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WO2011074695A1 - Suppresseur de tremblement - Google Patents

Suppresseur de tremblement Download PDF

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Publication number
WO2011074695A1
WO2011074695A1 PCT/JP2010/072937 JP2010072937W WO2011074695A1 WO 2011074695 A1 WO2011074695 A1 WO 2011074695A1 JP 2010072937 W JP2010072937 W JP 2010072937W WO 2011074695 A1 WO2011074695 A1 WO 2011074695A1
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WO
WIPO (PCT)
Prior art keywords
shivering
pharmaceutically acceptable
acceptable salt
remifentanil
salt
Prior art date
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Ceased
Application number
PCT/JP2010/072937
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English (en)
Japanese (ja)
Inventor
万三 鈴木
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Individual
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Priority to JP2011546194A priority Critical patent/JPWO2011074695A1/ja
Publication of WO2011074695A1 publication Critical patent/WO2011074695A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a shivering inhibitor.
  • Narcotic drugs are widely used for analgesia during surgery, postoperative analgesia, and management of cancer pain.
  • Synthetic narcotics such as fentanyl, in addition to opium alkaloids represented by morphine, have recently been used.
  • Remifentanil is a synthetic narcotic that significantly shortens the action time and enables rapid awakening from anesthesia. It was remifentanil that anesthesiologists had been waiting for, but as a problem that I actually used, I found that tremors called shivering occur quite frequently in about 2 hours after waking up from anesthesia. I came.
  • Shivering is an involuntary shake that is generally performed by the body to raise the body temperature due to a decrease in body temperature (precisely, central temperature).
  • a shivering inhibitor such as an opioid analgesic such as meperidine or alfentanil, and its effect are enhanced. Therefore, it is known to use an antiemetic together (for example, WO2004 / 041171).
  • opioid analgesics such as meperidine are used to suppress shivering, but opioid analgesics also have an effect of suppressing airway reflexes. For this reason, when an opioid type analgesic is used after an operation in the oral cavity or the like, there is a concern that the possibility of occurrence of aspiration increases.
  • the problem to be solved is to provide a shivering inhibitor, an anesthetic and kit, and a shivering suppression method that suppresses the occurrence of strong shivering when waking up from anesthesia with remifentanil or within 2 hours after waking up It is to be.
  • Each aspect of the present invention provides the following shivering inhibitor, anesthetic agent, kit and shivering inhibitor method, respectively.
  • the said shivering inhibitor used as a component.
  • [6] A method for suppressing shivering that occurs after administration of an anesthetic, comprising administering remifentanil or a pharmaceutically acceptable salt thereof as the anesthetic, and administering the shivering inhibitor according to [1].
  • the said shivering suppression method including doing.
  • the shivering according to [6] comprising administering naloxone or a pharmaceutically acceptable salt thereof at a rate of 0.2 ⁇ g / kg / hr to 4 ⁇ g / kg / hr immediately after administration of the anesthetic agent and from awakening. Suppression method.
  • FIG. 1 is a graph showing suppression of shivering by administration of naloxone according to an example.
  • FIG. 2 is a graph showing a decrease in the degree of shivering by administration of naloxone according to the example.
  • the shivering inhibitor of the present invention is a shivering inhibitor that suppresses shivering that occurs after administration of an anesthetic, wherein the anesthetic is remifentanil or a pharmaceutically acceptable salt thereof, and naloxone or a pharmaceutically acceptable salt thereof. Salt as an active ingredient.
  • the combined use of remifentanil and naloxone significantly suppresses shivering after anesthesia with remifentanil.
  • the suppression effect of naloxone on shivering is not constrained by any specific theory, but shivering is a withdrawal phenomenon when opioids begin to diverge from the narcotic receptors (opioid receptors), and low-concentration opioids act at the last minute. It is assumed that postoperative shivering is suppressed by blocking the receptor that should be present with an opioid antagonist in advance. Therefore, the need for warming during surgery is reduced, and remifentanil can be used safely in surgery such as neurosurgery and cardiac surgery, where warming during surgery is not recommended. Also, remifentanil can be used safely in oral surgery and the like in order to reduce the frequency of occurrence of shivering.
  • the term “process” is not limited to an independent process, and is included in this term if the intended action of this process is achieved even when it cannot be clearly distinguished from other processes. .
  • a numerical range indicated by using “to” indicates a range including the numerical values described before and after “to” as the minimum value and the maximum value, respectively.
  • the notation of “/ kg” with respect to the administration rate of the drug means “per kg of body weight of the administration subject”.
  • the notation of “/ kg / hr” is “1” It means “per hour, per kg body weight of administration subject”.
  • the present invention when referring to the amount of each component in the composition, when there are a plurality of substances corresponding to each component in the composition, the plurality present in the composition unless otherwise specified. Means the total amount of substances. The present invention will be described below.
  • the shivering inhibitor of the present invention is a shivering inhibitor that suppresses shivering that occurs after anesthetic administration, wherein the anesthetic is remifentanil or a pharmaceutically acceptable salt thereof, and Naloxone or a pharmaceutically acceptable salt thereof is an active ingredient.
  • the present shivering inhibitor can suppress the occurrence of shivering when waking up from anesthesia with remifentanil or within 2 hours after waking up.
  • the “pharmaceutically acceptable salt” of naloxone means that it reacts with an acid when it has a basic group such as an amino group, and a base when it has an acidic group such as a carboxyl group. Can be converted into a salt by reacting with, so that salt is shown.
  • the salt based on the basic group is preferably a hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfuric acid.
  • Inorganic acid salts such as salts and phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate, aryl sulfones such as benzene sulfonate and p-toluene sulfonate
  • Acid salt acetate salt, malate salt, fumarate salt, succinate salt, citrate salt, ascorbate salt, tartrate salt, succinate salt, maleate salt, etc .
  • glycine salt, lysine salt, arginine Mention may be made of amino acid salts such as salts, ornithine salts, glutamates and aspartates. From the viewpoint of stability
  • the salt based on an acidic group is preferably an alkali metal salt such as a sodium salt, potassium salt or lithium salt, an alkaline earth metal salt such as a calcium salt or magnesium salt, an aluminum salt or an iron salt.
  • Metal salt such as ammonium salt, t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, Triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethylanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) aminomethane Like salt And amine salts such as organic salts; and
  • naloxone hydrochloride is preferably administered in an amount of 0.2 ⁇ g / kg / hr to 4 ⁇ g / kg / hr between anesthesia and awakening, and 0.4 ⁇ g / kg / hr to 2 ⁇ g / hr. It is more preferable to administer in an amount of kg / hr. “After anesthesia” means after the start of administration of the anesthetic, and “until awake” ends the administration of the anesthetic and stabilizes the patient's breathing or consciousness without the assistance of an anesthesiologist Means up to.
  • the shivering inhibitor according to the present invention is preferably administered in combination with remifentanil or a pharmaceutically acceptable salt thereof as an anesthetic agent.
  • the term “combination” means administration under conditions that can exist simultaneously in the body of the administration subject, and if the conditions can exist in the body at the same time, they are administered simultaneously or separately at different times. May be. It is preferred that they are administered simultaneously as a mixed solution.
  • Remifentanil may be used alone or in the form of a pharmaceutically acceptable salt.
  • the “pharmaceutically acceptable salts thereof” of remifentanil can include the same salts as described for naloxone.
  • hydrochloride is preferable from the viewpoint of stability.
  • dosage forms of remifentanil include, but are not limited to, injection (intravenous, muscle, topical, etc.), oral administration, oral mucosal administration, intranasal administration, percutaneous absorption, and the like. Of these, intravenous injection (including infusion) is particularly preferred.
  • remifentanil in the case of infusion, can generally be administered at 0.05 ⁇ g / kg / min to 2 ⁇ g / kg / min, more preferably 0.05 ⁇ g / kg / min to 1 ⁇ g / kg / min. Further, the shivering inhibitor and remifentanil may be administered by the same route or by different routes.
  • the mixing ratio of remifentanil or a pharmaceutically acceptable salt to naloxone or a pharmaceutically acceptable salt thereof (the ratio at the time of combination) is From the above viewpoint, the mass ratio of remifentanil or a pharmaceutically acceptable salt to naloxone or a pharmaceutically acceptable salt thereof (remifentanil: naloxone) is preferably 500: 1 to 1: 1. Moreover, at the time of combined use, the administration rate of remifentanil may not be constant and may be administered rapidly.
  • the shivering inhibitor of the present invention may be used in combination with another anesthetic other than remifentanil from the viewpoint of sedation.
  • anesthetic agent that can be used in this way include propofol, an inhalation anesthetic sevoflurane (sevoflurane TM, Abbott), and the like.
  • the dosage of these other anesthetic agents that can be used in combination is appropriately selected according to the type of the other anesthetic used.
  • each of the shivering inhibitor of the present invention, remifentanil or a pharmaceutically acceptable salt, and other anesthetics used in combination (in the present specification, each drug is collectively referred to as “pharmaceutical formulation”). May also be administered orally as the dosage form.
  • the pharmaceutical preparation of the present invention can be used as a preparation capable of oral administration such as tablets, capsules, pills, granules or fine granules, but is preferably a tablet.
  • the pharmaceutical preparation may contain pharmaceutically acceptable additives as appropriate.
  • additives include, for example, excipients (eg sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbitol; corn starch, potato starch, pregelatinized starch, dextrin, carboxymethyl starch, carboxymethyl starch sodium Starch derivatives such as: pregelatinized starch; cellulose such as crystalline cellulose, methylcellulose, hydroxypropylcellulose, low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carmellose, carmellose calcium, croscarmellose, croscarmellose sodium Derivatives; gum arabic; dextran; pullulan; light anhydrous silicic acid, calcium silicate, silicate hydrate, synthetic aluminum silicate, metasilicate aluminate Silicate derivatives such as gnesium; phosphate derivatives such as dicalcium phosphate; chloride derivatives such as sodium chloride; carbonate derivatives such as calcium
  • the content of the binder is generally 1 to 10 parts by weight (preferably 2 to 5 parts by weight) in the whole pharmaceutical preparation, and the content of the disintegrant is usually 1 to 40 parts by mass (preferably 5 to 30 parts by mass), and the content of lubricant is usually 0.1 to 10 parts by mass (preferably 0.5 to 3 parts by mass).
  • the content of the fluidizing agent is 0.1 to 10 parts by mass (preferably 0.5 to 5 parts by mass).
  • the pharmaceutical preparation of the present invention is easily produced by known methods (for example, a kneading method using water, a wet granulation method, etc.) using pharmaceutically acceptable additives.
  • Examples of such production include, for example, the addition of active ingredients, stabilizers, excipients, binders, disintegrants and other types of auxiliaries as required, and mixing with a high speed agitation granulator.
  • an aqueous solution of a binder is added to the obtained mixture and kneaded to obtain a granulated product.
  • the obtained granulated product is dried using a fluidized bed dryer, and the dried granulated product is forcibly passed through a screen using a crushing granulator and granulating agent.
  • other types of auxiliaries and the like may be added and mixed in a V-type mixer, and the resulting mixture may be tableted or filled into capsules to produce tablets or capsules, respectively. it can.
  • the obtained tablets can be sugar-coated or coated (preferably, coated) as necessary.
  • a coating solution consisting of hydroxypropylmethylcellulose, talc, titanium oxide, lactose, triacetin or polyethylene glycol, yellow iron or iron dioxide, and water in a pan coating machine. Film coating can be applied.
  • the kneaded product is granulated using an extrusion granulator, and then with a fence-type dryer Granules can be produced by forcing the dried granules to pass through a screen using a crushing and granulating machine.
  • the dosage and administration ratio of each pharmaceutical preparation used in the present invention can vary greatly depending on various conditions such as the activity of individual substances, patient symptoms, age, weight and the like.
  • the amount of naloxone or a pharmaceutically acceptable salt thereof contained in the shivering inhibitor is not particularly limited and is appropriately selected in a wide range, but is usually 1 to 70% by mass, preferably in the total mass of the shivering inhibitor. Is suitably contained in an amount of 1 to 40% by mass.
  • the dose varies depending on symptoms, age, body weight, dosage form, etc., but is usually 1 day for an adult (weight 50 kg), and the lower limit is 0.001 mg (preferably 0.01 mg, more preferably 0.1 mg).
  • the upper limit of 1.0 mg (preferably 0.5 mg, more preferably 0.4 mg) can be administered.
  • naloxone or a pharmaceutically acceptable salt thereof, or remifentanil or a pharmaceutically acceptable salt thereof, each of the above doses is divided once or several times as necessary, Each is administered at the same time or separately at different times.
  • the anesthetic agent of the present invention comprises remifentanil or a pharmaceutically acceptable salt and naloxone or a pharmaceutically acceptable salt thereof as active ingredients. Since this anesthetic contains naloxone or a pharmaceutically acceptable salt thereof together with remifentanil, which is an active ingredient as an anesthetic, or a pharmaceutically acceptable salt, remifentanil and naloxone can be conveniently administered by one administration. Can be used together. Thereby, generation
  • the present anesthetic agent may be in a form in which remifentanil or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof can be administered simultaneously, and one drug is preceded in the body before the other drug.
  • the anesthetic may be configured as an operable form, for example, a sustained release form. Examples of such forms include transdermal drugs.
  • details of remifentanil or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof, a form as a drug, and the like are the same as those described for the above-mentioned shivering inhibitor.
  • the mixing ratio of remifentanil or a pharmaceutically acceptable salt and naloxone or a pharmaceutically acceptable salt thereof is not particularly limited as long as it is within the above dose range.
  • the mass ratio of remifentanil or a pharmaceutically acceptable salt to naloxone or a pharmaceutically acceptable salt thereof is preferably 100: 1 to 10: 1 (remifentanil: naloxone).
  • the kit of the present invention is a kit for suppressing anesthesia and its side effects, a compartment containing remifentanil or a pharmaceutically acceptable salt thereof, and a compartment containing naloxone or a pharmaceutically acceptable salt thereof. And including. According to this kit, the shivering resulting from remifentanil can be conveniently suppressed.
  • the “compartment” in this kit is not particularly limited as long as it is an effective form because each drug exists independently without mixing, and may be, for example, a container or an individual packaging form. It may be in the form of a sheet-like area that is independently divided.
  • the kit may also contain instructions describing the method of anesthesia with remifentanil or a pharmaceutically acceptable salt, and the method of using naloxone or a pharmaceutically acceptable salt used in combination therewith. .
  • the dosage, dosage form, and mode of combined use of the shivering inhibitor and remifentanil or a pharmaceutically acceptable salt thereof in the kit of the present invention are the same as those described with respect to the shivering inhibitor.
  • the present invention also includes a shivering suppression method.
  • the method for inhibiting shivering of the present invention is a method for inhibiting shivering that occurs after administration of an anesthetic agent, wherein remifentanil or a pharmaceutically acceptable salt thereof is administered as the anesthetic agent (hereinafter referred to as “remifentanil administration”). Step)), administration of naloxone or a pharmaceutically acceptable salt thereof (hereinafter referred to as “naloxone administration step”).
  • naloxone administration step administration of naloxone or a pharmaceutically acceptable salt thereof
  • naloxone or a pharmaceutically acceptable salt thereof is administered at a rate of 0.2 ⁇ g / kg / hr to 4 ⁇ g / kg / hr immediately after administration of the anesthetic agent and from awakening. It is preferable to include it in order to surely suppress shivering.
  • each active ingredient in the method for inhibiting shivering of the present invention is the same as those described for the shivering inhibitor and anesthetic agent.
  • the remifentanil administration step and the naloxone administration step may be performed first or simultaneously.
  • n 25
  • naloxone administration group 21
  • Saline was administered to the subject group
  • naloxone hydrochloride 0.4 ⁇ g / kg / hr was administered to the naloxone administration group from immediately after induction of anesthesia to awakening. This dose corresponds to about one-tenth or less of the dose when naloxone hydrochloride is administered for the purpose of antagonism from arousal delay by narcotics.
  • the anesthesia method mainly consisted of total intravenous anesthesia using remifentanil (0.25 ⁇ g / kg / min) and propofol (3 ⁇ g / ml: predicted blood concentration) (dipribanTM, AstraZeneca).
  • remifentanil 0.25 ⁇ g / kg / min
  • propofol 3 ⁇ g / ml: predicted blood concentration
  • epidural anesthesia was used in combination.
  • the administration rate of remifentanil and propofol was adjusted based on the blood pressure or pulse of the patient.
  • body temperature was controlled with a warm air heating device with the target of an eardrum temperature of 36 ° C or higher.
  • Remifentanil or a pharmaceutically acceptable salt thereof a shivering inhibitor containing naloxone or a pharmaceutically acceptable salt thereof as an active ingredient, naloxone or a pharmaceutically acceptable salt thereof, and remifentanil or a pharmaceutically acceptable salt thereof
  • an anesthetic containing a salt and a kit shivering that occurs at the time of waking after anesthesia with remifentanil or within 2 hours after waking up can be suppressed.

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  • Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
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Abstract

L'invention porte sur un suppresseur de tremblement apte à supprimer les tremblements survenant après un dosage par un agent anesthésique, ledit agent anesthésique étant du remifentanil ou un sel pharmaceutiquement acceptable de celui-ci, et ledit suppresseur de tremblement comprenant du naloxone ou un sel pharmaceutiquement acceptable de celui-ci en tant qu'ingrédient actif, et sur un agent anesthésique comprenant, en tant qu'ingrédients actifs, du remifentanil ou un sel pharmaceutiquement acceptable de celui-ci et du naloxone ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/JP2010/072937 2009-12-18 2010-12-20 Suppresseur de tremblement Ceased WO2011074695A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2011546194A JPWO2011074695A1 (ja) 2009-12-18 2010-12-20 シバリング抑制剤

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2009-288524 2009-12-18
JP2009288524 2009-12-18

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WO2011074695A1 true WO2011074695A1 (fr) 2011-06-23

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PCT/JP2010/072937 Ceased WO2011074695A1 (fr) 2009-12-18 2010-12-20 Suppresseur de tremblement

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006504805A (ja) * 2002-11-01 2006-02-09 メディヴァンス インコーポレイテッド 低体温に冷却中のシバリング抑制
JP2007526796A (ja) * 2003-12-15 2007-09-20 アレックザ ファーマシューティカルズ， インコーポレイテッド 薬剤エアロゾル吸入による突出痛の治療

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006504805A (ja) * 2002-11-01 2006-02-09 メディヴァンス インコーポレイテッド 低体温に冷却中のシバリング抑制
JP2007526796A (ja) * 2003-12-15 2007-09-20 アレックザ ファーマシューティカルズ， インコーポレイテッド 薬剤エアロゾル吸入による突出痛の治療

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
HESHAM M.AMIN: "Naloxone-Induced and Spontaneous Reversal of Depressed Ventilatory Responses to Hypoxia during and after Continuous Infusion of Remifentanil or Alfentanil", THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 274, no. 1, 1995, pages 34 - 39 *
SATOSHI OSADA: "Suguni Yakudatsu Remifentanil (Ultiva) no Shiyoho Shiyojo no Ryuiten", THE JOURNAL OF JAPAN SOCIETY FOR CLINICAL ANESTHESIA, vol. 27, no. 5, 14 September 2007 (2007-09-14), pages 572 - 578 *
TATSUHIKO KANO: "Mitochondria Nokinsho Kanji ni Taisuru TIVA Keiken", JOURNAL OF CLINICAL ANESTHESIA, vol. 33, no. 7, 20 July 2009 (2009-07-20), pages 1199 - 1200 *
TOSHIHARU NOMURA: "Ultiva(Remifentanil En San En) Jochuyo 2mg-5mg no Yakurigakuteki Tokucho Oyobi Rinsho Shiken Seiseki", NIPPON YAKURI GAKKAISHI, vol. 130, no. 4, 1 October 2007 (2007-10-01), pages 321 - 329 *
TOSHIYA KOITABASHI: "Remifentanil Masui no Koyo to Fukusayo Taisaku", THE JOURNAL OF JAPAN SOCIETY FOR CLINICAL ANESTHESIA, vol. 29, no. 4, 15 July 2009 (2009-07-15), pages 455 - 466 *

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