HK1247877A1 - Pharmaceutical composition and device for treating pain - Google Patents

Description

Pharmaceutical compositions and devices for the treatment of pain

The present invention relates to the field of pain management, including that based on active ingredients that may have respiratory depression side effects.

Among the active ingredients which may have a respiratory depression effect, the invention relates in particular to opioid agonists and benzodiazepinesAnd (4) class.

Opioid agonists are substances whose action is similar to that of opioids (opium) but are chemically unrelated. Opioid agonists exert their effects by stimulating opioid receptors. Relative to the type of opioid receptor (also known as opioid receptor), the formation of an opioid agonist/receptor complex elicits a pharmacological response.

Opioid agonists are used therapeutically for the treatment of pain and also as a replacement during drug withdrawal treatment.

Many opioid agonists are commonly used. For example, a non-exhaustive list includes alfentanil, anileridine, apomorphine, buprenorphine, butorphanol, carfentanil, codeine, diacetylmorphine ("heroin"), dextropropoxyphene (dexproxyp ex ne), dihydromorphine, fentanyl, hydrocodone, hydromorphone, levorphanol (levallorphane), levorphanol, methadone, morphine, nalbuphine, nalprofen (nalorphine), norlevorphanol (norlevaphanol), oxycodone, oxymorphone, pentazocine, pethidine, propoxyphene, remifentanil, sufentanil, tramadol and the like.

Furthermore, many endogenous substances can be classified as opioid agonists: dynorphin, endomorphin (endomorphin), endorphin, enkephalin, nociceptin (nociceptin).

Opioid agonists can have many undesirable side effects including lethargy, respiratory depression, constipation, nausea/vomiting, and the like. Its use should be carefully treated, especially in a hospital or any medical facility.

Treatment with opioid agonists poses a number of abuse problems as they may be alternatives to hard drugs (hydrogusdures). Therefore, the supply clinic requires an expensive security system. Finally, the rapid addiction to this type of treatment associated with long-term treatment leads to increased doses that can be relied upon by the patient, especially when administered "on demand". Thus, opioid agonist-based therapies require strict management and vigorous involvement by medical personnel, which is problematic in a cost-optimized context.

There are three main types of opioid receptors, μ, and κ. These receptors are widely distributed in the brain and in some peripheral areas.

Unlike opioid agonists, opioid antagonists are characterized by inhibitory activity at least one opioid receptor. They can be divided into two main categories: specific opioid antagonists (only certain opioid receptors) and non-specific opioid antagonists. In particular, non-specific opioid antagonists are naloxone, naltrexone, and nalmefene.

In the case of opioid intoxication, opioid agonists may be combined with opioid antagonists in order to limit certain side effects.

For the administration of opioids, injectable solutions are mainly used today, especially in hospital environments. This form of administration has a number of advantages, for example, a very rapid action and a reasonably well controlled bioavailability. However, injection administration is not perfect. In fact, in addition to the discomfort of injection and the need for professional administration, some side effects are very significant, including but not limited to respiratory depression.

Dinitrogen benzeneClasses are mainly used for their main properties: hypnosis, anxiolysis, anti-epilepsy, muscle relaxation and amnesia.

A plurality of benzodiazepinesClasses are commonly used. For example, a non-exhaustive list includes alprazolam, bromodiazepam, clozapine (clordiaz poxide), clobazam, clonazepam, chlordiazepam, clonazepam(clorazepate), diazepam, estazolam, flunitrazepam, chlorprazolam (loprazolam), lorazepam, chlordiazepam (lormem taz epam), midazolam, nitrazepam, nordiazepam (nordazzepam), oxazepam, pramipeam, temazepam, tetrahydrozepam (tretrazepam), triazolam, and the like.

Dinitrogen benzeneClasses have many undesirable side effects including forgetfulness, abnormal behavior, tolerance, respiratory depression, and the like.

Unlike benzodiazepineBenzodiazepinesThe antagonist is characterized by a benzodiazepineInhibitory activity of the like activity. The best known benzodiazepinesThe antagonist-like is flumazenil.

In the presence of dinitrogen benzeneIn the case of toxoids, benzodiazepines are used in order to limit certain side effects (e.g. respiratory depression)Optionally with benzodiazepineAntagonist-like combinations.

In the context of the present application, the term "active ingredient from the DR group" means an active ingredient which has at least one respiratory depression side effect.

In the context of the present application, the term "active ingredient from the ADR group" refers to an active ingredient that counteracts the respiratory depression caused by the active ingredients of the DR group.

For example, opioid agonists and benzodiazepinesA class is an active ingredient of the DR group that has at least one respiratory depression side effect.

For example, opioid antagonists and benzodiazepinesAntagonists-like agents are active ingredients of the ADR group against respiratory depression.

In accordance with the appended claims and the disclosure provided herein, the following terms are defined with the following meanings.

"active formulation" includes formulations comprising one or more active pharmaceutical ingredients. The active ingredient may be formulated as a solution or non-molecular dispersion. The active ingredient may also be formulated in a form that modifies its properties, especially those associated with the passage of membranes and bioavailability; microcapsules, liposomes, fast-acting forms, and the like.

"intranasal administration" is the administration of the active ingredient in the nasal cavity of a patient. The active ingredient may be in different forms: gases, vapors, droplets, suspended powders, and the like. In one embodiment, the active ingredient is in the form of an aerosol, for example in the form of a suspension of fine solid particles in a liquid or gas, wherein the particles fall below 50cm per second. Intranasal administration is also characterized by the fact that most of the active ingredient is absorbed by the nasal mucosa of the patient.

"sequential administration" is an administration consisting of several successive administrations.

"respiratory depression" is a side effect following administration of one or more active ingredients that can lead to the appearance of one or more signs of respiratory depression: hypoxia, elevated carbon dioxide levels in exhaled air, reduced oxygen levels in exhaled air, reduced respiratory rate, reduced respiratory amplitude, and the like.

An "undesirable side effect" is one that is not directly expected of an active ingredient. Undesirable side effects can be limited by administering an amount of active ingredient that counters the undesirable side effects.

By "administered independently" is meant without intervention by a medical professional when the patient is self-administered. When administration is performed in animals, it is understood that administration is performed by a breeder.

An "energy source" is an independent energy source that can be used to allow independent application as described above. The energy source is typically portable and is preferably incorporated into a portable system of intranasal delivery devices. For example, the energy source may be a battery, a source of photovoltaic energy, energy recovered from the patient, such as heat generated or motion generated, and the like.

By "administration without any medical facility" is meant that the sequence of one or more successive administrations can be carried out without any supervision by a medical professional. Optionally, the treatment may be prescribed by a health care professional, and the administration itself may occur where such a professional is not present and is not necessary.

The "initial phase" is the period of time during which the first administration of treatment is performed.

By "subsequent phase" is meant any period of administration after the first administration of treatment.

"simultaneous administration/simultaneous administration" is the simultaneous administration of at least two active ingredients. Alternatively, each active ingredient may be administered such that its pharmacological effects begin at the same time and/or generally at the same time. Alternatively, the active ingredients may be formulated as a mixture.

The "choice of administration" is when the patient receives administration as intended.

The "information part (moyen de sensignment)" is an element whose function is to acquire and transmit information for decision making, such as selection of application. It may be a timing means (moyen de com de temps) or a means for measuring at least one biological parameter.

"timing feature" refers to any feature that measures a time interval. Which may include a clock, stopwatch, countdown timer, microprocessor operating at a known frequency, etc.

"biological parameter" refers to a biological characteristic of a patient, which is in the form of a numerical or quantifiable value. For example, it may be oxygen saturation or respiration rate.

"means for measuring at least one biological parameter" is a means for generating a value corresponding to a biological parameter of a patient.

A "means for measuring at least one simultaneously introduced biological parameter" is a device wherein at least a part is located in the nasal cavity at least at the beginning of administration.

A "patient signal component (patient signal) is an element that emits a patient perceptible signal upon activation of the control component, thereby allowing the patient to obtain information about the administration options. The signal may be an optical signal. When the signal is positive, this means that an active preparation containing an active ingredient from the DR group but not containing an active ingredient from the ADR group can be released. When the signal is negative, this means that an active preparation containing an active ingredient from the ADR group but not an active ingredient from the DR group can be released. In summary, the patient signal component delivers a negative signal to the patient when at least one information component delivers information to the information processing unit with the opposite connection between the active preparation containing the active ingredient of the DR group but not containing the active ingredient of the ADR group and the dispensing component (molecules de distribution).

A "liquid spray" is a liquid that can be transformed into droplets and/or microdroplets.

A "mixture of active ingredients" is an active ingredient that is present in a single storage space. The mixture may be a liquid, solid or gas. In the case of liquid or gaseous mixtures, molecules of different active ingredients can be dispersed within the same storage space, which is referred to as a molecular mixture.

An "opioid agonist" is an active ingredient that acts on at least one opioid receptor in a manner similar to an opioid.

An "opioid antagonist" is an active ingredient that acts on at least one opioid receptor in opposition to an opioid.

By "initial activation of the system" is meant the first activation of the therapy administration system by the patient who wishes to receive the initial administration. There may be only one initial start-up of the system during a single treatment.

"subsequent system activation" refers to a subsequent activation of the therapy administration system by the patient wishing to receive administration. There may be one or more subsequent system activations during a single treatment.

A "portable device for intranasal administration" is a device that can be carried by a patient, but is not a burden that limits their mobility. In particular, the device can be transported so easily that it makes it reasonable to incorporate it in a separate apparatus whenever there is a possibility to use it (for example in an emergency). It can be placed in small containers such as a pocket, hand, bag, glove box (boot) bag, handbag, water-resistant and/or sand.

A "storage space" is an enclosed space containing an active agent. In the enclosed space, there is little or no gas exchange with the outside, and there is no qualitative and/or quantitative change of the preparation during short-term operation. The closed space may communicate with the outside during use.

"connecting means (refer to all elements allowing communication between the storage space and the dispensing means)". It may in particular be a mechanical barrier, such as a valve.

The "signal processing unit" is an element related to both the information part and the connection part. The information component transmits information evaluated by the signal processing unit. The operation of the signal processing unit allows the signal processing unit to send an operation control signal to the connection section based on the evaluation made.

"hyperpnea suppression" is a state of respiratory suppression in which the risk/benefit of the simultaneous administration of at least one active ingredient of the DR group (with or without at least one active ingredient of the ADR group) is undesirable. For example, when the measured biological parameter is oxygen saturation, respiratory depression may be considered excessive when the oxygen saturation value is below 85%. For example, when the biological parameter is respiratory rate, respiratory depression may be considered excessive when the value of the respiratory rate is less than 12 cycles per minute of inhalation/exhalation.

A "removable storage space" is a storage space that can be removed from a device without making it permanently unavailable.

An "exchangeable memory space" is a memory space that can be accessed independently of the device according to current regulations. The replaceable reservoir can be removed and replaced with a new reservoir containing the same active ingredient in order to reload the device.

A "dispensing means suitable for an active agent to be delivered through the nasal mucosa" is an element or group of elements required to bring the active agent into contact with the nasal mucosa.

The "power source" is a source that supplies current to the portable device. The current may be generated by, for example, a battery, a capacitor, a solar energy collection component, a component for collecting patient energy (e.g., mechanical energy or body heat), or the like.

Although there is a strong need for analgesic active ingredients (e.g. opioid agonists and benzodiazepines)Class), but this need is limited by side effects (particularly respiratory depression). In the future, these treatments will provide a number of improvements:

from an ergonomic point of view of treatment: safety management becomes easier, non-invasive administration, limiting injury after treatment, etc.

From a financial point of view: limiting caregiver intervention, reducing hospital stay, reducing abuse to medical systems, reducing the cost of a distribution network (des aseaux de distribution), and the like.

From a public health point of view: reduction of respiratory depression, limitation of abuse, etc.

In particular, the need has long been felt for a technical solution for delivering in an independently controlled manner by the patient himself, without any medical facilities, an active ingredient for the treatment of pain, while managing the adverse side effects of such a treatment. This perception of demand is particularly apparent to persons (e.g., soldiers, journalists, adventures, questers, hunters, hikers, mountain climbers) who are remote from any medical personnel or treatment center (e.g., hospitals, clinics, healthcare centers, etc.). In fact, these people are often found to be at a considerable position where the objective risk involved in maintaining the health of the person is considerable, and the risk of causing traumatic injuries is considerable. Thus, these people need a single treatment regimen that enables them to manage multiple conditions with pain manifestations by appropriate administration of appropriate products, while avoiding suffering from undesired side effects.

Various efforts have been made to improve opioid therapy, but satisfactory results have not been obtained.

For example, chinese application CN 102068697 describes the combination of opioid agonists with opioid antagonists in an attempt to limit the adverse effects of opioid agonists without affecting their effects. In particular, this application teaches nasal sprays containing a fentanyl/naltrexone mixture. However, this application does not describe any method of limiting the number of administrations or controlling the potential side effects once the opioid antagonist is metabolized.

U.S. patent publication No.2007/0186923, assigned to AcelRx Pharmaceuticals, describes a drug delivery device for administering opioid agonists in the oral mucosa. The device has a safety component that prevents the opioid antagonist from spilling when attempting to recover the opioid agonist solution. This application is therefore a safety system ensuring that in the event of attempted metastasis, the action of the opioid agonist composition is neutralized, rendering the composition unusable. Under normal conditions, no mixing between opioid agonist and opioid antagonist occurs, and no antagonist administration occurs.

WO 2012024106 assigned to University of Florida describes a complex system consisting of acquisition of pharmacokinetic and pharmacodynamic data, algorithmic analysis, where the response may be variable. The application states that oximeters are not considered reliable means for detecting anomalies, but that other probes are preferred. Furthermore, the device is not portable.

WO 1996040332, assigned to Go Medical, describes a Medical device for intranasal administration of opioid agonists. The device contains an opioid agonist solution and other active molecules in addition to the opioid antagonist, and therefore does not take into account the incorporation of the opioid antagonist. This application does not describe limiting abuse, but only describes a control system in which the patient uses "faithfulness".

U.S. Pat. No. 4,464,378 describes methods for intranasal administration of antagonists and corresponding formulations (e.g., in gel form). The object expressed in this patent is to circumvent the difficulties encountered with the use of certain known products with insufficient bioavailability during oral administration. This patent describes solutions, gels, suspensions and ointments containing opioid agonist-antagonists formulated for intranasal administration.

U.S. patent No.5,629,011 describes intranasal formulations of opioid agonist polar metabolites in combination with absorption enhancers that act in the mucosa.

U.S. patent No.5,767,125 describes a method of co-administering an opioid agonist with an opioid antagonist. The opioid agonist is selected from: morphine, codeine, fentanyl analogs, pentazocine, buprenorphine, methadone, enkephalin, dynorphin, endorphin, and alkaloids and opioid peptides that function in the same manner. The opioid antagonist is selected from: naltrexone, naloxone, etorphine, diprenorphine, dihydroetorphine, as well as alkaloids and opioid peptides that function in the same manner. The product is administered to mice by intraperitoneal injection, but the patent suggests the possibility of preparing formulations for oral, sublingual, intravenous, intramuscular, subcutaneous and transdermal administration.

WO 2001058447 describes compositions containing opioid agonists and opioid antagonists that can be formulated for intranasal administration. It should be noted here that the opioid antagonist is coated with a matrix (e.g., a polysaccharide) to form microspheres to control its release on the mucosa in order to ensure the action of the opioid antagonist during onset.

U.S. patent No.6,948,492 describes a system and intranasal delivery device for controlling the minimum time between intranasal self-administration of multiple unit doses of a pharmaceutical composition. The unit doses contained in the bottles are deposited on a support star (support) around the centre, which can be rotated after each use to advance the unit dose, but only after a certain predetermined time has elapsed. The support star is constantly biased to rotate and advance the bottle, the progress of which is maintained by the metal spring and the shape memory alloy wire. The lock is controlled by a microprocessor counting down between each application. The patent does not describe co-administration of an opioid agonist and an opioid antagonist, or other form of control that prevents improper administration of the composition. Indeed, although the disclosed device may self-administer subsequent doses of the opioid composition, the doses are not in the physiological conditions to undergo such administration.

In summary, none of the above mentioned solutions solves all the problems mentioned above.

As will be discussed below, the device according to the present invention solves the above problems.

The present invention relates to uses, systems, devices incorporating such systems, and methods of administration for managing pain. Various aspects of the invention are described in more detail below.

The implementation of the invention will have the following advantages:

ergonomics with respect to treatment: easier safety management, non-invasive administration, limiting post-treatment injuries, and the like.

-in terms of finance: limiting caregiver intervention, reducing hospital stays, reducing abuse affecting medical systems, reducing costs of distribution networks, and the like.

From a public health point of view: reduction of respiratory depression, limitation of abuse, etc

The invention also relates to uses, systems, devices incorporating such systems, and methods of administration for managing pain in an animal. In this case, it is understood that administration is by the owner/breeder of the animal, rather than being the patient/subject of the animal.

The invention relates to a method for the sequential intranasal administration of at least one active ingredient from the DR group having at least one respiratory depression side effect and at least one active ingredient of the ADR group counteracting the respiratory depression that can be caused by the active ingredients of the DR group. The method may be performed independently by the patient without any medical facility and comprises:

-an initial phase of intranasal administration of at least one active ingredient from the DR group, and

-at least one subsequent phase of intranasal administration of at least one active principle from the ADR group alone or of at least one active principle from the DR group,

wherein the selection of at least one subsequent stage of administration of intranasal administration is controlled by one or more information means.

In one embodiment, the sequential intranasal administration method comprises:

-an initial phase of intranasal administration of at least one active ingredient from the DR group in combination with at least one active ingredient from the ADR group, and

at least one subsequent phase of intranasal administration of at least one active principle from the ADR group alone or of at least one active principle from the DR group and at least one active principle from the ADR group simultaneously,

wherein the selection of at least one subsequent stage of administration of intranasal administration is controlled by one or more information means.

In one embodiment, the initial phase of the sequential intranasal administration method further comprises administering at least one active ingredient from the ADR group simultaneously with at least one active ingredient from the DR group.

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 counters respiratory depression caused by the opioid (e.g., naloxone), it is contemplated that the active ingredients of the ADR group (e.g., naloxone) may be administered simultaneously when the opioid from the DR group is administered.

In one embodiment, when at least one active ingredient from the DR group is benzodiazepineAnd at least one active ingredient from the ADR group is resistant to benzodiazepinesClass of respiratory depression inducing active ingredients (e.g., flumazenil), it is expected that benzodiazepines of the DR group, when administeredSimilarly, the active ingredients of the ADR group (e.g., flumazenil) may be administered simultaneously.

In one embodiment, the sequential intranasal administration method comprises:

-an initial phase of intranasal administration of at least one active ingredient from the DR group, and

-at least one subsequent phase of intranasal administration of at least one active ingredient from the ADR group alone,

wherein the selection of at least one subsequent stage of administration of intranasal administration is controlled by one or more information means.

In one embodiment, the sequential intranasal administration method comprises:

-an initial phase of intranasal administration of at least one active ingredient from the DR group, and

-at least one subsequent phase of simultaneous intranasal administration of at least one active principle from the DR group and at least one active principle from the ADR group,

wherein the selection of at least one subsequent stage of administration of intranasal administration is controlled by one or more information means.

In one embodiment, the sequential intranasal administration method comprises:

-an initial phase of intranasal administration of at least one active principle from the DR group and at least one active principle from the ADR group, and

-at least one subsequent stage of intranasal administration of at least one active ingredient from the ADR group alone,

wherein the selection of at least one subsequent stage of administration of intranasal administration is controlled by one or more information means.

In one embodiment, the sequential intranasal administration method comprises:

-an initial phase of intranasal administration of at least one active principle from the DR group and at least one active principle from the ADR group, and

-at least one subsequent phase of simultaneous intranasal administration of at least one active principle from the DR group and at least one active principle from the ADR group,

wherein the selection of at least one subsequent stage of administration of intranasal administration is controlled by one or more information means.

In one embodiment, the initial phase is also controlled by one or more information components.

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

In one embodiment, the information means is at least one device for measuring at least one biological parameter and/or a timing means.

In one embodiment, the information means is at least one device for measuring at least one biological parameter and a timing means.

In one embodiment, the information component is at least one oximeter, and/or a respiration rate sensor, and/or a timing component.

In one embodiment, the information component is at least one of an oximeter, a respiration rate sensor, and a timing component.

In one embodiment:

-when the timing means indicate a dose interval below a threshold, a subsequent phase of intranasal administration comprises administration of at least one active ingredient from the ADR group;

and/or

-when the at least one device for measuring at least one biological parameter indicates hyperpnoea inhibition, a subsequent phase of intranasal administration comprises the administration of at least one active ingredient from the ADR group;

and

in all other cases, the subsequent phase of intranasal administration comprises the administration of at least one active ingredient from the DR group.

In one embodiment:

-when the timing means indicate a dose interval below a threshold, a subsequent phase of intranasal administration comprises administration of at least one active ingredient from the ADR group;

and/or

-when the at least one device for measuring at least one biological parameter indicates hyperpnoea inhibition, a subsequent phase of intranasal administration comprises the administration of at least one active ingredient from the ADR group;

and

-in all other cases, the subsequent phase of intranasal administration comprises the simultaneous administration of at least one active principle from the DR group and at least one active principle from the ADR group.

The invention also provides the use of at least one active ingredient from the DR group having at least one respiratory depression side effect and at least one active ingredient from the ADR group counteracting the respiratory depression caused by the active ingredients of the DR group for the treatment of pain. The use may be part of a sequential intranasal administration performed by the patient himself without any medical facilities, wherein the sequential intranasal administration comprises:

-an initial phase of intranasal administration of at least one active ingredient from the DR group, and

-at least one subsequent phase of intranasal administration of at least one active ingredient from the ADR group alone or in combination with at least one active ingredient from the DR group,

wherein the selection of at least one subsequent stage of administration of intranasal administration is controlled by one or more information means.

The invention also provides a method for the intranasal administration of active ingredients from the DR group with respiratory depression side effects for the treatment of pain, characterized in that it can be administered according to an intranasal administration method carried out independently outside any medical facility, together with or sequentially with at least one active ingredient from the ADR group that counteracts respiratory depression caused by the active ingredients from the DR group, and comprises:

-an initial phase of intranasal administration of at least one active ingredient from the DR group, and

-at least one subsequent phase of intranasal administration of at least one active ingredient from the ADR group alone or in combination with at least one active ingredient from the DR group,

wherein the selection of at least one subsequent stage of administration of intranasal administration is controlled by one or more information means.

In one embodiment, the active ingredient for use in the method of treating pain is characterized in that at least one active ingredient from the DR group is benzodiazepineAnd at least one active ingredient from the ADR group is flumazenil.

In one embodiment, the active ingredient for use in the method of treating pain is characterized in that at least one active ingredient from the DR group is sufentanil and at least one active ingredient from the ADR group is naloxone.

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 (e.g., naloxone) that counters respiratory depression caused by the opioid, it is contemplated that the active ingredients from the ADR group (e.g., naloxone) may be administered concurrently when the opioid from the DR group is administered.

In one embodiment, when from at least one of the DR groupsAn active ingredient is benzodiazepineAnd at least one active ingredient from the ADR group is resistant to benzodiazepinesClass-induced respiratory depression of active ingredients (e.g., flumazenil), expected when administered benzodiazepines from the DR groupWhen so desired, the active ingredients from the ADR group (e.g., flumazenil) may be administered simultaneously.

In one embodiment, the active ingredient from the DR group having at least one respiratory depression side effect in the method for the treatment of pain is characterized in that it can be administered intranasally according to a method carried out separately intranasally outside any medical facility, in sequence with at least one active ingredient from the ADR group counteracting the respiratory depression caused by the active ingredients of the DR group, and comprises:

-an initial phase of intranasal administration of at least one active principle from the DR group and at least one active principle from the ADR group, and

at least one subsequent phase of intranasal administration of at least one active principle from the ADR group alone or of at least one active principle from the DR group and of at least one active principle from the ADR group simultaneously,

wherein the selection of at least one subsequent stage of administration of intranasal administration is controlled by one or more information means.

In one embodiment, the active ingredient from the DR group having at least one respiratory depression side effect for use in the method of treating pain is characterized in that it can be intranasally administered according to an intranasal administration method carried out independently outside any medical facility, in sequence with at least one active ingredient from the ADR group counteracting respiratory depression caused by the active ingredient of the DR group, and comprises:

-an initial phase of intranasal administration of at least one active ingredient from the DR group, and

-at least one subsequent stage of intranasal administration of at least one active ingredient from the ADR group alone,

wherein the selection of at least one subsequent stage of administration of intranasal administration is controlled by one or more information means.

In one embodiment, the method of administering a dose comprises:

-an initial phase of intranasal administration of at least one active ingredient from the DR group, and

-at least one subsequent phase of simultaneous intranasal administration of at least one active ingredient from the DR group and at least one active ingredient from the ADR group, wherein the selection of the at least one subsequent phase of intranasal administration is controlled by one or more information means.

In one embodiment, the method of administering a dose comprises:

-an initial phase of intranasal administration of at least one active principle from the DR group and at least one active principle from the ADR group, and

-at least one subsequent phase of intranasal administration of at least one active ingredient from the ADR group alone,

wherein the selection of at least one subsequent stage of administration of intranasal administration is controlled by one or more information means.

In one embodiment, the method of administering a dose comprises:

-an initial phase of intranasal administration of at least one active principle from the DR group and at least one active principle from the ADR group, and

-at least one subsequent phase of simultaneous intranasal administration of at least one active ingredient from the DR group and at least one active ingredient from the ADR group, wherein the selection of the at least one subsequent phase of intranasal administration is controlled by one or more information means.

In one embodiment, the initial phase is also controlled by one or more information components.

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

In one embodiment, the information means is at least one device for measuring at least one biological parameter and/or a timing means.

In one embodiment, the information means is at least one device for measuring at least one biological parameter and a timing means.

In one embodiment, the information component is at least one oximeter and/or a respiration rate sensor and/or a timing component.

In one embodiment, the information component is at least one of an oximeter, a respiration rate sensor, and a timing component.

In one embodiment:

-when the timing means indicate a dose interval below a threshold, a subsequent phase of intranasal administration comprises administration of at least one active ingredient from the ADR group;

and/or

-when the at least one device for measuring at least one biological parameter indicates hyperpnoea inhibition, a subsequent phase of intranasal administration comprises the administration of at least one active ingredient from the ADR group;

and

in all other cases, the subsequent phase of intranasal administration comprises the administration of at least one active ingredient from the DR group.

In one embodiment:

-when the timing means indicate a dose interval below a threshold, a subsequent phase of intranasal administration comprises administration of at least one active ingredient from the ADR group;

and/or

-when the at least one device for measuring at least one biological parameter indicates hyperpnoea inhibition, a subsequent phase of intranasal administration comprises the administration of at least one active ingredient from the ADR group;

and

-in all other cases, the subsequent phase of intranasal administration comprises the simultaneous administration of at least one active principle from the DR group and at least one active principle from the ADR group.

In one embodiment, the sequential intranasal administrations carried out by the patient himself without any medical facilities comprise:

-an initial phase of intranasal administration of at least one active principle from the DR group and at least one active principle from the ADR group, and

at least one subsequent phase of intranasal administration of at least one active principle from the ADR group alone or of at least one active principle from the DR group and of at least one active principle from the ADR group simultaneously,

wherein the selection of at least one subsequent stage of administration of intranasal administration is controlled by one or more information means.

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

In one embodiment, when the at least one active ingredient from the DR group is an opioid, the at least one active ingredient from the ADR group is an active ingredient (e.g., naloxone) that counters respiratory depression caused by the opioid, and the opioid from the DR group is administered concurrently with the active ingredient (e.g., naloxone) from the ADR group.

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

In one embodiment, when at least one active ingredient from the DR group is benzodiazepineAnd at least one active ingredient from the ADR group is resistant to benzodiazepinesBenzodiazepines from the DR group when they are active ingredients causing respiratory depression (e.g. flumazenil)Class (e.g. famciclib) is administered simultaneously with the active ingredient from the ADR group.

In one embodiment, the sequential intranasal administrations carried out by the patient himself without any medical facilities comprise:

-an initial phase of intranasal administration of at least one active ingredient from the DR group, and

-at least one subsequent phase of intranasal administration of at least one active ingredient from the ADR group alone,

wherein the selection of at least one subsequent stage of administration of intranasal administration is controlled by one or more information means.

In one embodiment, the sequential intranasal administrations carried out by the patient himself without any medical facilities comprise:

-an initial phase of intranasal administration of at least one active ingredient from the DR group, and

-at least one subsequent phase of intranasal administration of at least one active ingredient from the DR group,

wherein the selection of at least one subsequent stage of administration of intranasal administration is controlled by one or more information means.

In one embodiment, the sequential intranasal administrations carried out by the patient himself without any medical facilities comprise:

-an initial phase of intranasal administration of at least one active principle from the DR group and at least one active principle from the ADR group, and

-at least one subsequent phase of intranasal administration of at least one active ingredient from the ADR group alone,

wherein the selection of at least one subsequent stage of administration of intranasal administration is controlled by one or more information means.

In one embodiment, the sequential intranasal administrations carried out by the patient himself without any medical facilities comprise:

-an initial phase of intranasal administration of at least one active principle from the DR group and at least one active principle from the ADR group, and

-at least one subsequent phase of simultaneous intranasal administration of at least one active principle from the DR group and at least one active principle from the ADR group,

wherein the selection of at least one subsequent stage of administration of intranasal administration is controlled by one or more information means.

In one embodiment, the initial phase is also controlled by a plurality of information means.

In one embodiment, the information means is at least one device for measuring at least one biological parameter and/or a timing means.

In one embodiment, the information means is at least one device for measuring at least one biological parameter and a timing means.

In one embodiment, the information component is at least one oximeter, and/or a respiration rate sensor and/or a timing component.

In one embodiment, the information component is at least one of an oximeter, a respiration rate sensor, and a timing component.

In one embodiment:

-when the timing means indicate a dose interval below a threshold, a subsequent phase of intranasal administration comprises administration of at least one active ingredient from the ADR group;

and/or

-when the at least one device for measuring at least one biological parameter indicates hyperpnoea inhibition, a subsequent phase of intranasal administration comprises the administration of at least one active ingredient from the ADR group;

and

in all other cases, the subsequent phase of intranasal administration comprises the administration of at least one active ingredient from the DR group.

In one embodiment:

-when the timing means indicate a dose interval below a threshold, a subsequent phase of intranasal administration comprises administration of at least one active ingredient from the ADR group;

and/or

-when the at least one device for measuring at least one biological parameter indicates hyperpnoea inhibition, a subsequent phase of intranasal administration comprises the administration of at least one active ingredient from the ADR group;

and

-in all other cases, the subsequent phase of intranasal administration comprises the simultaneous administration of at least one active principle from the DR group and at least one active principle from the ADR group.

The invention also relates to a sequential intranasal administration system.

In a case similar to the above, the administration system may be particularly useful for isolated persons.

In particular, the present invention relates to a system for the sequential intranasal administration of at least one active ingredient from the DR group having at least one respiratory depression side effect and at least one active ingredient from the ADR group counteracting the respiratory depression caused by the active ingredients of the DR group, said system comprising:

- (a) in response to an initial priming of the system by a patient wishing to receive a drug administration, simultaneously administering at least one active ingredient from the DR group, this administration constituting an initial administration recorded by the system;

- (B) in response to at least one subsequent activation of the system by a patient wishing to receive a subsequent administration of the drug, at least one subsequent administration of the initial administration of at least one active principle from the ADR group or of at least one active principle from the DR group, which administration constitutes a subsequent administration recorded by the system;

wherein the selection of subsequent applications is controlled by one or more informational components.

In one embodiment, the system comprises:

- (a) in response to an initial priming of the system by a patient wishing to receive a drug administration, simultaneously administering at least one active principle from the DR group and at least one active principle from the ADR group, the administration constituting an initial administration recorded by the system;

- (B) in response to at least one subsequent activation of the system by the patient wishing to receive a subsequent administration of the drug, at least one subsequent administration of the at least one active principle from the ADR group of the initial administration, or of the at least one active principle from the DR group and of the at least one active principle from the ADR group simultaneously, the administrations constituting subsequent administrations recorded by the system;

wherein the selection of subsequent applications is controlled by one or more informational components.

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

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 (e.g., naloxone) that counters respiratory depression caused by the opioid, the opioid of the DR group may be administered simultaneously with the active ingredient (e.g., naloxone) from the ADR group.

In one embodiment, when at least one active ingredient from the DR group is benzodiazepineAnd at least one active ingredient from the ADR group is resistant to benzodiazepinesBenzodiazepines of the DR group when they are active ingredients causing respiratory depression (e.g. flumazenil)The class may be administered simultaneously with the active ingredient from the ADR group (e.g. flumazenil).

In one embodiment, the system comprises:

-initial intranasal administration of at least one active ingredient from the DR group, and

at least one subsequent intranasal administration of the initial administration of at least one active ingredient from the ADR group alone,

wherein selection of subsequent intranasal administrations is controlled by one or more informational components.

In one embodiment, the system comprises:

-initial intranasal administration of at least one active ingredient from the DR group, and

-at least one subsequent intranasal administration of at least one active ingredient from the DR group,

wherein selection of subsequent intranasal administrations is controlled by one or more informational components.

In one embodiment, the system comprises:

-initial intranasal administration of at least one active principle from the DR group and at least one active principle from the ADR group, and

at least one subsequent intranasal administration of the initial administration of at least one active ingredient from the ADR group alone,

wherein selection of subsequent intranasal administrations is controlled by one or more informational components.

In one embodiment, the system comprises:

-initial intranasal administration of at least one active principle from the DR group and at least one active principle from the ADR group, and

-at least one subsequent intranasal administration of at least one active principle from the DR group and at least one active principle from the ADR group simultaneously,

wherein the selection of subsequent applications is controlled by one or more informational components.

In one embodiment, the administering (a) is further controlled by one or more informative means comprising at least measuring a biological parameter.

In one embodiment, the information means is at least one device for measuring at least one biological parameter and/or a timing means.

In one embodiment, the information means is at least one device for measuring at least one biological parameter and a timing means.

In one embodiment, the information component is at least one oximeter and/or a respiration rate sensor and/or a timing component.

In one embodiment, the information component is at least one of an oximeter, a respiration rate sensor, and a timing component.

In one embodiment:

-when the timer indicates a dosing interval of less than the threshold, the subsequent administration comprises administering at least one active ingredient from the ADR group;

and/or

-when the at least one means for measuring at least one biological parameter indicates excessive respiratory depression, the subsequent administration comprises administering at least one active ingredient from the ADR group;

and

-in all other cases, the subsequent administration comprises the administration of at least one active ingredient from the DR group.

In one embodiment:

-when the timer indicates a dosing interval of less than the threshold, the subsequent administration comprises administering at least one active ingredient from the ADR group;

and/or

-when the at least one means for measuring at least one biological parameter indicates excessive respiratory depression, the subsequent administration comprises administering at least one active ingredient from the ADR group;

and

-in all other cases, the subsequent administration comprises the simultaneous administration of at least one active principle from the DR group and at least one active principle from the ADR group.

The invention also relates to an intranasal administration system having a portable device for sequential intranasal administration according to the present disclosure.

In one embodiment, an intranasal administration system having a portable device for sequential intranasal administration according to the present disclosure comprises:

-at least a first storage space containing a first active sprayable formulation comprising at least one active ingredient from the DR group;

-at least a second storage space containing a second active sprayable formulation different from the first active formulation, said second active sprayable formulation comprising at least one active ingredient from the ADR group;

-a signal processing unit;

-a first and a second storage space with a first and a second active agent, respectively, are operatively connected to the connection part of the dispensing part, which is operatively connected to the signal processing unit;

-one or more information components operatively connected to the signal processing unit;

-a control means allowing the patient to receive the active agent by self-administration without any medical facilities;

-a dispensing member for delivering the active agent through the nasal mucosa; and

-an autonomous power source,

wherein the signal processing unit, the connecting means, the information means and the control means are configured to allow connecting the first active agent in the first storage space with the dispensing means or connecting the second active agent in the second storage space with the dispensing means based on one or more signals received by the signal processing unit from the information means.

In one embodiment, an intranasal administration system having a portable device for sequential intranasal administration according to the present disclosure comprises:

-at least a first storage space containing a first active sprayable formulation comprising at least one active ingredient from the DR group and at least one active ingredient from the ADR group mixed;

-at least a second storage space having a second active sprayable formulation different from the first active formulation, said second active sprayable formulation comprising at least one active ingredient from the ADR group;

-a signal processing unit;

-the first and second active agents of the first and second storage spaces, respectively, are operatively connected to a connection part of the dispensing member, which is operatively connected to the signal processing unit;

-one or more information components operatively connected to the signal processing unit;

-a control means allowing the patient to receive the active agent by self-administration without any medical facilities;

-a dispensing member for delivering the active agent through the nasal mucosa; and

-an autonomous power source,

wherein the signal processing unit, the connecting means, the information means and the control means are configured to allow connecting the first active agent in the first storage space with the dispensing means or connecting the second active agent in the second storage space with the dispensing means based on one or more signals received by the signal processing unit from the information means.

When the at least one active ingredient from the DR group is an opioid and the at least one active ingredient from the ADR group is an active ingredient (e.g., naloxone) that counters respiratory depression caused by the opioid, the first storage space having the first active formulation disposed therein may contain both the active ingredient from the DR group selected from the opioid and the active ingredient from the ADR group (e.g., naloxone).

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

When at least one active ingredient from the DR group is benzodiazepineClass and from ADR groupAt least one active ingredient is active against benzodiazepinesWhen an active ingredient that causes respiratory depression (e.g., flumazenil) is a class, the first storage space having the first active agent disposed therein may contain a second storage space selected from the group consisting of benzodiazepinesBoth active ingredients from the DR group and active ingredients from the ADR group (e.g., flumazenil) of the class.

In one embodiment, the energy source is electrical energy.

In one embodiment, the signal processing unit comprises a microprocessor.

In one embodiment, the signal processing unit is operatively connected to one or more memory areas configured to store data received from the information component.

In one embodiment, the information means is at least one device for measuring at least one biological parameter and/or a timing means.

In one embodiment, the information means is at least one device for measuring at least one biological parameter and a timing means.

In one embodiment, the information component is at least one oximeter and/or a respiration rate sensor and/or a timing component.

In one embodiment, the information component is at least one of an oximeter, a respiration rate sensor, and a timing component.

In one embodiment, the dispensing component of the active agent is a nasal strip (embout nasal) and the oximeter and respiration rate sensor are located on the nasal strip for measuring and/or calculating physiological values of the patient receiving the active agent.

In one embodiment, the timing component is integrated into a microprocessor of the signal processing unit.

In one embodiment:

-the means for measuring and/or calculating at least one biological parameter send information to a signal processing unit having a memory area configured to store physiological values;

-the signal processing unit, upon receiving information from the means for measuring at least one biological parameter, interrogates the timing means to obtain a current time value and stores the time value in the memory area.

In one embodiment:

-the signal processing unit makes a comparison between the physiological value obtained from the means for measuring at least one biological parameter and the threshold value stored in the memory area;

-the signal processing unit makes a comparison between the time value stored in the memory area and the updated time value received from the timing member at the time of the comparison, to calculate the time interval elapsed since the previous application;

-upon determination of these comparisons, the signal processing unit sends a signal to the connection means to allow the patient to receive the administration of the active agent, thereby activating the control means and self-administering one of the active agents.

In one embodiment:

-if the signal processing unit determines that the physiological value is greater than the threshold value and that a sufficient time interval has elapsed since the previous administration, the signal processing unit sends a signal to the connecting means to enable a subsequent administration of the first active agent; or

-if the signal processing unit determines that the physiological value is less than the threshold value, or that an insufficient time interval has elapsed since the previous administration, the signal processing unit sends a signal to the connecting means to enable a subsequent administration of the second active agent.

In one embodiment, the storage space is removable.

In one embodiment, the storage space is variable. The storage space is "variable" in that it can be removed and replaced by a new storage space containing the same active ingredient.

In one embodiment, the storage space is removable and variable.

Indeed, as noted above, the medical device may incorporate a variety of active agents, each of which may be suitable for a given patient in terms of qualitative and quantitative composition. The choice of dosage and the active ingredient used can be determined by the medical staff. In addition, the time interval may be predetermined by medical personnel.

In one embodiment, the medical device further comprises a patient signaling component.

In one embodiment, the patient signal component is an optical signal.

The invention will be better understood upon reading the following description of the drawings.

FIG. 1: exemplary device according to the invention

Fig. 1 illustrates a portable device 1 for intranasal administration according to the principles of the present disclosure. The first storage space 2 may contain a first active agent 12 comprising an active ingredient 12a from the DR group and an active ingredient 12b from the ADR group. The second storage space 3 may contain a second active agent 11 comprising at least one active ingredient 11a from the ADR group.

The signal processing unit 4 is connected to the connection part 5. The connecting part 5 comprises a dosing chamber 5a, a valve 5c with a valve axis 5b and conduits 5d and 5e connected to the first and second storage spaces 3 and 2, respectively. The signal processing unit 4 is also connected to an information part 6. The information means 6 also contains a clock 6a, a respiration rate sensor 6b and/or an oximeter 6 c.

When using the device 1, the user inserts the nose strip 7a into the nasal cavity (not shown) of the patient. The information component (e.g., oximeter 6c and/or respiration rate sensor 6b) may measure and determine values and communicate the values to the signal processing unit 4. The signal processing unit 4 may also communicate with the 6a clock to calculate the time elapsed since the last administration of the active agent 12. Alternatively, the signal processing unit 4 may have a clock (e.g. a PSTN circuit or other timer integrated therewith) to avoid providing a separate clock.

When the user activates the control means 8, as shown in fig. 1, the signal processing unit 4 controls the connection, for example by means of the dispensing conduit 5f, by connecting the connecting means 5 of the first storage space 2 or the second storage space 3 with the dispensing means 7, for example the nose piece 7a, on the basis of the information provided by the information means 6, for the push button 8 a.

As shown in fig. 1. The connection comprises an actuator valve 5c mounted on a valve shaft 5b in the dosing chamber 5 a. The valve 5c may be switched to either side of the valve shaft 5b to press against the side wall of the dosing chamber 5a and may therefore close one of the conduits 5d or 5e based on the active agent that is decided to be administered by the signal processing unit 4.

The selected active agent to be administered from the device 1 flows through the dispensing tube 5f and out of the outlet 13 before coming into contact with the nasal mucosa.

At any time, the user may obtain information about the active agent being administered from the activation button 8a through the patient signaling means 9 (e.g., light 9 a).

The user may then decide whether to activate the button 8 a.

Autonomous power source 10 supplies power to device 1 and may be a rechargeable battery, a photovoltaic cell, or other suitable source.

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

Fig. 2 is a schematic block diagram illustrating various features of the apparatus 1 according to the principles of the present disclosure.

Fig. 2 shows that the signal processing unit 4 is connected to:

-an information component 6;

-a connecting member 5;

-a control unit 8; and

a lamp 9a

The connecting part 5 is further connected to

First and second storage spaces 2 and 3;

-a dispensing member 7.

When the device 1 is used, the information means 6 supply information to the signal processing unit 4.

When the user activates the control means 8, the signal processing unit 4 is in control connection with the connection means 5 of the allocation means 7 via the first memory space 2 or the second memory space 3 on the basis of the information provided by the information means 6.

Autonomous power source 10 supplies power to device 1 and may be a rechargeable battery, a photovoltaic cell, or other suitable source.

The device 1 may be used by a patient desiring a treatment for intranasal administration. The device 1 may be used by a person in isolation as described above. To use the device 1, the patient can quickly find the device 1, for example from a backpack or its optional case. The user then positions the dispensing member 7, for example the nose piece 7 a. The patient signaling means 9 (e.g. light 9a) may communicate to the patient which of the two active agents will be administered upon activation of the control means 8. Finally, to use the device 1, the patient activates a control member 8, such as a button 8 a. The control member 8 may also be any device capable of receiving activating mechanical stress, voice, etc. As part of the treatment, the patient may be given as many intranasal administrations as possible. While this therapy may be an "on-demand" treatment, it is completely safe and reliable.

The device 1 may incorporate a plurality of active agents, such as active agents 11 and 12, each of which may be available in qualitative and quantitative composition for a given patient. The choice of dosage and which active ingredient to use can be determined by the medical practitioner. The time interval, e.g. the minimum duration between administration of the active ingredients from the DR and/or ADR group as calculated by the timing means, e.g. clock 6a, may be predetermined by the medical staff.

Therefore, the apparatus 1 can be simplified in difficult situations, particularly in use environments such as armed conflicts, natural disasters, and the like.

In one embodiment, an intranasal delivery system having a portable device 1 for sequential intranasal administration according to the principles of the present disclosure comprises:

-at least a first storage space 2 containing a first sprayable active formulation 12, said first sprayable active formulation 12 comprising at least one active ingredient 12a from the DR group;

-at least a second storage space 3 containing a second sprayable active formulation 11 different from the first sprayable active formulation 12, said second sprayable active formulation 11 containing at least one active ingredient 11a from the ADR group;

-a signal processing unit 4;

the active agents 12 and 11 of the first and second storage spaces 2 and 3, respectively, are operatively connected to the connection means 5 of the dispensing means 7, which is operatively connected to the signal processing unit 4;

one or more information means 6 operatively connected to the signal processing unit 4;

a control component 8 configured to allow self-administration of the active agent by a patient receiving the active agent without any medical facilities;

a dispensing member 7 for delivering the active agent through the nasal mucosa; and

-an autonomous power supply 10, and,

wherein the signal processing unit 4, the connecting means 5, the information means 6 and the control means 8 are configured to allow connecting the first active formulation 12 in the first storage space 2 with the dispensing means 7 or connecting the second active formulation 11 in the second storage space 3 with the dispensing means 7 based on one or more signals from the information means 6 received by the processing unit 4.

In one embodiment, an intranasal delivery system having a portable device 1 for sequential intranasal administration according to the principles of the present disclosure comprises:

-at least one first storage space 2 containing a first sprayable active formulation 12, said first sprayable active formulation 12 comprising at least one active ingredient 12a from the DR group and at least one active ingredient 12b from the ADR group;

-at least one second storage space 3 containing a second sprayable active formulation 11 different from the first active formulation 12, said second sprayable active formulation 11 comprising at least one active ingredient 11a from the ADR group;

-a signal processing unit 4;

the active agents 12 and 11 of the first and second storage spaces 2 and 3, respectively, are operatively connected to the connection means 5 of the dispensing means 7, which is operatively connected to the signal processing unit 4;

one or more information means 6 operatively connected to the signal processing unit 4;

a control component 8 configured to allow self-administration of the active agent by a patient receiving the active agent without any medical facilities;

a dispensing member 7 for delivering the active agent through the nasal mucosa; and

-an autonomous power supply 10, and,

wherein the signal processing unit 4, the connecting means 5, the information means 6 and the control means 8 are configured to allow connecting the first active formulation 12 in the first storage space 2 with the dispensing means 7 and/or connecting the second active formulation 11 in the second storage space 3 with the dispensing means 7 based on one or more signals from the information means 6 received by the signal processing unit 4.

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 (e.g., naloxone) that counters respiratory depression caused by the opioid, the first storage space 2 having the first active formulation 12 disposed therein may contain both an active ingredient from the DR group selected from the opioid and an active ingredient (e.g., naloxone) from the ADR group.

In one embodiment, when at least one active ingredient from the DR group is benzodiazepineAnd at least one active ingredient from the ADR group is resistant to benzodiazepinesWhen an active ingredient that causes respiratory depression (e.g., flumazenil) is to be classed, the first storage space 2 having the first active agent 12 disposed therein may contain a second ingredient selected from the group consisting of benzodiazepinesBoth active ingredients from the DR group and active ingredients from the ADR group (e.g. flumazenil) of the class.

In one embodiment, the energy source 10 is electrical energy.

In one embodiment, the signal processing unit 4 comprises a microprocessor.

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

In one embodiment, the information means 6 comprises at least one device for measuring at least one biological parameter and/or timing means.

In one embodiment, the information means 6 comprises at least one device for measuring at least one biological parameter and a timing means.

In one embodiment, information component 6 comprises at least one oximeter 6c and/or respiration rate sensor 6b and/or a timing component.

In one embodiment, information component 6 comprises at least one oximeter 6c, a respiration rate sensor 6b and a timing component.

In one embodiment, dispensing component 7 comprises a nose strip 7a, such that oximeter 6c and respiration rate sensor 6b are located on nose strip 6a for measuring and/or calculating physiological values of the patient receiving the administration of the active agent.

In one embodiment, the timing means is integrated in the microprocessor of the signal processing unit 4.

In one embodiment:

one or more means for measuring and/or calculating at least one biological parameter send information to the signal processing unit 4 having a memory area configured to store physiological values; and

the signal processing unit 4, upon receiving information from the means for measuring at least one biological parameter, interrogates the timing means to obtain the current time value and stores the time value in the memory area.

In one embodiment:

the signal processing unit 4 performs a comparison between the physiological values obtained from the one or more devices for measuring at least one biological parameter and the threshold values stored in the memory area;

the signal processing unit 4 performs a comparison between the time values stored in the memory area and the updated time values received from the timing means at the time of comparison, to calculate the time interval elapsed since the previous application;

on the basis of the determination of these comparisons, the signal processing unit 4 sends a signal to the connection means 5 to subject the patient to administration, thereby activating the control means 8 to self-administer an active agent.

In one embodiment:

if the signal processing unit 4 determines that the physiological value is greater than the threshold value and that a sufficient time interval has elapsed since the previous administration, the signal processing unit 4 sends a signal to the connecting means 5 to allow the subsequent administration of the first active agent 12; or

If the signal processing unit 4 determines that the physiological value is less than the threshold value, wherein an insufficient time interval has elapsed since the previous administration, the signal processing unit 4 sends a signal to the connecting means 5 to allow a subsequent administration of the second active agent 11.

In one embodiment, the storage space is removable.

In one embodiment, the storage space is variable. The storage space is "variable" indicating that it can be removed and replaced by a new storage space containing the same active ingredient.

In one embodiment, storage space 2 and storage space 3 are removable and variable.

Indeed, as noted above, the device 1 may contain a plurality of active agents, each of which may be available in a qualitative and quantitative composition for a given patient. The choice of dosage and the active ingredient used can be determined by the medical staff. In addition, the time interval may be predetermined by medical personnel.

In one embodiment, the device 1 further comprises a patient signaling component 9.

In one embodiment, the patient signaling component 9 may be a light 9 a.

With respect to the doses of active ingredient from the DR and ADR groups, all doses were estimated for patients of about 70kg (which represents the average body weight). These doses may vary, especially for patients of varying weight. The dosage may also be appropriate for the particular animal. The dosage may be adjusted as is well known in the art.

The following embodiments are applicable to methods, administration systems, and portable devices for administering active ingredients for treating pain according to the principles of the present disclosure.

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

In one embodiment, the threshold value of the timing component is 1 to 10 hours.

In one embodiment, the threshold value of the timing component is 4 to 8 hours.

In one embodiment, the threshold of the timing component is about 6 hours.

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

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

In one embodiment, the threshold value for the oxygen saturation measurement is 70% to 90%.

In one embodiment, the threshold value for the oxygen saturation measurement is 80% to 90%.

In one embodiment, the threshold for oxygen saturation measurements is about 85%.

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

In one embodiment, the threshold value for the measured respiration rate is 8 to 14 cycles/minute.

In one embodiment, the threshold value for the measured respiration rate is 8 to 12 cycles/minute.

In one embodiment, the threshold value for the measured respiration rate is about 12 cycles/minute.

In one embodiment, the biological parameters measured are oxygen saturation and respiration rate.

In one embodiment, the active ingredient is in the form of a sprayable liquid.

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

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

In one embodiment, the active ingredient from the DR group used during the initial phase and the active ingredient from the DR group used during at least one subsequent phase are the same.

In one embodiment, the active ingredient from the DR group used during the initial phase is different from the active ingredient from the DR group used during at least one subsequent phase.

In one embodiment, the active ingredient from the ADR group used during the initial phase and the active ingredient from the ADR group used during at least one subsequent phase are the same.

In one embodiment, the active ingredient from the ADR group used during the initial phase and the active ingredient from the ADR group used during at least one subsequent phase are different.

In one embodiment, the active ingredient from the DR group consists of an opioid agonist and the active ingredient from the ADR group consists of an opioid antagonist.

In one embodiment, at least one active ingredient from the DR group is selected from alfentanil, anileridine, apomorphine, buprenorphine, butorphanol, carfentanil, codeine, diacetylmorphine ("heroin"), dextropropoxyphene, dihydromorphine, fentanyl, hydrocodone, hydromorphone, levorphanol, methadone, morphine, nalbuphine, nalprofen, norlevorphanol, oxycodone, oxymorphone, pentazocine, pethidine, propoxyphene, remifentanil, sufentanil, tramadol and the like.

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

In one embodiment, at least one active ingredient from the DR group is sufentanil.

In one embodiment, at least one active ingredient from the ADR group is selected from naloxone and naltrexone.

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

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.

In one embodiment, the dose of sufentanil is from 2 to 50 μ g and the dose of naloxone is from 2 to 50 mg.

In one embodiment, the dose of sufentanil is from 5 to 30 μ g and the dose of naloxone is from 5 to 30 mg.

In one embodiment, the dose of sufentanil is from 10 to 20 μ g and the dose of naloxone is from 10 to 20 mg.

In one embodiment, the dose of sufentanil is 10 μ g and the dose of naloxone is 10 mg.

In one embodiment, the dose of sufentanil is 15 μ g and the dose of naloxone is 15 mg.

In one embodiment, the dose of sufentanil is 20 μ g and the dose of naloxone is 20 mg.

In one embodiment, the weight ratio of sufentanil to naloxone is from 0.00004 to 0.025.

In one embodiment, the weight ratio of sufentanil to naloxone is about 0.001.

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 a concomitant administration of ketamine.

In one embodiment, sufentanil, naloxone, and ketamine are a mixture.

In one embodiment, the dose of sufentanil is from 1 to 60 μ g, the dose of ketamine is from 1 to 60mg, and the dose of naloxone is from 1 to 60 mg.

In one embodiment, the dose of sufentanil is from 10 to 55 μ g, the dose of ketamine is from 10 to 55mg, and the dose of naloxone is from 10 to 55 mg.

In one embodiment, the dose of sufentanil is 17 to 50 μ g, the dose of ketamine is 17 to 50mg, and the dose of naloxone is 17 to 50 mg.

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

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

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

In one embodiment, the weight ratio of sufentanil to naloxone and the weight ratio of ketamine to naloxone are 0.00034 to 0.0029 and 0.34 to 2.9, respectively.

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

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.

In one embodiment, the dose of fentanyl is from 10 to 150g and the dose of naloxone is from 2 to 50 mg.

In one embodiment, the dose of fentanyl is from 30 to 120 μ g and the dose of naloxone is from 5 to 30 mg.

In one embodiment, the dose of fentanyl is from 50 to 100 μ g and the dose of naloxone is from 10 to 20 mg.

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

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

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

In one embodiment, the weight ratio of fentanyl to naloxone is from 0.0002 to 0.075.

In one embodiment, the weight ratio of fentanyl to naloxone is about 0.005.

In one embodiment, at least one active ingredient from the DR group is diacetylmorphine and at least one active ingredient from the ADR group is naloxone.

In one embodiment, the dose of diacetylmorphine is from 0.1 to 20mg and the dose of naloxone is from 2 to 50 mg.

In one embodiment, the dose of diacetylmorphine is in the range of 1 to 10mg and the dose of naloxone is in the range of 5 to 30 mg.

In one embodiment, the dose of diacetylmorphine is from 2 to 4mg and the dose of naloxone is from 10 to 20 mg.

In one embodiment, the dose of diacetylmorphine is 2mg and the dose of naloxone is 10 mg.

In one embodiment, the dose of diacetylmorphine is 3mg and the dose of naloxone is 15 mg.

In one embodiment, the dose of diacetylmorphine is 4mg and the dose of naloxone is 20 mg.

In one embodiment, the weight ratio of diacetylmorphine to naloxone is in the range of 0.02 to 10.

In one embodiment, the weight ratio of diacetylmorphine to naloxone is about 0.2.

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.

In one embodiment, the dose of buprenorphine is from 0.1 to 30mg and the dose of naloxone is from 0.1 to 5 mg.

In one embodiment, the dose of buprenorphine is from 1 to 15mg and the dose of naloxone is from 0.3 to 3 mg.

In one embodiment, the dose of buprenorphine is from 2 to 8mg and the dose of naloxone is from 0.5 to 2 mg.

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

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

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

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

In one embodiment, the weight ratio of buprenorphine to naloxone is from 0.02 to 300.

In one embodiment, the weight ratio of buprenorphine to naloxone is about 4.

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.

In one embodiment, the dose of carfentanil is from 70 to 1900 μ g and the dose of naloxone is from 0.3 to 3.7 mg.

In one embodiment, the dose of carfentanil is from 140 to 1400 μ g and the dose of naloxone is from 0.5 to 3.0 mg.

In one embodiment, the dose of carfentanil is from 350 to 1000 μ g and the dose of naloxone is from 0.7 to 2.0 mg.

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

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

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

In one embodiment, the weight ratio of carfentanil to naloxone is in the range of 0.019 to 6.6.

In one embodiment, the weight ratio of carfentanil to naloxone is about 0.5.

In one embodiment, in the active formulation without active ingredient from the DR group, the at least one active ingredient from the ADR group is naloxone and the dosage of naloxone is 1 to 40 mg.

In one embodiment, in the active formulation without active ingredient from the DR group, the at least one active ingredient from the ADR group is naloxone and the dosage of naloxone is 5 to 20 mg.

When the at least one active ingredient from the DR group is buprenorphine, the at least one active ingredient from the ADR group is naloxone and the dosage of naloxone is 3 to 7mg in an active formulation without an active ingredient from the DR group.

In one embodiment, the DR group consists of phenylenediNitrogen is present inOf the class and the ADR group consisting of benzodiazepinesThe antagonist-like composition.

In one embodiment, benzodiazepinesThe class is selected from lorazepam, midazolam and flunitrazepam.

In one embodiment, benzodiazepinesThe antagonist-like is flumazenil.

In one embodiment, benzodiazepinesThe class is lorazepam and benzodiazepineThe antagonist-like is flumazenil.

In one embodiment, the dose of lorazepam is 2 to 5 mg.

In one embodiment, benzodiazepinesThe class is midazolam and benzodiazepineThe antagonist-like is flumazenil.

In one embodiment, the dose of midazolam is 3.5 to 10 mg.

In one embodiment, benzodiazepinesThe class is flunitrazepam and benzodiazepinesThe antagonist-like is flumazenil.

In one embodiment, the dose of flunitrazepam is 2 to 10 mg.

In one embodiment, in the active formulation without active ingredient from the DR group, the at least one active ingredient from the ADR group is flumazenil and the dose of flumazenil is from 0.1 to 1 mg.

In one embodiment, in the active formulation without active ingredient from the DR group, the at least one active ingredient from the ADR group is flumazenil and the dose of flumazenil is from 0.6 to 1 mg.

In one embodiment, the active ingredient from the DR group is selected from benzodiazepinesActive preparations that are classified and contain an active ingredient from the DR group do not contain an active ingredient from the ADR group.

In one embodiment, the at least one active ingredient from the DR group is lorazepam and the active formulation comprising lorazepam does not comprise flumazenil.

In one embodiment, the at least one active ingredient from the DR group is midazolam and the active formulation comprising midazolam does not comprise flumazenil.

In one embodiment, the at least one active ingredient from the ADR group is flunitrazepam and the active formulation comprising flunitrazepam does not comprise flumazenil.

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

In one embodiment, the biological parameter is measured by means of a device for measuring at least one biological parameter accompanying each administration into the nasal cavity, the threshold value of the timing means is 4 to 8 hours, the measured biological parameters are oxygen saturation and respiration rate, the at least one active ingredient from the DR group and the 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 phase and the active ingredient from the DR group used during at least one subsequent phase are the same, 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, wherein the dose of sufentanil is 17 to 50 μ g and the dose of naloxone is 17 to 50 mg.

In one embodiment, the biological parameter is measured by means of a device for measuring at least one biological parameter accompanying each administration into the nasal cavity, the threshold value of the timing means is 4 to 8 hours, the measured biological parameters are oxygen saturation and respiration rate, the at least one active ingredient from the DR group and the 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 an initial phase and the active ingredient from the DR group used during at least one subsequent phase are the same, the at least one active ingredient from the DR group is sufentanil, the at least one active ingredient from the ADR group is naloxone, the dose of sufentanil is 17 to 50 μ g and the dose of naloxone is 17 to 50mg, any administration of sufentanil is accompanied by a simultaneous administration of ketamine, wherein sufentanil and ketamine are in the mixture, and ketamine doses of 17 to 50 mg.

In one embodiment, the biological parameter is measured by means of a device for measuring at least one biological parameter accompanying each administration into the nasal cavity, the threshold value of the timing means is 4 to 8 hours, the measured biological parameters are oxygen saturation and respiration rate, the at least one active ingredient from the DR group and the at least one active ingredient from the ADR group are in a mixture when administered simultaneously, the active ingredient from the DR group used during the initial phase and the active ingredient from the DR group used during the at least one subsequent phase are the same, the at least one active ingredient from the DR group is fentanyl and the at least one active ingredient from the ADR group is naloxone, wherein the dose of fentanyl is 50 to 100 μ g and the dose of naloxone is 10 to 20 mg.

In one embodiment, the biological parameter is measured by means of a device for measuring at least one biological parameter accompanying each administration into the nasal cavity, the threshold value of the timing means is 4 to 8 hours, the measured biological parameters are oxygen saturation and respiration rate, the at least one active ingredient from the DR group and the at least one active ingredient from the ADR group are in a mixture when administered simultaneously, the active ingredient from the DR group used during the initial phase and the active ingredient from the DR group used during the at least one subsequent phase are the same, the at least one active ingredient from the DR group is diacetylmorphine and the at least one active ingredient from the ADR group is naloxone, wherein the dose of diacetylmorphine is 2 to 4mg and the dose of naloxone is 10 to 20 mg.

In one embodiment, the biological parameters are measured by means of a device for measuring at least one biological parameter accompanying each administration into the nasal cavity, the threshold value of the timing means is 4 to 8 hours, the measured biological parameters are oxygen saturation and respiration rate, the at least one active ingredient from the DR group and the at least one active ingredient from the ADR group are in a mixture when administered simultaneously, the active ingredient from the DR group used during the initial phase and the active ingredient from the DR group used during the at least one subsequent phase are the same, the at least one active ingredient from the DR group is buprenorphine and the at least one active ingredient from the ADR group is naloxone, wherein the dose of buprenorphine is 2 to 8mg and the dose of naloxone is 0.5 to 2 mg.

In one embodiment, the biological parameters are measured by means of a device for measuring at least one biological parameter accompanying each administration into the nasal cavity, the threshold value of the timing means is 4 to 8 hours, the measured biological parameters are oxygen saturation and respiration rate, the at least one active ingredient from the DR group and the at least one active ingredient from the ADR group are in a mixture when administered simultaneously, the active ingredient from the DR group used during the initial phase and the active ingredient from the DR group used during the at least one subsequent phase are the same, the at least one active ingredient from the DR group is carfentanil and the at least one active ingredient from the ADR group is naloxone, wherein the dose of carfentanil is 350 to 1000 μ g and the dose of naloxone is 0.7 to 2.0 mg.

In one embodiment, the active ingredient from the DR group consists of an opioid agonist and the active ingredient from the ADR group consists of an opioid antagonist, and when at least one active ingredient from the DR group is administered, no active ingredient from the ADR group is administered.

In one embodiment, the biological parameter is measured by means of a device for measuring at least one biological parameter accompanying each administration into the nasal cavity, the threshold value of the timing means is 4 to 8 hours, the measured biological parameters are oxygen saturation and respiration rate, the active ingredient from the DR group used during the initial phase and the active ingredient from the DR group used during the at least one subsequent phase are the same, 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, wherein the dose of sufentanil is 17 to 50 μ g and the dose of naloxone is 17 to 50 mg.

In one embodiment, the biological parameter is measured by means of a device for measuring at least one biological parameter accompanying each administration into the nasal cavity, the threshold value of the timing element is 4 to 8 hours, the measured biological parameters are oxygen saturation and respiration rate, the active ingredient from the DR group used during the initial phase and the active ingredient from the DR group used during the at least one subsequent phase are the same, the at least one active ingredient from the DR group is sufentanil, the at least one active ingredient from the ADR group is naloxone, the dose of sufentanil is 17 to 50 μ g and the dose of naloxone is 17 to 50mg, any administration of sufentanil is accompanied by a simultaneous administration of ketamine, wherein sufentanil and ketamine are in a mixture and the dose of ketamine is 17 to 50 mg.

In one embodiment, the biological parameter is measured by means of a device for measuring at least one biological parameter accompanying each administration into the nasal cavity, the threshold value of the timing element being 4 to 8 hours, the biological parameter measured being the oxygen saturation and the respiration rate, the active ingredient from the DR group used during the initial phase and the active ingredient from the DR group used during the at least one subsequent phase being the same, the at least one active ingredient from the DR group being fentanyl and the at least one active ingredient from the ADR group being naloxone, wherein the dose of fentanyl is 50 to 100 μ g and the dose of naloxone is 10 to 20 mg.

In one embodiment, the biological parameter is measured by means of a device for measuring at least one biological parameter accompanying each administration into the nasal cavity, the threshold value of the timing means is 4 to 8 hours, the measured biological parameters are oxygen saturation and respiration rate, the active ingredient from the DR group used during the initial phase and the active ingredient from the DR group used during at least one subsequent phase are the same, the at least one active ingredient from the DR group is diacetylmorphine and the at least one active ingredient from the ADR group is naloxone, wherein the dose of diacetylmorphine is 2 to 4mg and the dose of naloxone is 10 to 20 mg.

In one embodiment, the biological parameter is measured by means of a device for measuring at least one biological parameter accompanying each administration into the nasal cavity, the threshold value of the timing means being 4 to 8 hours, the measured biological parameters being oxygen saturation and respiration rate, the active ingredient from the DR group used during the initial phase and the active ingredient from the DR group used during the at least one subsequent phase being the same, the at least one active ingredient from the DR group being buprenorphine and the at least one active ingredient from the ADR group being naloxone, wherein the dose of buprenorphine is 2 to 8mg and the dose of naloxone is 0.5 to 2 mg.

In one embodiment, the biological parameter is measured by means of a device for measuring at least one biological parameter accompanying each administration into the nasal cavity, the threshold value of the timing element is 4 to 8 hours, the measured biological parameters are oxygen saturation and respiration rate, the active ingredient from the DR group used during the initial phase and the active ingredient from the DR group used during the at least one subsequent phase are the same, the at least one active ingredient from the DR group is carfentanil and the at least one active ingredient from the ADR group is naloxone, wherein the dose of carfentanil is 350 to 1000 μ g and the dose of naloxone is 0.7 to 2.0 mg.

In one embodiment, the active ingredient from the DR group is composed of benzodiazepinesAre composed of and the active ingredient from the ADR group consists of benzodiazepineAntagonist-like compositions and, when at least one active ingredient from the DR group is administered, the active ingredient from the ADR group is administered simultaneously.

In one embodiment, the biological parameter is measured by means of a device for measuring at least one biological parameter associated with each administration into the nasal cavity, the timing means having a threshold value of 4 to 8 hours, the measured biological parameters are oxygen saturation and respiration rate, at least one active ingredient from the DR group and at least one active ingredient from the ADR group being in a mixture when administered simultaneously, the active ingredient from the DR group used during the initial phase and the active ingredient from the DR group used during the at least one subsequent phase are the same, the at least one active ingredient from the DR group is midazolam, wherein the dose of midazolam is between 3.5 and 10mg and, when the active formulation does not contain an active ingredient from the DR group, the at least one active ingredient from the ADR group is flumazenil, wherein the dose of flumazenil is between 0.6 and 1 mg.

In one embodiment, the biological parameter is measured by means of a device for measuring at least one biological parameter associated with each administration into the nasal cavity, the timing means having a threshold value of 4 to 8 hours, the measured biological parameters are oxygen saturation and respiration rate, at least one active ingredient from the DR group and at least one active ingredient from the ADR group being in a mixture when administered simultaneously, the active ingredient from the DR group used during the initial phase and the active ingredient from the DR group used during the at least one subsequent phase are the same, the at least one active ingredient from the DR group is lorazepam, wherein the dose of lorazepam is between 2 and 5mg, and when the active agent does not contain an active ingredient from the DR group, the at least one active ingredient from the ADR group is flumazenil, wherein the dose of flumazenil is between 0.6 and 1 mg.

In one embodiment, the biological parameter is measured by means of a device for measuring at least one biological parameter associated with each administration into the nasal cavity, the timing means having a threshold value of 4 to 8 hours, the measured biological parameters are oxygen saturation and respiration rate, at least one active ingredient from the DR group and at least one active ingredient from the ADR group being in a mixture when administered simultaneously, the active ingredient from the DR group used during the initial phase and the active ingredient from the DR group used during the at least one subsequent phase are the same, the at least one active ingredient from the DR group is flunitrazepam, wherein the dose of flunitrazepam is between 2 and 10mg, and when the active preparation does not comprise an 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.

In one embodiment, the active ingredient from the DR group is composed of benzodiazepinesAre composed of and the active ingredient from the ADR group consists of benzodiazepineThe antagonist-like composition and, when at least one active ingredient from the DR group is administered, no active ingredient from the ADR group is administered.

In one embodiment, the biological parameter is measured by means of a device for measuring at least one biological parameter accompanying each administration into the nasal cavity, the threshold value of the timing means is 4 to 8 hours, the measured biological parameters are oxygen saturation and respiration rate, the active ingredient from the DR group used during the initial phase and the active ingredient from the DR group used during the at least one subsequent phase are the same, the at least one active ingredient from the DR group is midazolam, wherein the dose of midazolam is 3.5 to 10mg, and when the active formulation does not contain an active ingredient from the DR group, the at least one active ingredient from the ADR group is flumazenil, wherein the dose of flumazenil is 0.6 to 1 mg.

In one embodiment, the biological parameter is measured by means of a device for measuring at least one biological parameter accompanying each administration into the nasal cavity, the threshold value of the timing means is 4 to 8 hours, the measured biological parameters are oxygen saturation and respiration rate, the active ingredient from the DR group used during the initial phase and the active ingredient from the DR group used during the at least one subsequent phase are the same, the at least one active ingredient from the DR group is lorazepam, wherein the dose of lorazepam is 2 to 5mg, and in an active preparation without active ingredients from the DR group, the at least one active ingredient from the ADR group is flumazenil and the dose of flumazenil is 0.6 to 1 mg.

In one embodiment, the biological parameter is measured by means of a device for measuring at least one biological parameter accompanying each administration into the nasal cavity, the threshold value of the timing means is 4 to 8 hours, the measured biological parameters are oxygen saturation and respiration rate, the active ingredient from the DR group used during the initial phase and the active ingredient from the DR group used during the at least one subsequent phase are the same, the at least one active ingredient from the DR group is flunitrazepam, wherein the dose of flunitrazepam is 2 to 10mg, and in an active preparation without active ingredient from the DR group, the at least one active ingredient from the ADR group is flumacini, wherein the dose of flumacini is 0.6 to 1 mg.

In one embodiment, at least one of the active agents comprises at least one active pharmaceutical ingredient configured to alter membrane passage properties and bioavailability.

Examples

This example illustrates the use of the device 1 according to the principles of the present disclosure.

Specification of the apparatus 1:

-two removable storage spaces;

a first storage space 2 with a first active agent 12 disposed therein:

the amount of active agent used in each dose was 0.2mL, so active agent 12 contained about 50 doses: sufentanil (37.5 μ g/dose)/ketamine (37.5 mg/dose)/naloxone (37.5 mg/dose).

The second storage space 3 contains an active agent 11:

the amount of active agent used in each dose was 0.2mL, so active agent 11 contained about 50 doses: naloxone (15 mg/dose).

Two means of measuring biological parameters: 6c oximeter (measure oxygen saturation, threshold 85%) and respiration rate sensor 6b (threshold: 12 inspiration/expiration cycles per minute);

-a timing member: clock 6a (threshold: 6 hours);

patient signal component 9: the light 9a emits light on the device 1 when one of the oximeter sensor 6c, respiration rate 6b or clock 6a thresholds is not favorable for administering sufentanil again.

Thus, the patient will know what will be administered after the control means 8 has been activated. The patient may then decide whether to activate the control unit 8.

The treatment process comprises the following steps:

at T ═ 0, the patient activates the control means 8 of the device 1 at the first time without any medical facility: the patient administers the active formulation 12.

At T3 hours, the patient introduces the nose piece 7a of the device 1 into one nostril. After about 20 seconds, the lamp 9a emits light, indicating that the clock (and potentially the biological parameters) prohibit the application of the active agent 12: the patient has selected whether to administer active formulation 11.

At T ═ 6.1 hours, the patient introduces the nose piece 7a of the device 1 into one nostril. After about 20 seconds, the lamp 9a emits light, indicating that at least one of its two biological parameters (oxygen saturation and respiration rate) inhibits the administration of the active agent 12: the patient has selected whether to administer active formulation 11.

At T-8 hours, the patient introduces the nose piece 7a of the device 1 into one nostril. After about 20 seconds, the lamp 9a remains off: the patient may be administered the active formulation 12.

Claims (16)

1. A system for sequential intranasal administration of at least one active ingredient selected from the DR group having at least one respiratory depression side effect and at least one active ingredient selected from the ADR group that counters respiratory depression that may be caused by active ingredients of the DR group, the system comprising:

(a) administering at least one active ingredient from the DR panel in response to an initial priming of the system by a patient wishing to receive drug administration, wherein initial administration is recorded by the system; and

(b) at least one subsequent administration of at least one active ingredient from the ADR group or at least one active ingredient from the DR group in response to at least one subsequent activation of the system by a patient desiring to receive a subsequent drug administration, wherein the subsequent administration is recorded by the system;

wherein selection of the subsequent administration is controlled by one or more informational components.

2. The system for sequential intranasal administration of claim 1, further comprising:

(a) concurrently administering at least one active ingredient from the DR panel and at least one active ingredient from the ADR panel in response to an initial priming of the system by a patient desiring to receive a drug administration, wherein initial administration is recorded by the system; and

(b) at least one subsequent administration of at least one active ingredient from the ADR group, or at least one subsequent simultaneous administration of at least one active ingredient from the DR group and at least one active ingredient from the ADR group, in response to at least one subsequent activation of the system by a patient desiring to receive a subsequent drug administration, wherein the subsequent administrations are recorded by the system,

wherein selection of the subsequent administration is controlled by one or more informational components.

3. A portable sequential intranasal administration medical device (1) incorporating a sequential intranasal administration system according to any one of claims 1 to 2.

4. A portable sequential intranasal administration medical device (1) as claimed in claim 3, comprising:

at least a first storage space (2) containing a sprayable first active formulation (12) comprising at least one active ingredient (12a) from the DR group;

at least a second storage space (3) containing a second active agent (11) different from the sprayable first active agent, the second active agent comprising at least one active ingredient (11a) from the ADR group;

a signal processing unit (4);

said first (12) and second (11) active agents of said first (2) and second (3) storage spaces are respectively connected with a connection part (5) of a dispensing part (7), which is operatively connected with said signal processing unit (4);

at least one or more information components (6) operatively connected to the signal processing unit (4);

a control means (8) for allowing a patient receiving the active agent to perform self-administration of the active agent without any medical facilities;

a dispensing member (7) for delivering the active agent through the nasal mucosa; and

a power source (10) for supplying power,

wherein the signal processing unit (4), the connecting means (5), the information means (6) and the control means (8) are configured to allow connecting the first active formulation (12) of the first storage space (2) with a dispensing means (7) or connecting the second active formulation (11) of the second storage space (3) with a dispensing means (7) based on one or more signals received by the signal processing unit (4) from the one or more information means (6).

5. Portable sequential intranasal administration medical device (1) according to claim 4, wherein the at least one active ingredient from the DR group is selected from benzodiazepinesAnd said at least one active ingredient from said ADR group is flumazenil.

6. A portable sequential intranasal administration medical device (1) according to any one of claims 3 to 4, further comprising:

at least a first storage space (2) containing a sprayable first active formulation (12), the sprayable first active formulation (12) comprising at least one active ingredient (12a) from the DR group and at least one active ingredient (12b) from the ADR group;

at least a second storage space (3) containing a second active agent (11) different from the sprayable first active agent, the second active agent (11) comprising at least one active ingredient (11a) from the ADR group;

a signal processing unit (4);

said first (12) and second (11) active agents of said first (2) and second (3) storage spaces are respectively connected with a connection part (5) of a dispensing part (7), which is operatively connected with said signal processing unit (4);

at least one or more information components (6) operatively connected to the signal processing unit (4);

a control means (8) for allowing a patient receiving the active agent to perform self-administration of the active agent without any medical facilities;

a dispensing member (7) for delivering the active agent through the nasal mucosa; and

a power source (10) for supplying power,

wherein the signal processing unit (4), the connecting means (5), the information means (6) and the control means (8) are configured to allow connecting the first active formulation (12) of the first storage space (2) with a dispensing means (7) or connecting the second active formulation (11) of the second storage space (3) with a dispensing means (7) based on one or more signals received by the signal processing unit (4) from the one or more information means (6).

7. The portable sequential intranasal administration medical device (1) according to claim 6, wherein the at least one active ingredient from the DR group is sufentanil and the at least one active ingredient of the ADR group is naloxone.

8. A portable sequential intranasal administration medical device (1) according to any one of claims 3 to 7, wherein the information means comprises at least a device for measuring at least one biological parameter and a timing means.

9. An active ingredient selected from the DR group having at least one respiratory depression side effect for use in a method of treating pain, wherein said active ingredient is administered intranasally together or sequentially with at least one active ingredient selected from the ADR group that counters respiratory depression that may be caused by active ingredients of said DR group, said method being performed independently without any medical facilities, said method comprising:

an initial phase of intranasal administration of at least one active ingredient from the DR group, and

intranasally administering at least one active ingredient from the ADR group alone or at least one subsequent stage of intranasally administering at least one active ingredient from the DR group,

wherein the selection of subsequent applications is controlled by one or more informational components.

10. Active ingredient for use in a method for the treatment of pain according to claim 9, wherein said at least one active ingredient from the DR group is selected from benzodiazepinesAnd said at least one active ingredient from said ADR group is flumazenil.

11. Active ingredient for use in a method for the treatment of pain according to claim 9, wherein said at least one active ingredient from the DR group is sufentanil and said at least one active ingredient from the ADR group is naloxone.

12. A method for the sequential intranasal administration of at least one active ingredient selected from the DR group having at least one respiratory depression side effect and at least one active ingredient selected from the ADR group counteracting respiratory depression that may be caused by active ingredients from the DR group, independently performed by a patient without any medical facilities, the method comprising:

an initial phase of intranasal administration of at least one active ingredient from the DR group; and

intranasally administering at least one active ingredient from the ADR group alone or at least one subsequent stage of intranasally administering at least one active ingredient from the DR group,

wherein the selection of subsequent applications is controlled by one or more informational components.

13. The method for sequential intranasal administration of claim 12, wherein the initial phase of the intranasal administration further comprises administering at least one active ingredient from the ADR group simultaneously with the administration of the at least one active ingredient from the DR group.

14. The method for sequential intranasal administration of any one of claims 12 to 13, wherein the at least one active ingredient from the DR group is selected from benzodiazepinesAnd said at least one active ingredient from said ADR group is flumazenil.

15. The method of any one of claims 12 to 13 for sequential intranasal administration, 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.

16. The method for sequential intranasal administration of any one of claims 12 to 15, wherein the information means comprises at least one device for measuring at least one biological parameter and a timing means.