00 4.01 1.34
When the maintenance phase started, surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. When infusion was stopped, the patient opened her eyes some minutes later.
Figure imgf000035_0001
Patient 15
Patient 15 was injected a total of 13,89 ml. of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of the benzodiazepine midazolam were administered to the patient at the beginning of induction just before the administration of the remifentanil-propofol mixture. The induction phase started and at the moment the effect-site concentration was of 6 μg/mL and the TCI system was not pumping any more volume, the patient was checked for negative pain stimuli reaction and he was intubated with a laryngoscope. Later, 6 mg of the benzoisoquinoline cisatracurium were administered to the patient.
Induction phase
Target effect- Cumulative Period of time Cumulative dose
Cumulative dose site cone, administered volume at these of administered
of administered setting for the (mL) of the solution conditions remifentanil
propofol (mg/kg) TCI Pump remifentanil /propofol (sec.) (μ9 ι 9)
2 μg/ml 4,50 22,00 1.59 0.53
6 μg/ml 13.89 72,00 4.90 1.63 When the maintenance phase started, surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. When infusion was stopped, the patient opened her eyes some minutes later.
Figure imgf000036_0002
Patient 36
Patient 36 was injected a total of 10.00 ml. of the combination of propofol and remifentanil prepared as indicated above. 1.7 mg of the benzodiazepine midazolam and 60 mg lidocaine were administered to the patient at the beginning of induction just before the administration of the remifentanil-propofol mixture. The induction phase started and at the moment the effect-site concentration was of 4 μg/mL and the TCI system was not pumping any more volume, then the patient was checked for negative pain stimuli reaction. The patient was then intubated with a laryngoscope.
Figure imgf000036_0001
Target effect- Cumulative Period of time Cumulative dose
Cumulative dose site cone, administered volume at these of administered
of administered setting for the (mL) of the solution conditions remifentanil
propofol (mg/kg) TCI Pump remifentanil /propofol (sec.) (MQ/kg)
2 Mg ml 4,50 22,00 1.16 0.39
4 μg/ml 10.00 47.00 2.59 0.86
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Nearly at the end of surgery, a pulmonary recruitment manoeuvre was performed by inflating an important volume of oxygen into the lungs of the patient and for which a bolus of 100 mg propofol was injected. Afterwards, continuous infusion was stopped and the patient opened his eyes, 1 1 minutes and 20 seconds later.
Figure imgf000037_0002
Patient 38
Patient 38 was injected a total of 5.31 mL of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of the benzodiazepine midazolam and 50 mg of lidocaine were administered to the patient at the beginning of induction just before the administration of the remifentanil-propofol mixture. The induction phase started and at the moment the effect-site concentration was of 4 μg/mL and the TCI system was not pumping any more volume, then the patient was checked for negative pain stimuli reaction. The patient was then intubated with a laryngoscope.
Figure imgf000037_0001
site cone, administered volume at these of administered of administered setting for the (mL) of the solution conditions remifentanil propofol (mg/kg) TCI Pump remifentanil /propofol (sec.) (MQ/kg)
2 Mg/ml 2.63 21.00 1.58 0.53
4 μς/ιηΙ 5.31 47.00 3.19 1.06
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened her eyes, 9 minutes and 45 seconds later.
Figure imgf000038_0001
Patient 39
Patient 39 was injected a total of 13.55 mL of the combination of propofol and remifentanil prepared as indicated above. Prior to the administration of the combination of propofol-remifentanil, 2.0 mg of the benzodiazepine midazolam and 60 mg of lidocaine were administered to the patient. The induction phase started and at the moment the effect-site concentration was of 4 μg/mL and the TCI system was not pumping any more volume, then the patient was checked for negative pain stimuli reaction. The patient was then intubated with a laryngoscope.
Induction phase
Target effect- Cumulative Period of time Cumulative dose
Cumulative dose site cone, administered volume at these of administered
of administered setting for the (mL) of the solution conditions remifentanil
propofol (mg/kg) TCI Pump remifentanil /propofol (sec.) ( g kg)
2 μg/ml 6.70 31.00 2.01 0.67
4 μg/ml 13.55 67.00 4.07 1.36 The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened her eyes, 10 minutes later.
Figure imgf000039_0002
Patient 41
Patient 41 was injected a total of 7.72 ml. of the combination of propofol and remifentanil prepared as indicated above. Prior to the administration of the combination of propofol-remifentanil, 1.5 mg of the benzodiazepine midazolam and 50 mg of lidocaine were administered to the patient. The induction phase started and at the moment the effect-site concentration was of 4 μg/mL and the TCI system was not pumping any more volume, then the patient was checked for negative pain stimuli reaction. The patient was then intubated with a laryngoscope.
Figure imgf000039_0003
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened her eyes, a few minutes later.
Figure imgf000039_0001
Target effect-site
Time cone, setting for the Administration rate of
Administration rate of
points TCI Pump Propofol
Remifentanil ^g/kg/min)
(min) ^g/kg/min)
(Mg/mL) (rnL/h)
15 1.5 25.4 0.195 65.13
30 3.0 55.5 0.427 142.31
45 2.0 28.4 0.218 72.82
60 2.0 28.9 0.222 74.10
Average 0.266 88.59
Patient 44
Patient 44 was injected a total of 7.82 mL of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of the benzodiazepine midazolam and 50 mg of lidocaine were administered to the patient prior to the administration of the combination of propofol-remifentanil. The induction phase started and at the moment the effect-site concentration was of 4 μg/mL and the TCI system was not pumping any more volume, then the patient was checked for negative pain stimuli reaction. The patient was then intubated with a laryngeal mask.
Figure imgf000040_0001
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened her eyes, 4 minutes later.
Maintenance phase
Target effect-site
Time cone, setting for the Administration rate of
Administration rate of
points TCI Pump Propofol
Remifentanil ^g/kg/min)
(min) ^g/kg/min)
^g/mL) (rnL/h)
10 2.0 35.8 0.293 97.81
20 2.0 33.1 0.271 90.44
30 2.0 31.5 0.258 86.07 40 2.0 30.6 0.251 83.61
50 2.0 29.9 0.245 81.69
Average 0.264 87.92
Patient 45
Patient 45 was injected a total of 9.50 ml. of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of the benzodiazepine midazolam and 50 mg of lidocaine were administered to the patient prior to the administration of the combination of propofol-remifentanil. The induction phase started and at the moment the effect-site concentration was of 4 μg/mL and the TCI system was not pumping any more volume, then the patient was checked for negative pain stimuli reaction. The patient was then intubated.
Figure imgf000041_0001
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 5 minutes 10 seconds later.
Figure imgf000041_0002
Patient 48
Patient 48 was injected a total of 8.26 mL of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of the benzodiazepine midazolam and 50 mg of lidocaine were administered to the patient at the beginning of induction just before the administration of the remifentanil-propofol mixture. The induction phase started and at the moment the effect-site concentration was of 4 μς/ΓηΙ. and the TCI system was not pumping any more volume, then the patient was checked for negative pain stimuli reaction. Because of a difficult airway situation in the patient, the intubation was performed with the use of Airtraq®. Later, cisatracurium was administered.
Figure imgf000042_0001
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened her eyes, 4 minutes and 10 seconds later.
Figure imgf000042_0002
Patient 49
Patient 49 was injected a total of 9.16 mL of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of the benzodiazepine midazolam and 50 mg of lidocaine were administered to the patient prior to the injection of propofol-remifentanil. The induction phase started and at the moment the effect-site concentration was of 4 μg/mL and the TCI system was not pumping any more volume, then the patient was checked for negative pain stimuli reaction. The patient was then intubated.
Induction phase
Target effect- Cumulative Period of time Cumulative dose
Cumulative dose site cone, administered volume at these of administered
of administered setting for the (mL) of the solution conditions remifentanil
propofol (mg/kg) TCI Pump remifentanil /propofol (sec.) ( g kg) 2 μς/ιηΙ 4.54 23.00 1.53 0.51
4 μς/ιηΙ 9.16 49.00 3.09 1.03
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. 1 mg of atropine and 7.5 mg of ephedrine were also injected during the maintenance phase at about 40 minutes from start of the anesthetic procedure. At the end of the procedure, infusion was stopped and the patient opened her eyes, 7 minutes and 30 seconds later.
Figure imgf000043_0001
Patient 60
Patient 60 was injected a total of 8.19 ml. of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of the benzodiazepine midazolam and 50 mg of lidocaine were administered to the patient prior to the injection of propofol-remifentanil. The induction phase started and at the moment the effect-site concentration was of 4 μg/mL and the TCI system was not pumping any more volume, then the patient was checked for negative pain stimuli reaction. The patient was then intubated.
Figure imgf000043_0002
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 6 minutes and 35 seconds later. Maintenance phase
Target effect-site
Time cone, setting for the Administration rate of
Administration rate of
points TCI Pump Propofol
Remifentanil ^g/kg/min)
(min) ^g/kg/min)
(Mg/mL) (rnL/h)
10 2.0 38.5 0.238 79.22
20 2.0 34.7 0.214 71.40
30 2.0 32.9 0.203 67.70
40 2.2 35.9 0.222 73.87
50 2.2 34.7 0.214 71.40
60 2.2 34.0 0.210 69.96
70 2.2 33.5 0.207 68.93
80 2.2 33.4 0.206 68.72
Average 0.214 71.40
Patient 64
Patient 64 was injected a total of 13.26 ml. of the combination of propofol and remifentanil prepared as indicated above. 1 .5 mg of the benzodiazepine midazolam, 50 mg of lidocaine were administered prior to the injection of propofol and remifentanil. A TAP block was performed. The induction phase started and at the moment the effect-site concentration was of 4 μg/mL and the TCI system was not pumping any more volume, then the patient was checked for negative pain stimuli reaction. The patient was intubated. Cisatracurium was administered around 10 minutes after intubation for patient positioning.
Figure imgf000044_0002
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened her eyes, 6 minutes and 35 seconds later.
Figure imgf000044_0001
Target effect-site
Time cone, setting for the Administration rate of
Administration rate of
points TCI Pump Propofol
Remifentanil ^g/kg/min)
(min) ^g/kg/min)
(Mg/mL) (rnL/h)
15 2.0 49.0 0.193 64.30
30 2.0 47.5 0.187 62.34
45 2.0 46.0 0.181 60.37
60 1 .9 42.5 0.167 55.77
75 1 .9 41.9 0.165 54.99
90 1 .9 41.6 0.164 54.59
105 1 .9 41.2 0.162 54.07
120 1 .9 40.9 0.161 53.67
135 1 .9 40.4 0.159 53.02
150 1 .9 40.2 0.158 52.76
165 1 .9 40.0 0.157 52.49
180 1 .9 39.8 0.157 52.23
195 1 .9 39.5 0.156 51.84
210 1 .9 39.2 0.154 51.44
225 2.0 41.2 0.162 54.07
240 1 .8 35.6 0.140 46.72
255 2.0 41.2 0.162 54.07
270 2.0 40.9 0.161 53.67
285 2.0 40.5 0.159 53.15
300 2.0 40.1 0.158 52.62
315 2.0 40.1 0.158 52.62
330 2.3 47.1 0.185 61.81
345 2.2 44.0 0.173 57.74
360 2.2 43.9 0.173 57.61
375 2.2 43.8 0.172 57.48
390 2.2 43.7 0.172 57.35
405 2.0 39.0 0.154 51.18
420 2.0 38.4 0.151 50.39
435 2.0 38.5 0.152 50.52
440 2.0 38.4 0.151 50.39
Average 0.164 54.51 Patient 67
1.5 mg of the benzodiazepine midazolam and 50 mg of lidocaine were administered to patient 67. Next, the patient was injected a total of 7.29 ml. of the combination of propofol and remifentanil prepared as indicated above. A PECS block was performed. The induction phase started and at the moment the effect-site concentration was of 4 μg/mL and the TCI system was not pumping any more volume, then the patient was checked for negative pain stimuli reaction. An Airtraq was used for intubation.
Figure imgf000046_0001
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened her eyes, 6 minutes and 10 seconds later.
Figure imgf000046_0002
Patient 68
1.5 mg of the benzodiazepine midazolam and 50 mg of lidocaine were administered to patient 68. Next the patient was injected a total of 6.82 mL of the combination of propofol and remifentanil prepared as indicated above. The induction phase started and at the moment the effect-site concentration was of 4 μg/mL and the TCI system was not pumping any more volume, then the patient was checked for negative pain stimuli reaction. The patient was intubated.
Figure imgf000047_0001
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened her eyes, 7 minutes and 20 seconds later.
Figure imgf000047_0002
For the patients above, administered the combination of drugs according to the invention, the doses administered were averaged and the relevant measured clinical parameters are displayed in the table below.
Propofol Average Mean
Remifentanil Remifentanil Average Average
at heart arterial
Patient concentration at induction remifentanil propofol
induction rate pressure ^g/ml) ( g kg) ^g/kg/min) ^g/kg/min)
(mg/kg) (/min) (mmHg)
1 30.00 4.20 1.4 0.219 72.990
2 30.00 3.07 1 .02 0.292 97.280 84 74
3 30.00 2.83 0.94 0.170 56.740 67 93
4 30.00 3.77 1 .26 0.216 71.840 51 88
5 30.00 3.09 1 .03 0.177 59.070 57 60
6 30.00 3.29 1.1 0.212 70.540 67 75 7 30.00 2.70 0.9 0.150 49.900 59 61
8 30.00 3.89 1.3 0.214 71.230 52 62
9 30.00 2.91 0.97 0.151 50.450 92 56
10 30.00 2.72 0.91 0.196 65.420 61 68
1 1 30.00 4.24 1.41 0.201 66.890 72 85
12 30.00 3.65 1.22 0.224 74.550 51 64
13 30.00 4.01 1.34 0.221 73.500 47 63
15 30.00 4.90 1.63 0.234 78.050 84 93
36 30.00 2.59 0.86 0.180 59.950 49 76
38 30.00 3.19 1.06 0.220 73.330 57 65
39 30.00 4.07 1.36 0.206 68.730 76 64
41 30.00 3.56 1.19 0.266 88.590 74 68
44 30.00 3.85 1.28 0.264 87.920 45 70
45 30.00 2.97 0.99 0.199 66.380 55 72
48 30.00 2.48 0.83 0.164 54.560 70 78
49 30.00 3.09 1.03 0.170 56.510 49 39
60 30.00 3.03 1.01 0.214 71.400 53 79
64 30.00 3.13 1.04 0.164 54.510 53 69
67 30.00 3.08 1.03 0.221 73.630 75 65
68 30.00 3.86 1.29 0.274 91.380 56 65
Average 30.00 3.36 1 .16 0.208 71.446 62 70
The administration of a combination comprising 30 μg/mL remifentanil and 10 mg/mL propofol during the induction phase allowed a more comfortable intubation for the patient, which was quicker - 1-2 min. instead of 3-4 min of the state of the art - and as easy for the practitioner. It further did not require - for most of the cases- the administration of muscle relaxants, which are usually administered during intubation procedures. Importantly, the heart rates and blood pressures for most of the patients undergoing anesthesia were maintained at normal levels (50-100 beats/min and 60-1 10 mmHg, respectively).
Example 2: Preparation of a combination of propofol and remifentanil with a 20uq/ml remifentanil concentration
A mixture of propofol and remifentanil was prepared according to the following protocol. 1 ml. of a syringe containing 10 mg/mL propofol solution of 50 ml. propofol from B.Braun, was drawn and injected into a vial of Ultiva®, obtained from the company GlaxoSmithKline containing 1 mg of base powder remifentanil. The entire 1 mL-solution remifentanil / propofol was then aspirated from the Ultiva® vial and injected into the propofol syringe. A 50 ml. solution was obtained containing 1 mg remifentanil and 500 mg of propofol, thus achieving a final concentration of 20 μg/mL of remifentanil and approximately 10 mg/mL of propofol, which may also be expressed as the dose ratio (w/w) of remifentanil to propofol of 0.002:1 .
An extension tubing was attached at one end to the syringe tip. The extension tubing was fixed at the other end to the IV line of the patient. The syringe was put into a syringe driver device in full control of the plunger of the syringe, which injected the remifentanil / propofol mixture into the IV line by means of a pump guided by a software.
The Schnider model was chosen amongst other pharmacokinetic models, such as Marsh and Minto. Then, parameters of age, gender, length and weight of the patient that was to be treated were entered. The software then calculated the amount of propofol that was injected, such as to stay in the appropriate therapeutic window.
Data was collected from patients undergoing general anesthesia before surgery. The patient data and type of surgery which each patient underwent is listed below.
Patient Gender (M/F) Age (years) Length (cm) Weight (kg) Type of surgery
Cardiac
14 M 61 190 126
catheterisation
17 M 46 182 86 Knee arthroscopy
18 F 69 164 60 LAPS operative
LAPS
19 F 32 161 55
myomectomy
Hysteroscopy et
21 F 27 165 56
LAPS operative
22 F 74 165 69 LAPS operative
24 F 64 155 67 Varices
25 F 54 160 51 Varices
26 F 64 160 92 Varices
27 F 62 159 44 Varices
Accessory
31 M 36 175 72
pathway
Anterior cervical
32 F 75 165 42
fusion
Ventricular Extra
33 F 63 162 74
Systole
Scar correction on
40 M 31 190 84
breast and back
43 F 51 156 80 Cholecystectomy
47 F 65 163 94 Cholecystectomy LHnR and
51 F 54 148 74
hemorroidal tags
57 M 58 175 74 Right foot fracture
61 F 24 173 59 Mammoplasty
69 F 49 175 67 Salpingectomy
70 F 48 170 84 Adnexectomy
During the anesthesia procedure there was an initial induction phase which normally took up to 2 minutes, at which moment intubation of the patient was performed to support his respiratory functions. The patient was checked for unconsciousness and reaction to pain. Following intubation, the maintenance phase was initiated, in which maintenance phase surgery took place. Following surgery or just before surgery was finished, the termination phase of anesthesia was initialized.
Patient 14
1.5 mg of the benzodiazepine midazolam were administered to patient 14. Next, the patient was injected a total of 10.08 ml. of the combination of propofol and remifentanil prepared as indicated above. The induction phase started and at the moment the effect-site concentration was of 4 μg/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
Figure imgf000050_0001
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, some minutes later.
Maintenance phase
Target effect-site
Time cone, setting for the Administration rate of
Administration rate of
points TCI Pump Propofol
Remifentanil ^g/kg/min)
(min) ^g/kg/min)
(Mg/mL) (rnL/h)
15 2.0 42.80 0.1 13 56.61
30 2.0 42.70 0.1 13 56.48 45 2.0 42.30 0.1 12 55.95
60 1 .8 36.90 0.098 48.81
75 1 .9 36.90 0.105 52.38
90 1 .9 39.00 0.103 51.59
105 1 .9 36.20 0.096 47.88
120 1 .8 36.20 0.096 47.88
150 1 .8 35.90 0.095 47.49
180 2.3 47.90 0.127 63.36
210 2.0 38.30 0.101 50.66
Average 0.105 52.65
Patient 17
1.5 mg of the benzodiazepine midazolam were administered to the patient 17 followed by injection of a total of 12.33 mL of the combination of propofol and remifentanil prepared as indicated above, at the beginning of induction just before the administration of the remifentanil-propofol mixture. The induction phase started and at the moment the effect- site concentration was of 6 μg/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
Figure imgf000051_0001
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 6 minutes and 23 seconds later.
Maintenance phase
Target effect-site
Time cone, setting for the Administration rate of
Administration rate of
points TCI Pump Propofol
Remifentanil ^g/kg/min)
(min) ^g/kg/min)
^g/mL) (mL/h)
15 2.0 36.20 0.140 70.16
25 2.4 43.40 0.168 84.1 1 35 2.6 45.50 0.176 88.18
45 2.6 43.50 0.169 84.30
Average 0.163 81.69
Patient 18
1.5 mg of the benzodiazepine midazolam and 30 mg of lidocaine were administered to patient 18 followed by injection of a total of 9,51 mL of the combination of propofol and remifentanil prepared as indicated above. The induction phase started and at the moment the effect-site concentration was of 6 μg/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
Figure imgf000052_0001
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. 6 mg of cisatracurium were administered to the patient during surgery. Infusion was stopped and the patient opened his eyes, 5 minutes and 50 seconds later.
Maintenance phase
Target effect-site
Time cone, setting for the Administration rate of
Administration rate of
points TCI Pump Propofol
Remifentanil ^g/kg/min)
(min) ^g/kg/min)
(Mg/mL) (mL/h)
15 2.2 35.60 0.198 98.89
30 2.2 34.30 0.191 95.28
45 2.2 33.50 0.186 93.06
60 2.2 32.90 0.183 91.39
75 2.4 35.30 0.196 98.06
90 2.4 34.90 0.194 96.94
105 2.4 34.20 0.190 95.00
120 2.6 37.40 0.208 103.89
135 2.4 33.20 0.184 92.22 Average 0.192 86.47
Patient 19
1.5 mg of the benzodiazepine midazolam and 30 mg of lidocaine were administered to patient 19 followed by injection of a total of 12.22 mL of the combination of propofol and remifentanil prepared as indicated above. The induction phase started and at the moment the effect-site concentration was of 6 μg/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
Figure imgf000053_0001
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. 4 mg of cisatracurium were administered to the patient during surgery. Infusion was stopped and the patient opened his eyes, 9 minutes and 20 seconds later.
Figure imgf000053_0002
Patient 21
1.5 mg of the benzodiazepine midazolam and 30 mg of lidocaine were administered to patient 21 , which was further injected a total of 13,01 mL of the combination of propofol and remifentanil prepared as indicated above. The induction phase started and at the moment the effect-site concentration was of 6 μg/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
Figure imgf000054_0001
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 8 minutes and 40 seconds later.
Figure imgf000054_0002
Patient 22
Patient 22 was injected a total of 9,71 mL of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of the benzodiazepine midazolam and 30 mg of lidocaine were administered to the patient at the beginning of induction just before the administration of the remifentanil-propofol mixture. The induction phase started and at the moment the effect-site concentration was of 6 μg/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
Induction phase
Target effect- Cumulative Period of time Cumulative dose
Cumulative dose site cone, administered volume at these of administered
of administered setting for the (mL) of the solution conditions remifentanil
propofol (mg/kg) TCI Pump remifentanil /propofol (sec.) (Mg/kg)
2 Mg ml 3.20 1 1.00 0.93 0.47
4 μg/ml 6.39 40.00 1.85 0.925 6 μς/ιηΙ 9.71 66.00 2.81 1.405
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 10 minutes later.
Figure imgf000055_0001
Patient 24
Patient 24 was injected a total of 10,22 ml. of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of the benzodiazepine midazolam and 40 mg of lidocaine were administered to the patient at the beginning of induction just before the administration of the remifentanil-propofol mixture. The induction phase started and at the moment the effect-site concentration was of 6 μg/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
Figure imgf000055_0002
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 6 minutes and 55 seconds later.
Figure imgf000056_0001
Patient 25
Patient 25 was injected a total of 9,99 ml. of the combination of propofol and remifentanil prepared as indicated above. 1.5 mg of the benzodiazepine midazolam and 40 mg of lidocaine were administered to the patient at the beginning of induction just before the administration of the remifentanil-propofol mixture. The induction phase started and at the moment the effect-site concentration was of 6 μg/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
Figure imgf000056_0002
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 6 minutes and 27 seconds later.
Maintenance phase
Time Target effect-site Administration rate of
Administration rate of
points cone, setting for the Propofol
Remifentanil ^g/kg/min)
(min) TCI Pump ^g/kg/min) (Mg/mL) (rnL/h)
15 2.0 30.8 0.201 100.65
30 1.8 25.8 0.169 84.31
35 1.8 25.3 0.165 82.68
45 1.6 21.2 0.139 69.28
Average 0.168 84.23
Patient 26
1.5 mg of the benzodiazepine midazolam and 40 mg of lidocaine were administered to patient 26, which was further injected a total of 14.62 mL of the combination of propofol and remifentanil prepared as indicated above. The induction phase started and at the moment the effect-site concentration was of 6 μg/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
Figure imgf000057_0001
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 10 minutes later.
Maintenance phase
Target effect-site
Time cone, setting for the Administration rate of
Administration rate of
points TCI Pump Propofol
Remifentanil ^g/kg/min)
(min) ^g/kg/min)
^g/mL) (mL/h)
15 1 .8 38.5 0.139 69.75
30 1 .8 37.9 0.137 68.66
45 1 .8 37.3 0.135 67.57
60 1 .8 37.0 0.134 67.03
75 1 .8 36.7 0.133 66.49
90 2.1 42.9 0.155 77.72 105 2.0 40.1 0.145 72.64
120 1 .9 37.5 0.136 67.93
135 1 .9 37.2 0.135 67.39
Average 0.139 69.46
Patient 27
1.5 mg of the benzodiazepine midazolam and 40 mg of lidocaine were administered to patient 27, which was further injected a total of 7.57 mL of the combination of propofol and remifentanil prepared as indicated above. The induction phase started and at the moment the effect-site concentration was of 5 μg/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
Figure imgf000058_0001
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 10 minutes later.
Figure imgf000058_0002
Patient 31
1.5 mg of the benzodiazepine midazolam and 40 mg of lidocaine were administered to patient 31 , which was further injected a total of 10.05 mL of the combination of propofol and remifentanil prepared as indicated above. Isuprel was administered to the patient during the procedure, for cardiac rhythm testing purposes. The induction phase started and at the moment the effect-site concentration was of 5 μg/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
Figure imgf000059_0001
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 5 minutes and 30 seconds later.
Figure imgf000059_0002
Patient 32
1.5 mg of the benzodiazepine midazolam and 40 mg of lidocaine were administered to patient 32, who was further injected a total of 7.00 mL of the combination of propofol and remifentanil prepared as indicated above. The induction phase started and at the moment the effect-site concentration was of 5 μς/ΓηΙ. and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
Figure imgf000060_0001
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 10 minutes later.
Figure imgf000060_0002
Patient 33 1.5 mg of the benzodiazepine midazolam and 40 mg of lidocaine were administered to patient 33, who was further injected a total of 9.27 mL of the combination of propofol and remifentanil prepared as indicated above. The induction phase started and at the moment the effect-site concentration was of 5 μg/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
Figure imgf000061_0001
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, some minutes later.
Figure imgf000061_0002
Patient 40
1.5 mg of the benzodiazepine midazolam and 40 mg of lidocaine were administered to patient 40, who was further injected a total of 14.03 mL of the combination of propofol and remifentanil prepared as indicated above. The induction phase started and at the moment the effect-site concentration was of 6 μς/ΓηΙ. and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated. 6 mg of cisatracurium and 35 mg of ketamine were administered to the patient during surgery.
Figure imgf000062_0001
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 5 minutes and 25 seconds later.
Maintenance phase
Target effect-site
Time cone, setting for the Administration rate of
Administration rate of
points TCI Pump Propofol
Remifentanil ^g/kg/min)
(min) ^g/kg/min)
(Mg/mL) (mL/h)
15 3.0 50.9 0.202 100.99
30 3.0 50.1 0.199 99.40
45 2.8 44.7 0.177 88.69
60 2.6 40.1 0.159 79.56
75 2.6 40.1 0.159 79.56
90 2.6 40.3 0.160 79.56
105 2.8 43.5 0.173 86.31
120 2.8 42.6 0.169 84.52
135 2.8 42.2 0.167 83.73
150 2.8 41.7 0.165 82.74
165 2.8 41.2 0.163 81.75
180 3.0 45.4 0.180 90.08
195 3.0 44.2 0.175 87.70 210 3.0 43.5 0.173 86.31
225 2.9 40.7 0.153 76.59
240 2.8 38.6 0.153 76.59
255 2.8 38.6 0.152 76.19
270 2.8 38.4 0.142 71.03
285 2.7 35.8 0.152 76.19
Average 0.167 83.57
Patient 43
1.5 mg of the benzodiazepine midazolam and 50 mg of lidocaine were administered to patient 43, who was further injected a total of 1 1.10 mL of the combination of propofol and remifentanil prepared as indicated above. The induction phase started and at the moment the effect-site concentration was of 5 μg/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
Figure imgf000063_0001
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 9 minutes and 25 seconds later.
Maintenance phase
Target effect-site
Time cone, setting for the Administration rate of
Administration rate of
points TCI Pump Propofol
Remifentanil ^g/kg/min)
(min) ^g/kg/min)
(Mg/mL) (mL/h)
15 2.0 40.3 0.168 83.96
30 2.6 50.5 0.210 105.21
45 2.5 45.8 0.191 95.42
60 2.4 42.8 0.178 89.17 75 2.2 37.8 0.158 78.75
Average 0.181 90.50
Patient 47
1.5 mg of the benzodiazepine midazolam, 50 mg of lidocaine were administered to patient 47, who was further injected a total of 12.02 ml. of the combination of propofol and remifentanil prepared as indicated above. The induction phase started and at the moment the effect-site concentration was of 5 μg/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated. After 70 minutes, butylhyoscinebromide was also administered.
Figure imgf000064_0001
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, more than 10 minutes later.
Figure imgf000064_0002
Patient 51
1 mg of the benzodiazepine midazolam and 50 mg of lidocaine were administered to patient 51 , who was further injected a total of 10.15 ml. of the combination of propofol and remifentanil prepared as indicated above. The induction phase started and at the moment the effect-site concentration was of 5 μς/ΓηΙ. and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated. 10 mg of cisatracurium and 50 mg of ketamine were administered to the patient during surgery.
Figure imgf000065_0001
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 3 minutes and 30 seconds later.
Figure imgf000065_0002
Patient 57
10 mg of ketamine and 10 mg of morphine were administered to patient 57 in the emergency department more than 1 hour prior to surgery. 1 ,5 mg of the benzodiazepine midazolam and 50 mg of lidocaine were administered to the patient, who was further injected a total of 8.50 mL of the combination of propofol and remifentanil prepared as indicated above. The induction phase started and at the moment the effect-site concentration was of 5 μς/ηιί and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
Figure imgf000066_0001
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 8 minutes and 30 seconds later.
Figure imgf000066_0002
Patient 61
1 ,5 mg of the benzodiazepine midazolam and 50 mg of lidocaine were administered to patient 61 , who was further injected a total of 1 1.65 mL of the combination of propofol and remifentanil prepared as indicated above. The induction phase started and at the moment the effect-site concentration was of 5 μg/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated. Induction phase
Target effect- Cumulative Period of time Cumulative dose
Cumulative dose site cone, administered volume at these of administered
of administered setting for the (mL) of the solution conditions remifentanil
propofol (mg/kg) TCI Pump remifentanil /propofol (sec.) (MQ/kg)
2 Mg ml 4.59 22.00 1.56 0.78
4 μg/ml 9.25 49.00 3.14 1.57
5 μg/ml 1 1.65 83.00 3.95 1.97
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 6 minutes and 15 seconds later.
Figure imgf000067_0001
Patient 69
1 ,5 mg of the benzodiazepine midazolam and 50 mg of lidocaine were administered to patient 69, who was further injected a total of 10.04 mL of the combination of propofol and remifentanil prepared as indicated above. The induction phase started and at the moment the effect-site concentration was of 5 μg/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
Figure imgf000068_0001
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 5 minutes later.
Figure imgf000068_0002
Patient 70
1 ,5 mg of the benzodiazepine midazolam and 50 mg of lidocaine were administered to patient 70, who was further injected a total of 1 1.74 mL of the combination of propofol and remifentanil prepared as indicated above. The induction phase started and at the moment the effect-site concentration was of 5 μg/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
Induction phase
Target effect- Cumulative Period of time Cumulative dose
Cumulative dose site cone, administered volume at these of administered
of administered setting for the (mL) of the solution conditions remifentanil
propofol (mg/kg) TCI Pump remifentanil /propofol (sec.) (Mg/kg)
2 Mg ml 4.60 31.00 1.10 0.55 4 μς/ιηΙ 9.32 58.00 2.22 1.1 1
5 μς/ιηΙ 1 1.74 82.00 2.80 1.40
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 4 minutes later.
Figure imgf000069_0001
Further, for this group of patients administered the combination of drugs according to the invention, the doses administered were averaged and the relevant clinical parameters measured and displayed in the table below.
Propofol Average Mean
Remifentanil Remifentanil Average Average
at heart arterial
Patient concentration at induction remifentanil propofol
induction rate pressure (Mg/ml) (Mg/kg) ^g/kg/min) ^g/kg/min)
(mg/kg) (/min) (mmHg)
14 20.00 1.60 0.8 0.105 52.650 60 66
17 20.00 2.87 1.43 0.163 81.690 87 87
18 20.00 3.17 1.59 0.192 86.470 64 74
19 20.00 4.44 2.22 0.206 73.640 62 77
21 20.00 4.65 2.32 0.204 102.180 54 73
22 20.00 2.81 1.41 0.173 86.440 81 86
24 20.00 3.05 1.53 0.147 73.710 51 62
25 20.00 3.92 1.96 0.168 84.230 52 57
26 20.00 3.18 1.59 0.139 69.460 56 66
27 20.00 3.44 1.72 0.213 106.630 48 60
31 20.00 2.79 1.4 0.128 64.040 52 68
32 20.00 3.33 1.67 0.178 89.020 59 54
33 20.00 2.51 1.25 0.105 52.250 46 58 40 20.00 3.34 1.67 0.167 83.570 63 65
43 20.00 2.78 1.39 0.181 90.500 59 68
47 20.00 2.56 1.28 0.159 79.430 69 71
51 20.00 2.74 1.37 0.224 1 1 1.860 69 75
57 20.00 2.30 1.15 0.131 65.430 60 57
61 20.00 3.95 1.97 0.185 92.260 51 54
69 20.00 3.00 1.50 0.228 1 13.870 51 103
70 20.00 2.80 1.40 0.161 80.610 50 72
Average 20.00 3.1 1 1 .55 0.169 82.854 59 69
The administration of a combination comprising 20 μg/mL remifentanil and 10 mg/mL propofol during the induction phase allowed a more comfortable intubation for the patient, which was quicker - 1 -2 min. instead of 3-4min - and easier for the practitioner. It further did not require - for most of the cases - the administration of muscle relaxants, which are usually administered during intubation procedures. Importantly, the heart rates and blood pressures for most of the patients undergoing anesthesia were maintained at normal levels (50-100 beats/min and 60-1 10 mmHg, respectively).
Example 3: Preparation of a combination of propofol and remifentanil with a 25 uq/ml remifentanil concentration
A mixture of propofol and remifentanil was prepared according to the following protocol. 2 mL of a syringe containing 10 mg/mL propofol solution of 50 mL propofol from B.Braun, were drawn and injected into a 2 mL vial of Ultiva®, obtained from the company GlaxoSmithKline containing 2 mg of base powder remifentanil. 1 .25 mL of the solution remifentanil / propofol was then aspirated from the Ultiva® vial and injected into the propofol syringe. Approximately, a 50 mL (49.25 mL) solution was obtained containing 1.25 mg remifentanil and about 500 mg of propofol, thus achieving a final concentration of 25 μg/mL of remifentanil and approximately 10 mg/mL of propofol, which may also be expressed as the dose ratio (w/w) of remifentanil to propofol of 0.0025:1 .
An extension tubing was attached at one end to the syringe tip. The extension tubing was fixed at the other end to the IV line of the patient. The syringe was put into a syringe driver device in full control of the plunger of the syringe, which injected the remifentanil / propofol mixture into the IV line by means of a pump guided by a software.
The Schnider model was chosen amongst other pharmacokinetic models, such as Marsh and Minto. Then, parameters of age, gender, length and weight of the patient that was to be treated were entered. The software then calculated the amount of propofol that was injected, such as to stay in the appropriate therapeutic window.
Data was collected from 4 patients undergoing general anesthesia before surgery. The patient data and type of surgery which each patient underwent is listed below.
Figure imgf000071_0001
During the anesthesia procedure there was an initial induction phase which normally took up to 2 minutes, at which moment intubation of the patient was performed to support his respiratory functions. The patient was checked for unconsciousness and reaction to pain. Following intubation, the maintenance phase was initiated, in which maintenance phase surgery took place. Following surgery or just before surgery was finished, the termination phase of anesthesia was initialized.
Patient 52
1.5 mg of the benzodiazepine midazolam and 20 mg of lidocaine were administered to patient 52, who was further injected a total of 10.35 mL of the combination of propofol and remifentanil prepared as indicated above. The induction phase started and at the moment the effect-site concentration was of 4 μg/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated. 8 mg of cisatracurium was administered during surgery.
Figure imgf000071_0002
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 3 minutes and 30 seconds later.
Maintenance phase
Time Target effect-site Administration rate of
Administration rate of
points cone, setting for the Propofol
Remifentanil ^g/kg/min)
(min) TCI Pump ^g/kg/min) (Mg/mL) (rnL/h)
15 1 .8 38.3 0.181 72.54
30 2.0 41.1 0.195 77.84
45 2.0 38.9 00.184 73.67
60 2.0 38.3 0.181 72.54
Average 0.185 74.15
Patient 53
1.5 mg of the benzodiazepine midazolam and 50 mg of lidocaine were administered to patient 53, who was further injected a total of 7.91 ml. of the combination of propofol and remifentanil prepared as indicated above. The induction phase started and at the moment the effect-site concentration was of 4 μg/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated with an Airtraq®.
Figure imgf000072_0001
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 7 minutes and 15 seconds later.
Maintenance phase
Target effect-site
Time cone, setting for the Administration rate of
Administration rate of
points TCI Pump Propofol
Remifentanil ^g/kg/min)
(min) ^g/kg/min)
^g/mL) (rnL/h)
15 2.0 40.4 0.210 84.17
30 1 .8 33.5 0.174 69.79
45 1 .6 29.0 0.151 60.42
60 1 .8 33.0 0.172 68.75
75 1 .7 30.3 0.158 63.13
90 1 .6 28.0 0.146 58.33 Average 0.169 67.43
Patient 54
1.5 mg of the benzodiazepine midazolam and 50 mg of lidocaine were administered to the patient 54, who was further injected a total of 9.05 mL of the combination of propofol and remifentanil prepared as indicated above. The induction phase started and at the moment the effect-site concentration was of 4 μg/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
Figure imgf000073_0001
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 6 minutes later.
Figure imgf000073_0002
Patient 55
1.5 mg of the benzodiazepine midazolam and 50 mg of lidocaine were administered to patient 55, who was further injected a total of 12.44 mL of the combination of propofol and remifentanil prepared as indicated above. The induction phase started and at the moment the effect-site concentration was of 5 μg/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
Figure imgf000074_0001
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 9 minutes and 30 seconds later.
Figure imgf000074_0002
Further, for this group of patients administered the combination of drugs according to the invention, the doses administered were averaged and the relevant clinical parameters measured and displayed in the table below.
Propofol Average Mean
Remifentanil Remifentanil Average Average
at heart arterial
Patient concentration at induction remifentanil propofol
induction rate pressure (Mg/ml) ( g kg) ^g/kg/min) ^g/kg/min)
(mg/kg) (/min) (mmHg)
52 25.00 2.94 1.18 0.185 74.150 56 73
53 25.00 2.47 0.99 0.169 67.430 66 64
54 25.00 3.54 1.41 0.212 84.810 55 84 55 25.00 3.95 1.57 0.253 101.200 70 76
Average 25.00 3.23 1 .29 0.205 81.898 62 74
The administration of a combination comprising 25 μg/mL remifentanil and 10 mg/mL propofol during the induction phase allowed a more comfortable intubation for the patient, which was quicker - 1 -2 min. instead of 3-4min - and easier for the practitioner. It further did not require the administration of muscle relaxants, which are usually administered during intubation procedures. Importantly, the heart rates and blood pressures for most of the patients undergoing anesthesia were maintained at normal levels (50-100 beats/min and 60- 1 10 mmHg, respectively).
Example 4: Preparation of a combination of propofol and remifentanil with a 40 uq/ml remifentanil concentration
A mixture of propofol and remifentanil was prepared according to the following protocol. 2 mL of a syringe containing 10 mg/mL propofol solution of 50 mL propofol from B.Braun, were drawn and injected into a 2 mL vial of Ultiva®, obtained from the company GlaxoSmithKline containing 2 mg of base powder remifentanil. The whole 2 mL of the solution remifentanil / propofol was then aspirated from the Ultiva® vial and injected into the propofol syringe. A 50 mL solution was obtained containing 2 mg remifentanil and 500 mg of propofol, thus achieving a final concentration of 40 μg/mL of remifentanil and approximately 10 mg/mL of propofol, which may also be expressed as the dose ratio (w/w) of remifentanil to propofol of 0.0040:1 .
An extension tubing was attached at one end to the syringe tip. The extension tubing was fixed at the other end to the IV line of the patient. The syringe was put into a syringe driver device in full control of the plunger of the syringe, which injected the remifentanil / propofol mixture into the IV line by means of a pump guided by a software.
The Schnider model was chosen amongst other pharmacokinetic models, such as Marsh and Minto. Then, parameters of age, gender, length and weight of the patient that was to be treated were entered. The software then calculated the amount of propofol that was injected, such as to stay in the appropriate therapeutic window.
Data was collected from patients undergoing general anesthesia before surgery. The patient data and type of surgery which each patient underwent is listed below.
Gender
Patient Age (years) Length (cm) Weight (kg) Type of surgery
(M/F)
16 F 40 173 108 Gastric bypass
20 F 23 164 83 Breast reduction
23 M 78 158 70 Aortic endoprosthesis
28 F 44 169 56 Varices 29 F 34 168 60 Varices
30 F 37 178 65 Varices
Circular
34 F 67 165 78
abdominoplasty
35 F 22 169 70 Mammoplasty
37 M 46 184 96 Thyroidectomy
Lifting and breast
42 F 60 175 55
augmentation
46 F 22 163 47 Wisdom teeth
50 F 47 156 69 Hysterectomy
Multiple teeth
56 M 26 183 90
extraction
58 M 27 178 62 Wisdom teeth
Lipo-aspiration
59 F 58 160 62
stomach
62 F 35 175 54 Amygdalectomy
63 F 34 165 72 Sinus endoscopy
65 F 45 178 70 Ovarian cyst LAPS
66 F 43 151 69 LAPS hysterectomy
During the anesthesia procedure there was an initial induction phase which normally took up to 2 minutes, at which moment intubation of the patient was performed to support his respiratory functions. The patient was checked for unconsciousness and reaction to pain. Following intubation, the maintenance phase was initiated, in which maintenance phase surgery took place. Following surgery or just before surgery was finished, the termination phase of anesthesia was initialized.
Patient 16
1.5 mg of the benzodiazepine midazolam were administered to patient 16, who was further injected a total of 13.73 mL of the combination of propofol and remifentanil prepared as indicated above. The induction phase started and at the moment the effect-site concentration was of 4 μg/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated. 6 mg of cisatracurium were administered to the patient during surgery.
Induction phase
Target effect- Cumulative Period of time Cumulative dose
Cumulative dose site cone, administered volume at these of administered
of administered setting for the (mL) of the solution conditions remifentanil
propofol (mg/kg) TCI Pump remifentanil /propofol (sec.) (MQ/kg) 2 μς/ιηΙ 6.80 31.00 2.52 0.63
4 μς/ιηΙ 13.73 66.00 5.09 1.27
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, some minutes later.
Figure imgf000077_0001
Patient 20
1.5 mg of the benzodiazepine midazolam and 30 mg of lidocaine were administered to patient 20, who was further injected a total of 1 1.23 mL of the combination of propofol and remifentanil prepared as indicated above. The induction phase started and at the moment the effect-site concentration was of 4 μg/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
Induction phase
Target effect- Cumulative Period of time Cumulative dose
Cumulative dose site cone, administered volume at these of administered
of administered setting for the (mL) of the solution conditions remifentanil
propofol (mg/kg) TCI Pump remifentanil /propofol (sec.) 2 μς/ιηΙ 5.60 21.00 2.70 0.68
4 μς/ιηΙ 1 1.23 46.00 5.41 1.35
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 6 minutes later.
Figure imgf000078_0001
Patient 23
1.5 mg of the benzodiazepine midazolam and 50 mg of lidocaine were administered to patient 23, who was further injected a total of 5.34 mL of the combination of propofol and remifentanil prepared as indicated above. Noradrenaline was administered during the procedure to ensure an adequate blood pressure. The induction phase started and at the moment the effect-site concentration was of 4 μg/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
Induction phase
Target effect- Cumulative Period of time Cumulative dose
Cumulative dose site cone, administered volume at these of administered
of administered setting for the (mL) of the solution conditions remifentanil
propofol (mg/kg) TCI Pump remifentanil /propofol (sec.)
2 μg/ml 2.65 21.00 1.51 0.38 4 μς/ιηΙ 5.34 46.00 3.05 0.76
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 10 minutes 10 seconds later.
Figure imgf000079_0001
Patient 28
1.5 mg of the benzodiazepine midazolam and 30 mg of lidocaine were administered to patient 28, who was further injected a total of 7.62 mL of the combination of propofol and remifentanil prepared as indicated above. The induction phase started and at the moment the effect-site concentration was of 4 μg/mL and the TCI system was not pumping any more volume, the patient was checked for a negative pain stimuli reaction. Next, the patient was intubated.
Induction phase
Target effect- Cumulative Period of time Cumulative dose
Cumulative dose site cone, administered volume at these of administered
of administered setting for the (mL) of the solution conditions remifentanil
propofol (mg/kg) TCI Pump remifentanil /propofol (sec.) 2 μς/ιηΙ 3.78 21.00 2.70 0.68
4 μς/ιηΙ 7.62 45.00 5.44 1.36
The maintenance phase started, at which time surgery started, and the combination of propofol and remifentanil prepared as indicated above was continuously infused at the conditions indicated in the following table. Infusion was stopped and the patient opened his eyes, 6 minutes later.
Figure imgf000080_0001
Further, for these patients and others who were administered the combination of drugs according to the invention, the doses administered were averaged and the relevant clinical parameters measured and displayed in the table below.
Propofol Average Mean
Remifentanil Remifentanil Average Average
at heart arterial
Patient concentration at induction remifentanil propofol
induction rate pressure (Mg/ml) ^g/kg/min) ^g/kg/min)
(mg/kg) (/min) (mmHg)
16 40.00 5.09 1.27 0.285 71.240 65 78
20 40.00 5.41 1.35 0.300 75.030 66 70
23 40.00 3.05 0.76 0.223 55.850 59 62
28 40.00 5.44 1.36 0.329 82.220 47 69
29 40.00 5.60 1.4 0.276 68.980 52 72
30 40.00 5.40 1.35 0.329 82.310 43 71
34 40.00 3.82 0.95 0.215 53.820 54 63
35 40.00 5.67 1.42 0.276 69.030 55 63
37 40.00 3.61 0,9 0.226 56.490 60 75
42 40.00 5.01 1.25 0.309 77.170 49 56
46 40.00 7.25 1.81 0.435 108.870 59 64
50 40.00 4.59 1.15 0.245 61.150 44 80 56 40.00 4.30 1.08 0.252 63.100 56 86
58 40.00 5.43 1.36 0.330 82.530 58 93
59 40.00 4.43 1.1 1 0.282 70.500 62 65
62 40.00 6.23 1.56 0.450 1 12.500 69 80
63 40.00 5.07 1.27 0.297 74.150 58 63
65 40.00 4.83 1.21 0.314 78.450 43 69
66 40.00 4.74 1.19 0.306 76.400 68 87
Average 40.00 5.00 1.25 0.299 74.726 56 72
The administration of a combination comprising 40 μg/mL remifentanil and 10 mg/mL propofol during the induction phase allowed a more comfortable intubation for the patient, which was quicker - 1 -2 min. instead of 3-4min - for the practitioner. Except or one patient, it further did not require the administration of muscle relaxants, which are usually administered during intubation procedures. Importantly, the heart rates and blood pressures for most of the patients undergoing anesthesia were maintained at normal levels (50-100 beats/min and 60-1 10 mmHg, respectively).
The administration of a combination of remifentanil (either at 20, 25, 30, and 40 μg/mL) and 10 mg/mL propofol in all cases reported in Examples 1-4 was possible at an induction dose of propofol between 0.5 and less than 2 mg/Kg, and at a maintenance administration rate of propofol between 50 and 100 μg/Kg/min, and with the desired clinical effects: effective anesthesia, and maintenance of normal heart rates and blood pressures. This is a clear benefit when compared to the FDA-approved induction doses of 2-2.5 mg/Kg and maintenance rates of propofol of 100-200 μg/Kg/min. These lower induction doses and maintenance administration rates of propofol may indeed save lives.

Claims

Claims
A product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in inducing general anesthesia, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 , characterized in that the product is administered during 40 to 90 seconds at a target effect-site concentration of 4 μg/mL; and in the case the dose ratio of remifentanil to propofol (w/w) is from 0.0020:1 to 0.0029:1 , the product is further administered during additional 45 to 90 seconds at a second target effect-site concentration of 5 or 6 μg/mL.
A product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in inducing general anesthesia, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 , characterized in that the product is administered during 45 to 90 seconds at a target effect-site concentration of 5 or 6 μg/mL.
A product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in inducing general anesthesia, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 , characterized in that the product is administered during less than 40 seconds at a first target effect-site concentration of 2 μg/mL, and during additional 40 to 90 seconds at a second target effect-site concentration of 4 μg/mL; and in the case the dose ratio of remifentanil to propofol (w/w) is from 0.0020:1 to 0.0029:1 , the product is further administered during additional 45 to 90 seconds at a third target effect-site concentration of 5 or 6 μg/mL.
A product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in inducing general anesthesia, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 , characterized in that the product is administered to adult patients.
The product according to any one of claims 1 to 4, wherein the dose of propofol during induction is between 0.5 and less than 2 mg/Kg.
A product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in maintaining general anesthesia in patients, wherein the dose ratio (w/w) of remifentanil to propofol is from 0.0020:1 to 0.0040:1 , characterized in that the administration rate of propofol is between 50 and less than 100 μς/Κς/Γπίη .
7. A product comprising remifentanil and propofol, or the pharmaceutically acceptable salts thereof, as a combined preparation for simultaneous use in inducing or maintaining general anesthesia, characterized in that the dose ratio (w/w) of remifentanil to propofol is from 0.0025:1 to 0.0039:1 , preferably from 0.0026:1 to 0.0034:1 , preferably from
0.0027:1 to 0.0033:1 , more preferably from 0.0028:1 to 0.0032:1 , even more preferably 0.0030:1.
8. The product according to any one of claims 1 to 7, wherein the remifentanil salt is remifentanil hydrochloride.
9. The product according to any one of claims 1 to 8, wherein remifentanil or the pharmaceutically acceptable salt thereof is formulated with a pharmaceutically acceptable carrier as a powder, wherein the amount of remifentanil base in the powder is
1 , 1 .25, 1 .5, 2, or 5 mg.
10. The product according to any one of claims 1 to 9, wherein propofol is formulated as an emulsion at a concentration of 10 mg/mL.
11. The product according to any one of claims 1 to 10, wherein said product is administered intravenously as a bolus injection, as a continuous infusion, or a combination thereof.
12. The product according to any one of claims 1 to 1 1 , for use in the prevention of muscle rigidity during anesthesia.
13. A kit for preparing a product according to any one of claims 1 to 12, the kit comprising a first container comprising remifentanil or the pharmaceutically acceptable salt thereof, a second container comprising propofol or the pharmaceutically acceptable salt thereof, and instructions for mixing the remifentanil and propofol to obtain said dose ratio (w/w).
14. A pharmaceutical composition consisting of remifentanil or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the content of remifentanil base is of 1 .25 or 1 .5 mg.
15. The pharmaceutical composition according to claim 14, wherein the pharmaceutical composition is in powder form.
16. An infusion system for time-controlled administration to a patient of the product according to any one of claims 1 to 12, said infusion system comprising:
a) a supply of the product according to any one of claims 1 to 12, in fluid form;
b) an infusion pump adapted to deliver the fluid product from the supply to the patient at a controlled infusion rate(s); and
c) a control device, operatively connected to the infusion pump and provided with a control algorithm for controlling the infusion rate, said control algorithm comprising steps for setting i) during an induction phase of the administration process one or more target plasma or effect-site concentration(s) of the product, ii) during a maintenance phase of the administration process one or more target plasma or effect-site concentration(s) of the product, and iii) during the termination phase of the administration process one or more target plasma or effect-site concentration(s) of the product.
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GB2602123A (en) * 2020-12-18 2022-06-22 The Centre London Ltd Composition for procedural sedation and use thereof
GB2602123B (en) * 2020-12-18 2023-08-16 The Centre London Ltd Composition for procedural sedation and use thereof

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