Pharmaceutical composition and device for treating pain

Abstract

The invention relates to a system for the sequential intranasal administration of at least one active ingredient selected from a DR group having at least one side effect of respiratory depression and at least one active ingredient selected from an ADR group that counteracts the respiratory depression that may be induced by the active ingredients of the DR group. The invention also relates to a portable sequential intranasal administration device comprising an intranasal administration system according to the principles of the invention.

Claims

1. A method for sequential intranasal administration of at least one active ingredient selected from a DR group having at least one side effect of respiratory depression and at least one active ingredient selected from an ADR group that counteracts respiratory depression that may he induced by the at least one active ingredient of the DR group, the method comprising: administering, from a first storage space, an initial dose of a first active formulation comprising the at least one active ingredient selected from the DR group, in response to an initial actuation of a portable sequential intranasal administration medical device by a patient wishing to receive pharmaceutical administration; and after administering the initial dose, administering, from at least a second storage space, at least one subsequent dose of a second active formulation different from the first active formulation comprising the at least one active ingredient selected from the ADR group without administering the first active formulation, in response to at least one subsequent actuation of the portable sequential intranasal administration medical device by the patient wishing to receive subsequent pharmaceutical administration.

2. The method for sequential intranasal administration of claim 1, wherein the first active formulation further comprises at least one active ingredient from the ADR group.

3. The method for sequential intranasal administration of claim 2, wherein the at least one active ingredient from the ADR group of the first active formulation is identical to the at least one active ingredient from the ADR group of the second active formulation.

4. The method for sequential intranasal administration of claim 1, wherein the portable sequential intranasal administration medical device comprises at least one device for measuring at least one of time or at least one biological parameter, the method further comprising measuring at least one of time or at least one biological parameter via the at least one device, wherein administering the at least one subsequent dose is based on the measured time and/or the at least one biological parameter.

5. The method for sequential intranasal administration of claim 4, wherein the at least one device for measuring at least one of time or at least one biological parameter is configured to measure at least one of oxygen saturation or respiratory rate.

6. The method for sequential intranasal administration of claim 1, wherein the second active formulation further comprises at least one active ingredient from the DR group.

7. The method for sequential intranasal administration of claim 6, wherein the at least, one active ingredient from the DR group of the second active formulation is identical to the at least one active ingredient from the DR group of the first active formulation.

8. The method for sequential intranasal administration of claim 1, wherein the at least one active ingredient from the DR group is selected from a group consisting of benzodiazepines and the least one active ingredient from the ADR group is flumazenil.

9. The method for sequential intranasal administration of claim 1, wherein the at least one active ingredient from the DR group is sufentanil and the at least one active ingredient from the ADR group is naloxone.

10. The method for sequential intranasal administration of claim 1, wherein the at least one active ingredient from the DR group is selected from a group consisting of opioid agonists and the at least one active ingredient from the ADR group is selected from a group consisting of opioid antagonists.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 illustrates an exemplary embodiment of a portable device for sequential intranasal administration in accordance with the principles of the present invention.

(2) FIG. 2 is an exemplary embodiment of a schematic block diagram illustrating various features of the device of FIG. 1 in accordance with the principles of the present invention.

DETAILED DESCRIPTION

(3) FIG. 1: example device according to the invention

(4) FIG. 1 illustrates portable device 1 for intranasal administration in according with the principles of the present disclosure. First storage space 2 may contain first active formulation 12 comprising active ingredient from the DR group 12a and active ingredient from the ADR group 12b. Second storage space 3 may contain second active formulation 11 comprising at least one active ingredient from the ADR group 11a.

(5) Signal processing unit 4 may be connected to linking means 5. Linking means 5 comprises dosage chamber 5a, valve Sc having valve shaft 5b, and ducts 5d and 5e connected to first and second storage spaces 3 and 2 respectively. Signal processing unit 4 may also be connected to information means 6. Information means 6 may comprise clock 6a, respiratory rate sensor 6b, and/or oximeter 6c.

(6) When using device 1, the user inserts nosepiece 7a into the nasal cavity of the patient. Information means, for example oximeter 6c and/or respiratory rate sensor 6b, may measure and determine values, and communicate the values to signal processing unit 4. Signal processing unit 4 may also communicate with 6a clock to calculate the time elapsed since the last administration of active formulation 12. Alternatively, signal processing unit 4 may have a clock, e.g., a PSTN circuit, or other timer integrated therewith to avoid providing a separate clock.

(7) When the user activates control means 8, illustrated in FIG. 1 as push button 8a, signal processing unit 4, based on information provided by information means 6, controls linking via linking means 5 of either first storage space 2 or second storage space 3 with dispensing means 7, e.g., nosepiece 7a, specifically through dispensing duct 5f.

(8) As shown in FIG. 1, linking comprises actuating valve Sc mounted on valve shaft 5b inside dosage chamber 5a. Valve Sc may switch to either side of valve shaft 5b to be pressed against a side wall of dosage chamber 5a, and thus may close one of ducts 5d or 5e based on the active formulation to be administered as determined by signal processing unit 4.

(9) The active formulation selected to be administered from device 1 flows through dispensing duct 5f and exits from outlet 13 before being brought into contact with the nasal mucosa.

(10) At any time, the user may obtain information about the active formulation administered from activating pushbutton 8a through patient signal means 9, e.g., light 9a.

(11) The user may then decide whether to activate push button 8a.

(12) Device 1 may include autonomous power source 10. Autonomous power source 10 supplies power to device 1; and may be a rechargeable battery, photovoltaic cells; or other suitable source.

(13) FIG. 2: functional diagram of a device according to the invention

(14) FIG. 2 is a schematic block diagram illustrating various features of device 1 in accordance with the principles of the present disclosure.

(15) FIG. 2 illustrates that signal processing unit 4 is connected to: information means 6; linking means 5; control means 8; and light 9a

(16) Linking means 5 is further connected to: first and second storage spaces 2 and 3; dispensing means 7.

(17) When using device 1, information means 6 provides information to signal processing unit 4.

(18) When the user activates control means 8, signal processing unit 4, based on the information provided by information means 6, controls linking via linking means 5 of either first storage space 2 or second storage space 3 with the dispensing means 7.

(19) Autonomous power source 10 supplies power to device 1, and may be a rechargeable battery; photovoltaic cells, or other suitable source.

(20) Device 1 may be used by a patient wishing to carry out the intranasal administration therapy. Device 1 may likely be used by people who are in isolated situations described above. To use device 1, the patient may quickly retrieve device 1 from, for example, a backpack, or its optional case. The user then positions dispensing means 7, e.g., nosepiece 7a. Patient signal means 9, e.g., light 9a, may communicate to the patient which of the two active formulations would be administered upon the activation of control means 8. Finally, to use device 1, the patient activates control means 8, e.g., pushbutton 8a. Control means 8 may also be any device capable of receiving a mechanical stress, voice activated, etc. The patient may, as part of the therapy, perform as many intranasal administrations as desired. Although this therapy may be an on demand therapy, it is completely safe and secure.

(21) Device 1 may incorporate multiple active formulations, e.g., active formulations 11 and 12, the qualitative and quantitative compositions of each of which may be adapted for a given patient. The choice of dosage as well as which active ingredients to use may be at the discretion of a medical personnel. The time interval, e.g., minimum duration between administrations of active ingredients from the DR and/or ADR groups, calculated by the time counting means, e.g., clock 6a, may be predetermined by the medical personnel.

(22) Accordingly, device 1 may simplify difficult situations, especially in the context of use during armed conflict, natural disasters, etc.

(23) In one embodiment, intranasal delivery system having portable device 1 for sequential intranasal administration in accordance with the principles of the present disclosure includes: at least first storage space 2 containing first sprayable active formulation 12 comprising at least one active ingredient from the DR group 12a; at least second storage space 3 containing second sprayable active formulation 11 different from first active formulation 12 comprising at least one active ingredient from the ADR group 11a; signal processing unit 4; linking means 5 of active formulations 12 and 11 of first and second storage spaces 2 and 3, respectively, and dispensing means 7, operatively connected to signal processing unit 4; one or more information means 6, operatively connected to signal processing unit 4; control means 8 configured to allow a patient receiving active formulations to perform self-administration of the active formulations without any medical facility; dispensing means 7 for transmission of the active formulations through the nasal mucosa; and autonomous power source 10,
wherein signal processing unit 4, linking means 5, information means 6, and control means 8 are configured to allow, based on one or more signals received by signal processing unit 4 from information means 6, linking of first active formulation 12 within first storage space 2 with dispensing means 7 and/or linking of second active formulation 11 within second storage space 3 with distribution means 7.

(24) In one embodiment, intranasal delivery system having portable device 1 for sequential intranasal administration in accordance with the principles of the present disclosure includes: at least first storage space 2 containing a first sprayable active formulation 12 comprising at least one active ingredient from the DR group 12a and at least one active ingredient from the ADR group 12b; At least second storage space 3 comprising a second active formulation 11 sprayable different from first active formulation 12 comprising at least one active ingredient from the ADR group 11a; signal processing unit 4; linking means 5 of active formulations 12 and 11 of first and second storage spaces 2 and 3, respectively, and dispensing means 7, operatively connected to signal processing unit 4; one or more information means 6, operatively connected to signal processing unit 4; control means 8 configured to allow a patient receiving active formulations to perform self-administration of the active formulations without any medical facility; dispensing means 7 for transmission of the active formulations through the nasal mucosa; and autonomous power source 10,
wherein signal processing unit 4, linking means 5, information means 6, and control means 8 are configured to allow, based on one or more signals received by signal processing unit 4 from information means 6, linking of first active formulation 12 within first storage space 2 with dispensing means 7 and/or linking of second active formulation 11 within second storage space 3 with distribution means 7.

(25) In one embodiment, when at least one active ingredient from the DR group is an opioid, and at least one active ingredient from the ADR group is an active ingredient that counteracts the opioid-induced respiratory depression, e.g., naloxone, first storage space 2 having first active formulation 12 disposed therein may include both an active ingredient from the DR group selected from opioids and an active ingredient from the ADR group, e.g., naloxone.

(26) In one embodiment, when at least one active ingredient from the DR group is a benzodiazepine, and at least one active ingredient from the ADR group is an active ingredient that counteracts the benzodiazepine-induced respiratory depression, e.g., flumazenil, first storage space 2 having first active formulation 12 disposed therein may include both an active ingredient from the DR group selected from benzodiazepines and an active ingredient from the ADR group, e.g., flumazenil.

(27) In one embodiment, energy source 10 is electric.

(28) In one embodiment, signal processing unit 4 comprises a microprocessor.

(29) In one embodiment, signal processing unit 4 is operatively connected to one or more memory areas configured to store data received from information means 6.

(30) In one embodiment, information means 6 includes at least one device for measuring at least one biological parameter, and/or a time counting means.

(31) In one embodiment, information means 6 includes at least one device for measuring at least one biological parameter, and a time counting means.

(32) In one embodiment, information means 6 includes at least one oximeter 6c, and/or respiratory rate sensor 6b, and/or time counting means.

(33) In one embodiment, information means 6 includes at least one oximeter 6c, respiratory rate sensor 6b, and a time counting means.

(34) In one embodiment, dispensing means 7 comprises nosepiece 7a, such that oximeter 6c and respiratory rate sensor 6b are located on nosepiece 6a for measuring and/or calculating a physiological value of the patient receiving the administration of active formulations.

(35) In one embodiment, the time counting means is integrated in the microprocessor of signal processing unit 4.

(36) In one embodiment: the one or more devices for measuring and/or calculating at least one biological parameter sends the information to signal processing unit 4 having a memory area configured to store the physiological value; and signal processing unit 4, upon receiving information from the device for measuring at least one biological parameter, interrogates the time counting means to obtain a current time value and stores the time value in a memory area.

(37) In one embodiment: signal processing unit 4 performs a comparison between a physiological value obtained from the one or more devices for measuring at least one biological parameter with a threshold value stored in a memory area; signal processing unit 4 performs a comparison between the time value stored in a memory area and an updated time value received from the time counting means at the time of the comparison to calculate the time elapsed since the previous administration; depending on the determination of these comparisons, signal processing unit 4 sends a signal to linking means 5 to enable the patient receiving the administration to actuate control means 8 to self-administer one of the active formulations.

(38) In one embodiment: if signal processing unit 4 determines that the physiological value exceeds a threshold value, and that sufficient time has elapsed since the previous administration, signal processing unit 4 sends a signal to linking means 5 to permit subsequent administration of first active formulation 12; or if signal processing unit 4 determines that the physiological value is less than a threshold value, where an insufficient time interval has elapsed since the previous administration, signal processing unit 4 sends a signal to linking means 5 to permit subsequent administration of second active formulation 11.

(39) In one embodiment, the storage spaces are removable.

(40) In one embodiment, the storage spaces are changeable. The storage spaces are changeable in that they may be removed and replaced with new storage spaces including, where appropriate, the same active ingredients

(41) In one embodiment, storage spaces 2 and 3 are removable and changeable.

(42) Indeed, as stated above, device 1 may include multiple active formulations, the qualitative and quantitative compositions of each of which may be adapted to a given patient. The choice of dosage as well as which active ingredients to use may be at the discretion of a medical personnel. In addition, the time interval may be predetermined by the medical personnel.

(43) In one embodiment, device 1 further includes patient signal means 9.

(44) In one embodiment; patient signal means 9 may be light 9a.

(45) With respect to the doses of active ingredients from the DR and ADR group, all doses were estimated for patients of about 70 kg, which represents an average weight. Such doses may vary, especially for patients of different weights. The doses may also be adapted for specific animals. The doses may be adjusted as is well known in the art.

(46) The following embodiments may be applied to the method of administration of the active ingredients for use in the treatment of pain, the administration system, and the portable device in accordance with the principles of the present disclosure.

(47) In one embodiment, the measurement of a biological parameter is obtained by a device for measuring at least one biological parameter introduced into the nasal cavity concomitantly with each administration.

(48) In one embodiment, the threshold value of the time counting means is between 1 and 10 hours.

(49) In one embodiment, the threshold value of the time counting means is between 4 and 8 hours.

(50) In one embodiment, the threshold value of the time counting means is about 6 hours.

(51) In one embodiment, the biological parameter measured is selected from at least one of oxygen saturation, intranasal rate of oxygen exhaled, intranasal rate of carbon dioxide exhaled, or respiratory rate.

(52) In one embodiment, the biological parameter measured is oxygen saturation.

(53) In one embodiment, the threshold value of the measurement of the oxygen saturation is between 70 and 90%.

(54) In one embodiment, the threshold value of the measurement of the oxygen saturation is between 80 and 90%.

(55) In one embodiment, the threshold value of the measurement of oxygen saturation is about 85%.

(56) In one embodiment, the biological parameter measured is respiratory rate.

(57) In one embodiment, the threshold value of the measured respiratory rate is between 8 and 14 cycles/minute.

(58) In one embodiment, the threshold value of the measured respiratory rate is between 8 and 12 cycles/minute.

(59) In one embodiment, the threshold value of measuring respiratory rate is about 12 cycles/minute.

(60) In one embodiment, the biological parameters measured are oxygen saturation and respiratory rate.

(61) In one embodiment, the active ingredients are in the form of sprayable liquid.

(62) In one embodiment, at least one active ingredient from the DR group and at least one active ingredient from the ADR group, when administered simultaneously, are in a mixture.

(63) In one embodiment, only one active ingredient from the DR group and only one active ingredient from the ADR group are used.

(64) In one embodiment, the active ingredients from the DR group used during the initial stage and the active ingredients from the DR group used during at least one subsequent stage are identical.

(65) In one embodiment, the active ingredients from the DR group used during the initial stage and the active ingredients from the DR group used during at least one subsequent stage are different.

(66) In one embodiment, the active ingredients from the ADR group used during the initial stage and the active ingredients from the ADR group used during at least one subsequent stage are identical.

(67) In one embodiment, the active ingredients from the ADR group used during the initial stage and the active ingredients from the ADR group used during at least one subsequent stage are different.

(68) In one embodiment, the active ingredients from the DR group consists of opioid agonists and the active ingredients from the ADR group consists of opioid antagonists.

(69) In one embodiment, at least one active ingredient from the DR group is selected from the group consisting of alfentanil, anileridine, apomorphine, buprenorphine, butorphanol, carfentanil, codeine, diamorphine (Heroin), dextropropoxyphene, dihydromorphine, fentanyl, hydrocodone, hydromorphone, levallorphan, levophenacylmorphan, levorphanol, methadone, morphine, nalbuphine, nalorphine, norlevophanol, oxycodone, oxymorphone, pentazocine, pethidine, propoxyphene, remifentanil, sufentanil, tramadol, etc.

(70) In one embodiment, at least one active ingredient from the DR group is selected from the group consisting of sufentanil, fentanyl, diamorphine, buprenorphine, and carfentanil.

(71) In one embodiment, at least one active ingredient from the DR group is sufentanil,

(72) In one embodiment, at least one active ingredient from the ADR group is selected from the group consisting of naloxone and naltrexone.

(73) In one embodiment, at least one active ingredient of the ADR group is naloxone.

(74) In one embodiment, at least one active ingredient from the DR group is sufentanil and at least one active ingredient from the ADR group is naloxone.

(75) In one embodiment, the dose of sufentanil is between 2 and 50 g and the dose of naloxone is between 2 and 50 mg.

(76) In one embodiment, the dose of sufentanil is between 5 and 30 g and the dose of naloxone is between 5 and 30 mg.

(77) In one embodiment, the dose of sufentanil is between 10 and 20 g and the dose of naloxone is between 10 and 20 mg.

(78) In one embodiment, the dose of sufentanil is 10 g and the dose of naloxone is 10 mg.

(79) In one embodiment, the dose of sufentanil is 15 g and the dose of naloxone is 15 mg.

(80) In one embodiment, the dose of sufentanil is 20 g and the dose of naloxone is 20 mg.

(81) In one embodiment, the weight ratio of sufentanil and naloxone is between 0.00004 and 0.025.

(82) In one embodiment, the weight ratio of sufentanil and naloxone is about 0.001.

(83) In one embodiment, at least one active ingredient of the DR group is sufentanil and at least one active ingredient of the ADR group is naloxone, and any administration of sufentanil is accompanied by the simultaneous administration of ketamine.

(84) In one embodiment, sufentanil, naloxone, and ketamine are in a mixture.

(85) In one embodiment, the dose of sufentanil is between 1 and 60 g, the dose of ketamine is between 1 and 60 mg, and the dose of naloxone is between 1 and 60 mg.

(86) In one embodiment, the dose of sufentanil is between 10 and 55 g, the dose of ketamine is between 10 and 55 mg, and the dose of naloxone is between 10 and 55 mg.

(87) In one embodiment, the dose of sufentanil is between 17 and 50 g, the dose of ketamine is between 17 and 50 mg, and the dose of naloxone is between 17 and 50 mg.

(88) In one embodiment, the dose of sufentanil is 17 g, the dose of ketamine is 17 mg, and the dose of naloxone is 17 mg.

(89) In one embodiment, the dose of sufentanil dose is 37.5 g, the dose of ketamine is 37.5 mg, and the dose of naloxone is 37.5 mg.

(90) In one embodiment, the dose of sufentanil dose is 50 g, the dose of ketamine is 50 mg, and the dose of naloxone is 50 mg.

(91) In one embodiment, the weight ratio of sufentanil and naloxone and the weight ratio of ketamine and naloxone are, respectively, between 0.00034 and 0.0029, and between 0.34 and 2.9.

(92) In one embodiment, the weight ratio of sufentanil and naloxone ratio is about 0.001 and the weight ratio of ketamine and naloxone ratio is about 1.

(93) In one embodiment, at least one active ingredient from the DR group is fentanyl and at least one active ingredient from the ADR group is naloxone.

(94) In one embodiment, the dose of fentanyl is between 10 and 150 g and the dose of naloxone is between 2 and 50 mg.

(95) In one embodiment, the dose of fentanyl is between 30 and 120 g and the dose of naloxone is between 5 and 30 mg.

(96) In one embodiment, the dose of fentanyl is between 50 and 100 g and the dose of naloxone is between 10 and 20 mg.

(97) In one embodiment, the dose of fentanyl is 50 g and the dose of naloxone is 10 mg.

(98) In one embodiment, the dose of fentanyl is 75 g and the dose of naloxone is 15 mg.

(99) In one embodiment, the dose of fentanyl is 100 g and the dose of naloxone is 20 mg.

(100) In one embodiment, the weight ratio of fentanyl and naloxone is between 0.0002 and 0.075.

(101) In one embodiment, the weight ratio of fentanyl and naloxone ratio is about 0.005.

(102) In one embodiment, at least one active ingredient from the DR group is diamorphine and at least one active ingredient from the ADR group is naloxone.

(103) In one embodiment, the dose of diamorphine is between 0.1 and 20 mg and the dose of naloxone is between 2 and 50 mg.

(104) In one embodiment, the dose of diamorphine is between 1 and 10 mg and the dose of naloxone is between 5 and 30 mg.

(105) In one embodiment, the dose of diamorphine is between 2 and 4 mg and the dose of naloxone is between 10 and 20 mg.

(106) In one embodiment, the dose of diamorphine is 2 mg and the dose of naloxone is 10 mg.

(107) In one embodiment, the dose of diamorphine is 3 mg and the dose of naloxone is 15 mg.

(108) In one embodiment, the dose of diamorphine is 4 mg and the dose of naloxone is 20 mg.

(109) In one embodiment, the weight ratio of diamorphine and naloxone is between 0.02 and 10.

(110) In one embodiment, the weight ratio of diamorphine and naloxone is about 0.2.

(111) In one embodiment, at least one active ingredient from the DR group is buprenorphine and at least one active ingredient from the ADR group is naloxone.

(112) In one embodiment, the dose of buprenorphine is between 0.1 and 30 mg and the dose of naloxone is between 0.1 and 5 mg.

(113) In one embodiment, the dose of buprenorphine is between 1 and 15 mg and the dose of naloxone is between 0.3 and 3 mg.

(114) In one embodiment, the dose of buprenorphine is between 2 and 8 mg and the dose of naloxone is between 0.5 and 2 mg.

(115) In one embodiment, the dose of buprenorphine is 2 mg and the dose of naloxone is 0.5 mg.

(116) In one embodiment, the dose of buprenorphine is 4 mg and the dose of naloxone is 1 mg.

(117) In one embodiment, the dose of buprenorphine is 6 mg and the dose of naloxone is 1.5 mg.

(118) In one embodiment, the dose of buprenorphine is 8 mg and the dose of naloxone is 2 mg.

(119) In one embodiment, the weight ratio of buprenorphine and naloxone is between 0.02 and 300.

(120) In one embodiment, the weight ratio of buprenorphine and naloxone is about 4.

(121) In one embodiment, at least one active ingredient from the DR group is carfentanil and at least one active ingredient from the ADR group is naloxone.

(122) In one embodiment, the dose of carfentanil dose is between 70 and 1900 g and the dose of naloxone is between 0.3 and 3.7 mg.

(123) In one embodiment, the dose of carfentanil dose is between 140 and 1400 g and the dose of naloxone is between 0.5 and 3.0 mg.

(124) In one embodiment, the dose of carfentanil dose is between 350 and 1000 g and the dose of naloxone is between 0.7 and 2.0 mg.

(125) In one embodiment, the dose of carfentanil dose is 350 g and the dose of naloxone is 0.70 mg.

(126) In one embodiment, the dose of carfentanil dose is 700 g and the dose of naloxone is 1.4 mg.

(127) In one embodiment, the dose of carfentanil dose is 1000 g and the dose of naloxone is 2 mg.

(128) In one embodiment, the weight ratio of carfentanil and naloxone is between 0.019 and 6.6.

(129) In one embodiment, the weight ratio of carfentanil and naloxone is about 0.5.

(130) In one embodiment, when the active formulation contains no active ingredient from the DR group, at least one active ingredient from the ADR group is naloxone and the dose of naloxone is between 1 and 40 mg.

(131) In one embodiment, when the active formulation contains no active ingredient from the DR group, at least one active ingredient from the ADR group is naloxone and the dose of naloxone is between 5 and 20 mg.

(132) When the at least one active ingredient from the DR group is buprenorphine and the active formulation contains no active ingredient from the DR group, at least one active ingredient from the ADR group is naloxone and the dose of naloxone is between 3 to 7 mg.

(133) In one embodiment, the DR group consists of benzodiazepines and the ADR group consists of benzodiazepines antagonists.

(134) In one embodiment, benzodiazepines are selected from the group consisting of lorazepam, midazolam and flunitrazepam.

(135) In one embodiment, the benzodiazepine antagonist s flumazenil.

(136) In one embodiment, the benzodiazepine is lorazepam and the benzodiazepine antagonist is flumazenil.

(137) In one embodiment, the dose of lorazepam is between 2 and 5 mg.

(138) In one embodiment, the benzodiazepine is midazolam and the benzodiazepine antagonist is flumazenil.

(139) In one embodiment, the dose of midazolam is between 3.5 and 10 mg.

(140) In one embodiment, the benzodiazepine is flunitrazepam and the benzodiazepine antagonist is flumazenil.

(141) In one embodiment, the dose of flunitrazepam is between 2 and 10 mg.

(142) In one embodiment, the active formulation contains no active ingredient from the DR group, at least one active ingredient from the ADR group is flumazenil, and the dose of flumazenil is between 0.1 and 1 mg.

(143) In one embodiment, when the active formulation contains no active ingredient from the DR group, at least one active ingredient from the ADR group is flumazenil and the dose of flumazenil is between 0.6 and 1 mg.

(144) In one embodiment, when the active formulation contains at least one active ingredient from the DR group and no active ingredient from the ADR group, at least one active ingredient from the DR group is selected from benzodiazepines.

(145) In one embodiment, when at least one active ingredient from the DR group is lorazepam, the active formulation containing lorazepam does not include flumazenil.

(146) In one embodiment, when at least one active ingredient from the DR group is midazolam, the active formulation containing midazolam does not include flumazenil.

(147) In one embodiment, when at least one active ingredient from the ADR group is flunitrazepam, the active formulation containing flunitrazepam does not include flumazenil.

(148) In one embodiment, the active ingredient from the DR group consists of opioid agonist and the active ingredient from the ADR group consists of opioid antagonists, and when at least one active ingredient from the DR group is administered, it is simultaneously administered with an active ingredient from the ADR group.

(149) In one embodiment, the biological parameter is measured by a device for measuring at least one biological parameter introduced into the nasal cavity concomitantly with each administration, the threshold value of the time counting means is between 4 and 8 hours, the biological parameters measured are oxygen saturation and respiratory rate, at least one active ingredient from the DR group and at least one active ingredient from the ADR group, when administered simultaneously, are in a mixture, the active ingredient from the DR group used during the initial stage and the active ingredient from the DR group used during the at least one subsequent stage are identical, at least one active ingredient from the DR group is sufentanil, and at least one active ingredient from the ADR group is naloxone, wherein the dose of sufentanil is between 17 and 50 g and the dose of naloxone is between 17 and 50 mg.

(150) In one embodiment, the biological parameter is measured by a device for measuring at least one biological parameter introduced into the nasal cavity concomitantly with each administration, the threshold value of the time counting means is between 4 and 8 hours, the biological parameters measured are oxygen saturation and respiratory rate, at least one active ingredient from the DR group and at least one active ingredient from the ADR group, when administered simultaneously, are in a mixture, the active ingredient from the DR group used during the initial stage and the active ingredient from the DR group used during the at least one subsequent stage are identical, at least one active ingredient from the DR group is sufentanil, at least one active ingredient from the ADR group is naloxone, the dose of sufentanil is between 17 and 50 g and the dose of naloxone is between 17 and 50 mg, any administration of sufentanil is accompanied by a simultaneous administration of ketamine, wherein the sufentanil and ketamine are in a mixture, and the dose of ketamine is between 17 and 50 mg.

(151) In one embodiment, the biological parameter is measured by a device for measuring at least one biological parameter introduced into the nasal cavity concomitantly with each administration, the threshold value of the time counting means is between 4 and 8 hours, the biological parameters measured are oxygen saturation and respiratory rate, at least one active ingredient from the DR group and at least one active ingredient from the ADR group, when administered simultaneously, are in a mixture, the active ingredient from the DR group used during the initial stage and the active ingredient from the DR group used during the at least one subsequent stage are identical, at least one active ingredient from the DR group is fentanyl, and at least one active ingredient from the ADR group is naloxone, wherein the dose of fentanyl is between 50 and 100 g and the dose of naloxone is between 10 and 20 mg.

(152) In one embodiment, the biological parameter is measured by a device for measuring at least one biological parameter introduced into the nasal cavity concomitantly with each administration, the threshold value of the time counting means is between 4 and 8 hours, the biological parameters measured are oxygen saturation and respiratory rate, at least one active ingredient from the DR group and at least one active ingredient from the ADR group, when administered simultaneously, are in a mixture, the active ingredient from the DR group used during the initial stage and the active ingredient from the DR group used during the at least one subsequent stage are identical, at least one active ingredient from the DR group is diamorphine, and at least one active ingredient from the ADR group is naloxone, wherein the dose of diamorphine is between 2 and 4 mg and the dose of naloxone is between 10 and 20 mg.

(153) In one embodiment, the biological parameter is measured by a device for measuring at least one biological parameter introduced into the nasal cavity concomitantly with each administration, the threshold value of the time counting means is between 4 and 8 hours, the biological parameters measured are oxygen saturation and respiratory rate, at least one active ingredient from the DR group and at least one active ingredient from the ADR group, when administered simultaneously, are in a mixture, the active ingredient from the DR group used during the initial stage and the active ingredient from the DR group used during the at least one subsequent stage are identical, at least one active ingredient from the DR group is buprenorphine, and at least one active ingredient from the ADR group is naloxone, wherein the dose of buprenorphine is between 2 and 8 mg and the dose of naloxone is between 0.5 and 2 mg.

(154) In one embodiment, the biological parameter is measured by a device for measuring at least one biological parameter introduced into the nasal cavity concomitantly with each administration, the threshold value of the time counting means is between 4 and 8 hours, the biological parameters measured are oxygen saturation and respiratory rate, at least one active ingredient from the DR group and at least one active ingredient from the ADR group, when administered simultaneously, are in a mixture, the active ingredient from the DR group used during the initial stage and the active ingredient from the DR group used during the at least one subsequent stage are identical, at least one active ingredient from the DR group is carfentanil, and at least one active ingredient from the ADR group is naloxone, wherein the dose of carfentanil is between 350 and 1000 g and the dose of naloxone is between 0.7 and 2.0 mg.

(155) In one embodiment, the active ingredients from the DR group consists of opioid agonist and the active ingredients of the ADR group consists of opioid antagonists, and when at least one active ingredient from the DR group is administered, no active ingredient from the ADR group is administered.

(156) In one embodiment, the biological parameter is measured by a device for measuring at least one biological parameter introduced into the nasal cavity concomitantly with each administration, the threshold value of the time counting means is between 4 and 8 hours, the biological parameters measured are oxygen saturation and respiratory rate, the active ingredient from the DR group used during the initial stage and the active ingredient from the DR group used during the at least one subsequent stage are identical, at least one active ingredient from the DR group is sufentanil, and at least one active ingredient from the ADR group is naloxone, wherein the dose of sufentanil is between 17 and 50 g and the dose of naloxone is between 17 and 50 mg.

(157) In one embodiment, the biological parameter is measured by a device for measuring at least one biological parameter introduced into the nasal cavity concomitantly with each administration, the threshold value of the time counting means is between 4 and 8 hours, the biological parameters measured are oxygen saturation and respiratory rate, the active ingredient from the DR group used during the initial stage and the active ingredient from the DR group used during the at least one subsequent stage are identical, at least one active ingredient from the DR group is sufentanil, at least one active ingredient from the ADR group is naloxone, the dose of sufentanil is between 17 and 50 g and the dose of naloxone is between 17 and 50 mg, any administration of sufentanil is accompanied by a simultaneous administration of ketamine, wherein the sufentanil and ketamine are in a mixture, and the dose of ketamine is between 17 and 50 mg.

(158) In one embodiment, the biological parameter is measured by a device for measuring at least one biological parameter introduced into the nasal cavity concomitantly with each administration, the threshold value of the time counting means is between 4 and 8 hours, the biological parameters measured are oxygen saturation and respiratory rate, the active ingredient from the DR group used during the initial stage and the active ingredient from the DR group used during the at least one subsequent stage are identical, at least one active ingredient from the DR group is fentanyl, and at least one active ingredient from the ADR group is naloxone, wherein the dose of fentanyl is between 50 and 100 g and the dose of naloxone is between 10 and 20 mg.

(159) In one embodiment, the biological parameter is measured by a device for measuring at least one biological parameter introduced into the nasal cavity concomitantly with each administration, the threshold value of the time counting means is between 4 and 8 hours, the biological parameters measured are oxygen saturation and respiratory rate, the active ingredient from the DR group used during the initial stage and the active ingredient from the DR group used during the at least one subsequent stage are identical, at least one active ingredient from the DR group is diamorphine, and at least one active ingredient from the ADR group is naloxone, wherein the dose of diamorphine is between 2 and 4 mg and the dose of naloxone is between 10 and 20 mg.

(160) In one embodiment, the biological parameter is measured by a device for measuring at least one biological parameter introduced into the nasal cavity concomitantly with each administration, the threshold value of the time counting means is between 4 and 8 hours, the biological parameters measured are oxygen saturation and respiratory rate, the active ingredient from the DR group used during the initial stage and the active ingredient from the DR group used during the at least one subsequent stage are identical, at least one active ingredient from the DR group is buprenorphine, and at least one active ingredient from the ADR group is naloxone, wherein the dose of buprenorphine is between 2 and 8 mg and the dose of naloxone is between 0.5 and 2 mg.

(161) In one embodiment, the biological parameter is measured by a device for measuring at least one biological parameter introduced into the nasal cavity concomitantly with each administration, the threshold value of the time counting means is between 4 and 8 hours, the biological parameters measured are oxygen saturation and respiratory rate, the active ingredient from the DR group used during the initial stage and the active ingredient from the DR group used during the at least one subsequent stage are identical, at least one active ingredient from the DR group is carfentanil, and at least one active ingredient from the ADR group is naloxone, wherein the dose of carfentanil is between 350 and 1000 g and the dose of naloxone is between 0.7 and 2.0 mg.

(162) In one embodiment, the active ingredients from the DR group consists of benzodiazepines and active ingredients from the ADR group consists of benzodiazepine antagonists, and when at least one active ingredient from the DR group is administered, an active ingredient from the ADR group is administered simultaneously.

(163) In one embodiment, the biological parameter is measured by a device for measuring at least one biological parameter introduced into the nasal cavity concomitantly with each administration, the threshold value of the time counting means is between 4 and 8 hours, the biological parameters measured are oxygen saturation and respiratory rate, at least one active ingredient from the DR group and at least one active ingredient from the ADR group, when administered simultaneously, are in a mixture, the active ingredient from the DR group used during the initial stage and the active ingredient from the DR group used during the at least one subsequent stage are identical, at least one active ingredient from the DR group is midazolam, wherein the dose of midazolam is between 3.5 and 10 mg, and when the active formulation contains no active ingredient from the DR group, at least one active ingredient from the ADR group is flumazenil, wherein the dose of flumazenil is between 0.6 and 1 mg.

(164) In one embodiment, the biological parameter is measured by a device for measuring at least one biological parameter introduced into the nasal cavity concomitantly with each administration, the threshold value of the time counting means is between 4 and 8 hours, the biological parameters measured are oxygen saturation and respiratory rate, at least one active ingredient from the DR group and at least one active ingredient from the ADR group, when administered simultaneously, are in a mixture, the active ingredient from the DR group used during the initial stage and the active ingredient from the DR group used during the at least one subsequent stage are identical, at least one active ingredient from the DR group is lorazepam, wherein the dose of lorazepam is between 2 and 5 mg, and when the active formulation contains no active ingredient from the DR group, at least one active ingredient from the ADR group is flumazenil, wherein the dose of flumazenil is between 0.6 and 1 mg.

(165) In one embodiment, the biological parameter is measured by a device for measuring at least one biological parameter introduced into the nasal cavity concomitantly with each administration, the threshold value of the time counting means is between 4 and 8 hours, the biological parameters measured are oxygen saturation and respiratory rate, at least one active ingredient from the DR group and at least one active ingredient from the ADR group, when administered simultaneously, are in a mixture, the active ingredient from the DR group used during the initial stage and the active ingredient from the DR group used during the at least one subsequent stage are identical, at least one active ingredient from the DR group is flunitrazepam, wherein the dose of flunitrazepam is between 2 and 10 mg, and when the active formulation contains no active ingredient from the DR group, at least one active ingredient from the ADR group is flumazenil, wherein the dose of flumazenil is between 0.6 and 1 mg.

(166) In one embodiment, the active ingredient from the DR group consists of benzodiazepines and the active ingredient from the ADR group consists of benzodiazepine antagonists, and when at least one active ingredient from the DR group is administered, no active ingredient from the ADR group is administered.

(167) In one embodiment, the biological parameter is measured by a device for measuring at least one biological parameter introduced into the nasal cavity concomitantly with each administration, the threshold value of the time counting means is between 4 and 8 hours, the biological parameters measured are oxygen saturation and respiratory rate, the active ingredient from the DR group used during the initial stage and the active ingredient from the DR group used during the at least one subsequent stage are identical, at least one active ingredient from the DR group is midazolam, wherein the dose of midazolam is between 3.5 and 10 mg, and when the active formulation contains no active ingredient from the DR group, at least one active ingredient from the ADR group is flumazenil, wherein the dose of flumazenil is between 0.6 and 1 mg.

(168) In one embodiment, the biological parameter is measured by a device for measuring at least one biological parameter introduced into the nasal cavity concomitantly with each administration, the threshold value of the time counting means is between 4 and 8 hours, the biological parameters measured are oxygen saturation and respiratory rate, the active ingredient from the DR group used during the initial stage and the active ingredient from the DR group used during the at least one subsequent stage are identical, at least one active ingredient from the DR group is lorazepam, wherein the dose of lorazepam is between 2 and 5 mg, and when the active formulation contains no active ingredient from the DR group, at least one active ingredient from the ADR group is flumazenil, wherein the dose of flumazenil is between 0.6 and 1 mg.

(169) In one embodiment, the biological parameter is measured by a device for measuring at least one biological parameter introduced into the nasal cavity concomitantly with each administration, the threshold value of the time counting means is between 4 and 8 hours, the biological parameters measured are oxygen saturation and respiratory rate, the active ingredient from the DR group used during the initial stage and the active ingredient from the DR group used during the at least one subsequent stage are identical, at least one active ingredient from the DR group is flunitrazepam, wherein the dose of flunitrazepam is between 2 and 10 mg, and when the active formulation contains no active ingredient from the DR group, at least one active ingredient from the ADR group is flumazenil, wherein the dose of flumazenil is between 0.6 and 1 mg.

(170) In one embodiment, at least one of the active formulations comprises at least one active pharmaceutical ingredient configured to modify the passage properties of membranes and bioavailability.

EXAMPLE

(171) This example illustrates a use of device 1 in accordance with the principles of the present disclosure.

(172) Specifications of device 1: two removable storage spaces; first storage space 2 having first active formulation 12 disposed therein: t,?

(173) The amount of active formulation used in each dose is 0.2 mL, thus active formulation 12 comprises about 50 doses: sufentanil (37.5 g/dose)/ketamine (37.5 mg/dose)/naloxone (37.5 mg/dose). second storage space 3 comprises active formulation 11: t,?

(174) The amount of active formulation used in each dose is 0.2 mL, thus active formulation 11 comprises about 50 doses: naloxone (15 mg/dose). two devices that measure biological parameters: 6c oximeter (measuring oxygen saturation having 85% threshold value) and respiratory rate sensor 6b (threshold value: 12 inspirations/expirations cycles per minute); time counting means: clock 6a (threshold value: 6 hours); patient signal means 9: when one of the threshold values of oximeter sensor 6c, respiratory rate 6b, or clock 6a are in favor of a re-administration of sufentanil, light 9a emits a light on device 1.
Accordingly, the patient will know what will be administered upon activation of control means 8. The patient may then make a decision whether or not to activate control means 8.

(175) Course of therapy: at T=0, the patient, without any medical facility, actuates control means 8 of the device 1 for the first time: the patient administers active formulation 12. at T=3 hours, the patient introduces nosepiece 7a of device 1 into one nostril. After about 20 seconds, light 9a emits alight indicating that the clock (and potentially the biological parameters) prohibits the administration of active formulation 12: the patient has the choice of whether or not to administer active formulation 11. at T=6.1 hours, the patient introduces nosepiece 7a of device 1 into one nostril. After about 20 seconds, light 9a emits a light, indicating that at least one of its two biological parameters (oxygen saturation and respiratory rate) prohibits the administration of active formulation 12: the patient has the choice of whether or not to administer active formulation 11. A T=8 hours, the patient introduces nosepiece 7a of device 1 into one nostril. After about 20 seconds, light 9a remains off: the patient may administer active formulation 12.