COMPOSITIONS COMPRISING SUBSTITUTED BENZOFUROQUINOLIZINE AND alpha2-ADRENERGIC AGONISTS

Abstract

The present invention relates to compositions for facilitating absorption and distribution of α.sub.2-adrenergic agonists, where said composition comprises a substituted benzofuroquinolizine and a α.sub.2-adrenoceptor agonist selected from substituted imidazoles and substituted thiazines and the composition is administered using parenteral extravascular administration to a subject in need of sedation.

Claims

1.-36. (canceled)

37. A composition for use in sedation, wherein the composition consists of MK-467, an α.sub.2-adrenoceptor agonist selected from substituted imidazoles and substituted thiazines, and one or more of physiologically acceptable aqueous media, pharmaceutically acceptable carriers and pharmaceutically acceptable excipients, and the composition is administered using parenteral extravascular administration to a subject in need of sedation.

38. The composition according to claim 37 for use in sedation, wherein the α.sub.2-adrenoceptor agonist is medetomidine, dexmedetomidine, detomidine, romifidine, clonidine or xylazine.

39. The composition according to claim 37 for use in sedation, wherein the α.sub.2-adrenoceptor agonist is medetomidine, dexmedetomidine, detomidine, romifidine or xylazine.

40. The composition according to claim 37 for use in sedation, wherein the subject is selected from humans and animals, preferably from wild animals and domestic animals.

41. The composition according to claim 37 for use in sedation, wherein the animals are selected from vertebrates, preferably from mammals, fish, birds and reptiles.

42. The composition according to claim 37 for use in sedation, wherein the composition is administered to a subject to provide a dosage of 1-5000 μg/kg of MK-467 and 0.1-20000 μg/kg of the α.sub.2-adrenoceptor agonist.

43. The composition according to claim 37 for use in sedation, wherein the composition is selected from solutions for intramuscular use and subcutaneous use; from gels, sprays, ointments, creams and patches for transdermal use; and from gels, ointments, creams, sprays and suppositories for transmucousal use.

44. The composition according to claim 37 for use in sedation, wherein the composition comprises 0.1-1000 mg/ml of MK-467 and 0.01-500 mg/ml of the α.sub.2-adrenoceptor agonist.

45. The composition according to claim 37 for use in sedation, wherein the composition is a solution for intramuscular use or subcutaneous use and it comprises 0.1-500 mg/ml of MK-467 and 0.01-500 mg/ml of the α.sub.2-adrenoceptor agonist.

46. The composition according to claim 37 for use in sedation, wherein the composition is a gel, spray, ointment, cream or patch for transdermal use and it comprises 0.1-1000 mg/ml of MK-467 and 0.01-500 mg/ml of the α.sub.2-adrenoceptor agonist.

47. The composition according to claim 37 for use in sedation, wherein the composition is a gel, ointment, cream, spray or suppository for transmucousal use and it comprises 0.1-1000 mg/ml of MK-467 and 0.01-100 mg/ml of the α.sub.2-adrenoceptor agonist.

48. The composition according to claim 37, wherein an α.sub.2-adrenoceptor antagonist selected from idazoxan, tolazoline, yohimbine, rauwolskine, atipamezole, mirtazapine and (±)-2-methyl-1,2,3,4,10,14b-hexahydropyrazino[2,1-a]pyrido[2,3-c][2]benzazepine is administered to the subject for use in reversing the sedation.

49. A method for sedation, where a composition consisting of MK-467, an α.sub.2-adrenoceptor agonist selected from substituted imidazoles and substituted thiazines, and one or more of physiologically acceptable aqueous media, pharmaceutically acceptable carriers and pharmaceutically acceptable excipientsis, is administered to a subject in need of sedation, wherein said administration is parenteral extravascular administration.

50. The method according to claim 49, wherein the α.sub.2-adrenoceptor agonist is medetomidine, dexmedetomidine, detomidine, romifidine, clonidine or xylazine.

51. The method according to claim 49, wherein the α.sub.2-adrenoceptor agonist is medetomidine, dexmedetomidine, detomidine, romifidine or xylazine.

52. The method according to claim 49, wherein the subject is selected from humans and animals, preferably from wild animals and domestic animals.

53. The method according to claim 49, wherein the animals are selected from vertebrates, preferably from mammals, fish, birds and reptiles.

54. The method according to claim 49, wherein the composition is administered to a subject to provide a dosage of 1-5000 μg/kg of MK-467 and 0.1-20000 μg/kg of the α.sub.2-adrenoceptor agonist.

55. The method according to claim 49, wherein the composition is selected from solutions for intramuscular use and subcutaneous use; from gels, sprays, ointments, creams and patches for transdermal use; and gels, ointments, creams, sprays and suppositories for transmucousal use.

56. The method according to claim 49, wherein the composition comprises 0.1-1000 mg/ml of MK-467 and 0.01-500 mg/ml of the α.sub.2-adrenoceptor agonist.

57. The method according to claim 49, wherein the composition is a solution for intramuscular use or subcutaneous use and it comprises 0.1-500 mg/ml of MK-467 and 0.01-500 mg/ml of the α.sub.2-adrenoceptor agonist.

58. The method according to claim 49, wherein the composition is a gel, spray, ointment, cream or patch for transdermal use and it comprises 0.1-1000 mg/ml of MK-467 and 0.01-500 mg/ml of the α.sub.2-adrenoceptor agonist.

59. The method according to claim 49, wherein the composition is a gel, ointment, cream, spray or suppository for transmucousal use and it comprises 0.1-1000 mg/ml of MK-467 and 0.01-100 mg/ml of the α.sub.2-adrenoceptor agonist.

60. The method according to claim 49, wherein an α.sub.2-adrenoceptor antagonist selected idazoxan, tolazoline, yohimbine, rauwolskine, atipamezole, mirtazapine and (±)-2-methyl-1,2,3,4,10,14b-hexahydropyrazino[2,1-a]pyrido[2,3-c][2]benzazepine is administered to the subject for use in reversing the sedation.

61. MK-467 for use in facilitating absorption and distribution of an α.sub.2-adrenoceptor agonist, wherein a composition consisting of MK-467, a α.sub.2-adrenoceptor agonist selected from substituted imidazoles and substituted thiazines, and one or more of physiologically acceptable aqueous media, pharmaceutically acceptable carriers and pharmaceutically acceptable excipients, is administered to a subject in need of sedation using parenteral extravascular administration.

62. MK-467 for use in facilitating absorption and distribution of the α.sub.2-adrenoceptor agonist according to claim 61, wherein the α.sub.2-adrenoceptor agonist is medetomidine, dexmedetomidine, detomidine, romifidine, clonidine or xylazine.

63. MK-467 for use in facilitating absorption and distribution of the α.sub.2-adrenoceptor agonist according to claim 61, wherein the α.sub.2-adrenoceptor agonist is medetomidine, dexmedetomidine, detomidine, romifidine or xylazine.

64. MK-467 for use in facilitating absorption and distribution of the α.sub.2-adrenoceptor agonist according to claim 61, wherein the subject is selected from humans and animals, preferably from wild animals and domestic animals.

65. MK-467 for use in facilitating absorption and distribution of the α.sub.2-adrenoceptor agonist according to claim 61, wherein the animals are selected from vertebrates, preferably from mammals, fish, birds and reptiles.

66. MK-467 for use in facilitating absorption and distribution of the α.sub.2-adrenoceptor agonist according to claim 61, wherein the composition is administered to a subject to provide a dosage of 1-5000 μg/kg of MK-467 and 0.1-20000 μg/kg of the α.sub.2-adrenoceptor agonist.

67. MK-467 for use in facilitating absorption and distribution of α.sub.2-adrenoceptor agonist according to claim 61, wherein the composition is selected from solutions for intramuscular use and subcutaneous use; from gels, sprays, ointments, creams and patches for transdermal use; and gels, ointments, creams, sprays and suppositories for transmucousal use.

68. MK-467 for use in facilitating absorption and distribution of the α.sub.2-adrenoceptor agonist according to claim 61, wherein the composition comprises 0.1-1000 mg/ml of MK-467 and 0.01-500 mg/ml of the α.sub.2-adrenoceptor agonist.

69. MK-467 for use in facilitating absorption and distribution of the α.sub.2-adrenoceptor agonist according to claim 61, wherein the composition is a solution for intramuscular use or subcutaneous use and it comprises 0.1-500 mg/ml of MK-467 and 0.01-500 mg/ml of the α.sub.2-adrenoceptor agonist.

70. MK-467 for use in facilitating absorption and distribution of the α.sub.2-adrenoceptor agonist according to claim 61, wherein the composition is a gel, spray, ointment, cream or patch for transdermal use and it comprises 0.1-1000 mg/ml of MK-467 and 0.01-500 mg/ml of the α.sub.2-adrenoceptor agonist.

71. MK-467 for use in facilitating absorption and distribution of the α.sub.2-adrenoceptor agonist according to claim 61, wherein the composition is a gel, ointment, cream, spray or suppository for transmucousal use and it comprises 0.1-1000 mg/ml of MK-467 and 0.01-100 mg/ml of the α.sub.2-adrenoceptor agonist.

72. MK-467 for use in facilitating absorption and distribution of the α.sub.2-adrenergic agonist according to claim 61, wherein an α.sub.2-adrenoceptor antagonist selected from idazoxan, tolazoline, yohimbine, rauwolskine, atipamezole, mirtazapine and (±)-2-methyl-1,2,3,4,10,14b-hexahydropyrazino[2,1-a]pyrido[2,3-c][2]benzazepine is administered to the subject for use in reversing the sedation.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0045] FIG. 1 presents sedation scores (mean±SD) of beagle dogs (n=8), treated IM with medetomidine 20 μg/kg (MED), medetomidine 20 μg/kg+MK-467 200 μg/kg (MK200), medetomidine 20 μg/kg+MK-467 400 μg/kg (MK400) and medetomidine 20 μg/kg+MK-467 600 μg/kg (MK600) mixed in the same syringe.

[0046] FIG. 2 presents plasma dexmedetomidine concentrations (mean±SD; ng/mL) of beagle dogs (n=8) treated IM with medetomidine 20 μg/kg (MED), medetomidine 20 μg/kg+MK-467 200 μg/kg (MK200), medetomidine 20 μg/kg+MK-467 400 μg/kg (MK400) and medetomidine 20 μg/kg+MK-467 600 μg/kg (MK600) mixed in the same syringe.

[0047] FIG. 3 shows sedation scores (mean±CI95%) of beagle dogs (n=7) treated with medetomidine (20 μg/kg IM, solid line), or medetomidine (20 μg/kg IM) and MK-467 (400 μg/kg IM) mixed in the same syringe (dotted line), at 0 min. Atipamezole (100 μg/kg IM) was administered at 30 min (arrow).

DETAILED DESCRIPTION OF THE INVENTION

[0048] It was surprisingly found that after parenteral extravascular administration of a composition comprising MK-467 and α.sub.2-adrenoceptor agonist to a subject in need of treatment, particularly sedation, the absorption rate and the speed of distribution of the α.sub.2-adrenoceptor agonist is increased. With the invention the development of sedative effect was accelerated even four fold when compared with administration of the α.sub.2-adrenoceptor agonist without MK-467. Particularly the composition consists of MK-467, a α.sub.2-adrenergic agonist selected from substituted imidazoles and substituted thiazines, pharmaceutically acceptable carriers and pharmaceutically acceptable excipients and the composition is administered using parenteral extravascular administration to a subject in need of sedation.

[0049] The treatment refers particularly to sedation, and it includes tranquillization, immobilization, muscle relaxation, analgesia, and premedication.

[0050] The active compounds MK-467 and α.sub.2-adrenoceptor agonist are administered in one composition, locally, at the same time and to the same site of administration, whereby surprisingly fast absorption and distribution are achieved. MK-467 is effective after parenteral extravascular administration, when combined to a drug having its actions via α.sub.2-adrenoceptors including α.sub.2-adrenoceptor agonists, which are used for treating an animal species for sedation, including tranquillization, immobilization, analgesia, and premedication. MK-467 acts as α.sub.2-adrenoceptor antagonist on postsynaptically located receptors on the vascular smooth muscle cells. The adverse effects of α.sub.2-adrenoceptor agonists can be reduced or even avoided after parenteral extravascular administration of the composition comprising MK-467 and α.sub.2-adrenoceptor agonist to a subject.

[0051] MK-467 is also effective when used with other α.sub.2-adrenoceptor antagonists which are used to prevent and/or reverse the effects of any alpha-2 adrenoceptor agonists in an animal species.

[0052] It was surprising found that effects of alpha-2 adrenoceptor agonists (induced by the composition of the invention) can be rapidly reversed, after an operation or procedure is finished or it is desirable for another reason to reverse the effects, by administering the α.sub.2-adrenoceptor antagonists to the subject, preferably by IM administration.

[0053] The present invention relates to the use of MK-467 for enhancing and/or facilitating absorption and distribution of α.sub.2-adrenergic agonist, where a composition comprising MK-467 and a α.sub.2-adrenergic agonist selected from substituted imidazoles and substituted thiazines is administered using parenteral extravascular administration to a subject in need of sedation.

[0054] According to another embodiment the present invention is directed to a composition comprising MK-467 and a α.sub.2-adrenergic agonist selected from substituted imidazoles and substituted thiazines for use in sedation, where the composition is administered using parenteral extravascular administration to a subject in need of sedation.

[0055] According to another embodiment the present invention is directed to a composition comprising MK-467 and a α.sub.2-adrenergic agonist selected from substituted imidazoles and substituted thiazines for use in sedation, where the composition is administered using parenteral extravascular administration to a subject in need of sedation, and α.sub.2-adrenoceptor antagonist is administered to the subject for use in reversing the sedation.

[0056] According to another embodiment the present invention relates to a method for sedation, where a composition comprising MK-467 and α.sub.2-adrenergic agonist selected from substituted imidazoles and substituted thiazines is administered to a subject in need of sedation, using parenteral extravascular administration.

[0057] The present invention also relates to a method for sedation, where a composition comprising MK-467 and a α.sub.2-adrenergic agonist selected from substituted imidazoles and substituted thiazines is administered to the subject using parenteral extravascular administration, followed by reversing the sedation by administering α.sub.2-adrenoceptor antagonist to the subject. In this embodiment the method for sedation includes sedation and reversing of sedation.

[0058] The composition of the invention is administered to a subject to provide a prescribed or approved dosage of the α.sub.2-adrenoceptor agonist. The dosage of the α.sub.2-adrenoceptor agonist depends of compound which is used and on the subject which receives treatment. Any doses of the α.sub.2-adrenoceptor agonist which are used to treat humans or any domestic or wild animal species are suitable.

[0059] The subject is selected from humans and animals. The animals are understood to mean vertebrate animal species selected from domestic animals and wild animals, including mammals, fish, birds, and reptiles. Examples of said animals are wild animals, animals kept is parks and zoos, laboratory animals, pets and livestock. The domestic animals include dogs, cats, rodents, reptiles, birds and other pets, horses, donkeys, pigs, bovine animals, sheep, goats, poultry, fish etc.

[0060] According to still another embodiment the present invention is directed to a method for enhancing and/or facilitating absorption and distribution of α.sub.2-adrenergic agonist, where a composition comprising MK-467 and a α.sub.2-adrenergic agonist is administered using parenteral extravascular administration to a subject in need of treatment.

[0061] MK-467 refers here to a peripherally acting α.sub.2-adrenoceptor antagonist, known also by code as L-659,066. MK-467 has the following systematic chemical name N-[2-[(2R,12bS)-2′-oxospiro[1,3,4,6,7,12b-hexahydro-[1]benzofuro[2,3-a]quinolizine-2,5′-imidazolidine]-1′-yl]-ethyl]-methanesulfonamide (IUPAC). It is a spirocyclic substituted benzofuroquinolizine having the chemical formula I:

##STR00001##

[0062] The composition of the invention is administered to a subject to provide a dosage of 1-5000 μg/kg of MK-467, preferably 10-3000 μg/kg of MK-467, particularly preferably 50-1500 μg/kg of MK-467.

[0063] The α.sub.2-adrenoceptor agonist is selected from peripherally acting α.sub.2-adrenoceptor agonists. Suitable α.sub.2-adrenoceptor agonists are substituted imidazoles and substituted thiazines.

[0064] Preferably the α.sub.2-adrenoceptor agonist is medetomidine ((RS)-4-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole of formula II), dexmedetomidine ((S)-4-[1-(2,3-Dimethylphenyl)ethyl]-3H-imidazole of formula III), detomidine (4-[(2,3-dimethylphenyl)methyl]-3H-imidazole of formula IV), romifidine (N(2-bromo-6-fluorophenyl)-4,5-dihydro-1H-imidazol-2-amine of formula V, clonidine (N-(2,6-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine of formula VI) or xylazine (N-(2,6-dimethylphenyl)-5,6-dihydro-4H-1,3-thiazin-2-amine of formula VII), which are all structurally similar to each other. Particularly preferably the α.sub.2-adrenoceptor agonist is detomidine, medetomidine, dexmedetomidine, romifidine or xylazine. Also any pharmaceutically acceptable salts of said compounds may be used in the invention.

##STR00002##

[0065] The dosage of detomidine is suitably 0.1-5000 μg/kg, preferably 0.2-3000 μg/kg, particularly preferably 0.5-1000 μg/kg.

[0066] The dosage of medetomidine is suitably 0.1-5000 μg/kg, preferably 0.2-3000 μg/kg, particularly preferably 0.5-1000 μg/kg.

[0067] The dosage of dexmedetomidine is suitably 0.05-3000 μg/kg, preferably 0.1-2000 μg/kg, particularly preferably 0.1-1000 μg/kg.

[0068] The dosage of romifidine is suitably 0.1-5000 μg/kg, preferably 0.2-3000 μg/kg, particularly preferably 0.5-1500 μg/kg.

[0069] The dosage of clonidine is suitably 0.1-5000 μg/kg, preferably 0.2-3000 μg/kg, particularly preferably 0.5-1000 μg/kg.

[0070] The dosage of xylazine is suitably 1-20000 μg/kg, preferably 10-10000 μg/kg, particularly preferably 50-5000 μg/kg.

[0071] According to the invention both compounds MK-467 and the α.sub.2-adrenoceptor agonist are administered at the same time, in the same composition, to the same administration site of the subject, using parenteral extravascular administration. Particularly the composition consists of MK-467, a α.sub.2-adrenergic agonist selected from substituted imidazoles and substituted thiazines, pharmaceutically acceptable carriers and pharmaceutically acceptable excipients and the composition is administered using parenteral extravascular administration to a subject in need of sedation.

[0072] Preferably the administration of the composition is carried out by the intramuscular route (IM), subcutaneous route (SC), transdermal route, or transmucousal route.

Composition

[0073] Examples of the compositions of the invention, for parenteral extravascular administration, comprise solutions for intramuscular use and subcutaneous use (IM and SC solutions); gels, sprays, ointments, creams and patches for transdermal use (transdermal gels, sprays, ointments, creams and patches); and gels, ointments, creams, sprays and suppositories for transmucousal use (transmucousal gels, ointments, creams, sprays and suppositories). Transmucousal use includes here also sublingual and intravaginal administration.

[0074] Solutions for intramuscular (IM) and subcutaneous (SC) use may comprise saline or another physiologically acceptable aqueous medium, where MK-467 and the α.sub.2-adrenoceptor agonist are dissolved to desired concentrations. Pharmaceutically acceptable excipients, such as solubility and stability enhancing agents and preservatives, known in the art may be added if necessary to the composition.

[0075] For example, the IM or SC composition may comprise 0.1-500 mg/ml of MK-467 and 0.01-500 mg/ml of the α.sub.2-adrenoceptor agonist and a suitable preservative. Sterile solutions for intramuscular (IM) and subcutaneous use may be packed in any vials, bottles, syringes etc devices or containers known in the art.

[0076] Compositions for transdermal use may comprise one or more pharmaceutically acceptable carriers, supports, MK-467 and the α.sub.2-adrenoceptor agonist in dissolved state in a pharmaceutically acceptable medium, and excipients, including preservatives known in the art, depending whether the compositions is in the form of a gel, spray, cream, ointment or patch etc.

[0077] For example, the transdermal composition may comprise 0.1-1000 mg/ml of MK-467 and 0.01-500 mg/ml of the α.sub.2-adrenoceptor agonist.

[0078] Compositions for transmucousal use may comprise one or more pharmaceutically acceptable carriers, MK-467 and the α.sub.2-adrenoceptor agonist in dissolved state in a pharmaceutically acceptable medium, and excipients including preservatives known in the art, depending whether the compositions is in the form of a gel, spray, ointment or cream etc.

[0079] For example an oromucosal gel for sublingual use may comprise 0.1-1000 mg/ml of MK-467 and 0.01-100 mg/ml of the α.sub.2-adrenoceptor agonist, dissolved in an aqueous carrier, optionally with solubility enhancing agent(s) and surfactant(s), where said composition is formed to a gel with a gelforming agent, such as hydroxypropylcellulose or the like.

Reversing of Effects of α.SUB.2.-Adrenoceptor Agonist

[0080] As a further advantage of the invention it was surprisingly found that when a α.sub.2-adrenoceptor antagonist, other than MK-467, was used for reversing the central and peripheral effects of the α.sub.2-adrenoceptor agonist after administration of the composition of the invention to a subject, such as an animal, the recovery of the subject takes place more smoothly and rapidly because MK-467 also enhances distribution and absorption of said α.sub.2-adrenoceptor antagonists, which in turn facilitates the elimination of the α.sub.2-adrenoceptor agonist.

[0081] α.sub.2-adrenoceptor antagonists, other than MK-467, are used to prevent and/or reverse the effects of α.sub.2-adrenoceptor agonists. α.sub.2-adrenoceptor antagonists useful for reversing effects of substituted imidazoles and substituted thiazines are selected from a group consisting of idazoxan, tolazoline, yohimbine, rauwolskine, atipamezole, mirtazapine and (±)-2-methyl-1,2,3,4,10,14b-hexahydropyrazino[2,1-a]pyrido[2,3-c][2]benzazepine. In a preferable embodiment atipamezole is used.

[0082] Said α.sub.2-adrenoceptor antagonists are administered using parenteral extravascular administration, suitably using IM or SC administration. The dosage of the α.sub.2-adrenoceptor antagonists is generally from 10 to 1000 μg/kg, depending on the subject and the α.sub.2-adrenoceptor agonist used. Preferably IM administration is used.

[0083] Atipamezole is a specific α.sub.2-adrenoceptor antagonist, which is used commonly for reversing the central and peripheral effects of medetomidine and dexmedetomidine in animals.

[0084] The present invention provides several advantages to the subject and to the practitioner. The inventors have found that after parenteral extravascular administration of the composition comprising MK-467 and α.sub.2-adrenoceptor agonist to a subject, such as an animal, in need of sedation, the absorption rate and the speed of distribution of the α.sub.2-adrenoceptor agonist is increased even four fold when compared with administration of the α.sub.2-adrenoceptor agonist without MK-467. The onset of action of the α.sub.2-adrenoceptor agonist, particularly sedation starts more rapidly as can be seen from the examples. Long waiting periods can be avoided as less time is needed before an operation or procedure can be started. Further, the effects of the α.sub.2-adrenoceptor agonist are reversed faster due to the improved distribution and absorption of α.sub.2-adrenoceptos antagonists, the animal recovers more rapidly and long recovery periods after the operation or procedure can be avoided or at least decreased significantly.

[0085] The wellbeing of the animal is improved because of less side-effects, easier administration, faster induction and recovery when sedatives are used and shorter and smoother visits to the veterinarian. Also potential re-sedation after the reversing α.sub.2-adrenoceptor antagonist, such as atipamezole, induced recovery from sedation is inhibited by the invention and the composition comprising MK-467 and the α.sub.2-adrenoceptor agonist.

[0086] More patients can be treated with a period of time as long waiting periods can be avoided both in the onset of sedation and recovery, which increases the productivity of the veterinarian and brings economic advantages.

[0087] Further, as the onset of the sedative action is faster, potentially dangerous animals can be sedated without unnecessary delay, which also increases the safety of the veterinarian.

EXAMPLES

[0088] The invention will now be illustrated with the following examples and with reference to the drawings.

Example 1

[0089] Sedation of Dogs with Medetomidine+MK-467, IM Administration with One Composition

[0090] The study was designed as a prospective, randomized, experimental cross-over study.

[0091] Each dog (n=8) received four different treatments with 14-days washout periods: [0092] Medetomidine 20 μg/kg IM [0093] Medetomidine 20 μg/kg+MK-467 200 μg/kg IM [0094] Medetomidine 20 μg/kg+MK-467 400 μg/kg IM [0095] Medetomidine 20 μg/kg+MK-467 600 μg/kg IM

[0096] MK-467 was diluted immediately prior to administration with standard saline solution to a concentration of 10 mg/ml. Prior to the intramuscular injection, calculated doses of medetomidine (1 mg/ml) and MK-467 were separately aspirated into two syringes. The contents of both syringes were mixed in a third, separate, empty syringe.

[0097] Sedation was scored by a veterinarian blinded for treatment with the following score:

Composite Sedation Score (0-16)

1. Palpebral Reflex (0-3)

[0098] 0 Normal [0099] 1 Slightly reduced [0100] 2 Weak [0101] 3 Absent

2. Position of the Eye (0-2)

[0102] 0 Middle [0103] 2 Turned down

3. Jaw and Tongue Relaxation (0-4)

[0104] 0 Normal, opens the jaws but resists manipulation of the tongue [0105] 1 Bites jaws together [0106] 2 Opens the jaws but strong resistance when tongue is pulled [0107] 3 Slight resistance when tongue is pulled [0108] 4 No resistance

4. Resistance to Positioning in Lateral Recumbency (0-3)

[0109] 0 Normal [0110] 1 Turns back to sternal position [0111] 2 Some resistance but stays in lateral recumbency [0112] 3 No resistance or the position is already lateral

5. General Appearance (0-4)

[0113] 0 Normal [0114] 1 Slightly tired, head drooping [0115] 2 Mild sedation, reacts clearly to surroundings [0116] 3 Moderate sedation, reacts slightly to surroundings [0117] 4 Deep sedation, no reaction to surroundings

[0118] The concentrations of dexmedetomidine and levomedetomidine in plasma were determined with HPLC-MS/MS.

[0119] In FIG. 1 sedation scores (mean±SD) of beagle dogs (n=8), treated with medetomidine 20 μg/kg (MED), medetomidine 20 μg/kg+MK-467 200 μg/kg (MK200), medetomidine 20 μg/kg+MK-467 400 μg/kg (MK400) and medetomidine 20 μg/kg+MK-467 600 μg/kg (MK600) are shown. The drugs were mixed in the same syringe and administered intramuscularly at time 0 min. It can be seen that the onset of the sedation was faster and the maximum sedative effect was better with MK-467. FIG. 1 also shows that the dogs recovered faster from sedation when MK-467 was used concomitantly with the sedative drug.

[0120] FIG. 2 shows plasma dexmedetomidine concentrations (mean±SD; ng/mL) measured during the same study as in FIG. 1. From FIG. 2 it can be concluded that the absorption of medetomidine was faster and the maximum plasma concentration was higher with MK-467, which explains the faster and deeper sedation seen in FIG. 1.

Example 2

[0121] Sedation with Medetomidine and MK-467 IM in One Composition, Followed by Reverse with Atipamezole

[0122] The study was designed as a prospective, randomized, experimental cross-over study.

[0123] Each dog (n=7) was treated twice with a 14-days washout period: [0124] Medetomidine (20 μg/kg) at 0 min, followed by Atipamezole (100 μg/kg) at 30 min [0125] Medetomidine (20 μg/kg)+MK-467 (400 μg/kg) at 0 min, followed by Atipamezole (100 μg/kg) at 30 min

[0126] Medetomidine and MK-467 were mixed in the same syringe and administered intramuscularly.

[0127] Sedation was scored by a veterinarian blinded for treatment with the following score:

Composite Sedation Score (0-20)

1. Position (0-4)

[0128] 0 Standing [0129] 1 Standing but staggers [0130] 2 Sternal head up [0131] 3 Sternal head down [0132] 4 Lateral head down

2. Palpebral Reflex (0-3)

[0133] 0 Normal [0134] 1 Slightly reduced [0135] 2 Weak [0136] 3 Absent

3. Position of the Eye (0-2)

[0137] 0 Middle [0138] 2 Turned down

4. Jaw and Tongue Relaxation (0-4)

[0139] 0 Normal, opens the jaws but resists manipulation of the tongue [0140] 1 Bites jaws together [0141] 2 Opens the jaws but strong resistance when tongue is pulled [0142] 3 Slight resistance when tongue is pulled [0143] 4 No resistance

5. Resistance to Positioning in Lateral Recumbency (0-3)

[0144] 0 Normal [0145] 1 Turns back to sternal position [0146] 2 Some resistance but stays in lateral recumbency [0147] 3 No resistance or the position is already lateral

6. General Appearance (0-4)

[0148] 0 Normal [0149] 1 Slightly tired, head drooping [0150] 2 Mild sedation, reacts clearly to surroundings [0151] 3 Moderate sedation, reacts slightly to surroundings [0152] 4 Deep sedation, no reaction to surroundings

[0153] In FIG. 3 the sedation scores (mean±CI95%) of dogs (n=7) treated with medetomidine (20 μg/kg IM, solid line), and medetomidine (20 μg/kg IM) and MK-467 (400 μg/kg IM) mixed in the same syringe (dotted line), at 0 min are presented. Atipamezole (100 μg/kg IM) was administered at 30 min (arrow). It can be seen that atipamezole reversed the medetomidine induced sedation when medetomidine was given alone or when given concomitantly with MK-467. However, when MK-467 was co-administered with medetomidine in the same syringe the resedation seen in dogs treated with medetomidine alone was prevented.

Example 3

[0154] Study with MK-467 and Detomidine when Administered as Oromucosal Gel in Sheep

[0155] The objective of the study is to evaluate the effect of MK-467 on the transmucosal absorption rate of detomidine when administered as oromucosal gel in sheep. The results will show that MK-467 incorporated in detomidine oromucosal gel increases the transmucosal absorption rate of detomidine, which will be detected by decreased time to maximum concentration (T.sub.max) and increased maximum plasma concentration of detomidine (C.sub.max).

[0156] Study design: Randomized, prospective, cross-over study with at least seven days wash-out period.

[0157] Animals: Three sheep

[0158] Methods: Each sheep will get two treatments:

[0159] 1. detomidine (50 μg/kg) oromucosal gel sublingually

[0160] 2. detomidine (50 μg/kg) oromucosal gel mixed with MK-467 (500 μg/kg) sublingually

[0161] Blood will be collected at 5, 10, 15, 20, 25, 30, 40, 50 and 60 minutes after drug administration, and plasma drug concentrations will be analysed with liquid chromatography and tandem mass spectrometry (LC/MS/MS). Maximum plasma concentration of detomidine (C.sub.max) and the time to maximum concentration (T.sub.max) will be calculated from the plasma detomidine concentration-time data.

[0162] The present invention has been described herein with reference to specific embodiments. It is, however clear to those skilled in the art that the invention may be varied within the bounds of the claims.