ES3058742T3 - Bi-dose nasal spray - Google Patents

Abstract

The present invention relates to a novel nasal spray containing an aqueous solution or fluid with an anxiolytic or anticonvulsant substance. This nasal spray is characterized by allowing the intranasal administration to the patient of two sprays with a defined equivalent volume of the aqueous solution or fluid of the active ingredient. Furthermore, it allows administration, regardless of the spatial orientation of the nasal spray, in any position of the patient (standing, sitting, lying down, or any intermediate position). The nasal spray can be used directly without prior activation. Preferably, the nasal spray allows visual confirmation of whether one or even a second spray has been administered. Preferably, the patient or a third person can administer a spray of the nasal spray with one hand. The active ingredient of the nasal spray of the invention is a benzodiazepine or a GABA receptor agonist, preferably midazolam, a derivative thereof, or a salt of these active ingredients. The nasal spray according to the present invention can be used for sedation, premedication, or treatment of patients with claustrophobia, anxiety disorders, or panic attacks, or for the treatment of seizures in diseases of the central nervous system (CNS), particularly epileptic seizures or other manifestations of convulsions (e.g., febrile seizures). The invention also relates to a method for hermetically sealing an active agent container for use in administering a nasal spray according to the invention. The invention further relates to a method of detecting the locally precise delivery of an active agent in nasal application, as well as to a nasal spray, preferably a dosed nasal spray, for which, by means of the aforementioned detection method, it has been demonstrated both visually (qualitatively) and quantitatively that uniform, locally precise delivery of the active agent, independent of the dose orientation, can be achieved on the nasal mucosa of a patient. A method for the airtight and airless sealing of an active agent container according to the invention is also provided. (Automatic translation using Google Translate, not legally binding)

Description

[0001] DESCRIPTION

[0002] Bidose nasal spray

[0003] This disclosure relates to a novel nasal spray containing a solution or fluid of an active agent with an anxiolytic or anticonvulsant active agent, wherein the nasal spray is characterized in that two sprays, each with a defined equivalent volume of the solution or fluid of the active agent, can be administered intranasally to the patient, and wherein the nasal spray allows for dose administration regardless of the spatial orientation of the nasal spray in any position of the patient (standing, sitting, lying down, or any intermediate position). The nasal spray is ready to use and can be used directly without prior activation. Preferably, it is evident from the nasal spray whether a spray or a second spray has already been administered. Preferably, a spray of the nasal spray can be administered with one hand by the patient or a third person. The active agent in the nasal spray is preferably an anxiolytic, sedative, muscle relaxant, or anticonvulsant, preferably a benzodiazepine or a GABA receptor agonist such as midazolam or its derivatives or a salt of such active agents (e.g., midazolam HCl). The nasal spray, according to this disclosure, may be used for sedation, as premedication or treatment of patients with claustrophobia, anxiety disorders, panic attacks; or for the treatment of seizures in CNS disorders, particularly epileptic seizures or other manifestations of seizures (e.g., febrile seizures). The disclosure also relates to a method for the qualitative and quantitative detection of the uniform, orientation-independent delivery of an active agent in a nasal spray, and for detecting the locally precise nasal deposition of an active agent in a nasal spray, preferably a bidosing nasal spray. It has been shown, using the aforementioned detection method, that locally precise, orientation-independent delivery of the active agent onto a patient's nasal mucosa can be achieved. The disclosure further provides a method that characterizes, and thereby aids in monitoring, the patient-specific detection of the locally precise deposition of an active agent in the nasal cavity. A method for airtight sealing an active agent container, in accordance with the disclosure, is also provided.

[0004] Background of the invention

[0005] The person skilled in the art is familiar with anxiolytic, sedative, muscle relaxant, or anticonvulsant substances that may be used therapeutically, such as the rapid-acting benzodiazepine midazolam (8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazol[1,5-a][1,4]-benzodiazepine, including all its salts). Midazolam has long been used as a drug for anesthetic preparation, sedation, seizure treatment, sleep induction, and as a sedative or anxiolytic (anti-anxiety drug), respectively. There is a substantial risk of tolerance with this drug, and it should preferably be prescribed or administered, respectively, only for a short time. Midazolam is on the World Health Organization's list of essential medicines. Midazolam can be administered orally, intravenously, by injection into a muscle, or by spraying into the nose or mouth.

[0006] Midazolam is known to be administered by means of a nasal spray for the treatment of acute cerebral seizures (epileptic seizures). Midazolam in the form of nasal sprays is also used for sedation and to prepare patients before minor procedures. Midazolam nasal sprays have also been used for some time to comfort patients before or during long-duration diagnostic imaging procedures (e.g., magnetic resonance imaging MRT or MRI, positron emission tomography PET, single-photon emission computed tomography/computed tomography SPECT, in part computed tomography CT, or combinations of these procedures) and to reassure them [J. Hollenhorste et al.; “Using intranasal midazolam spray to prevent claustrophobia induced by MRI imaging”; Am. J. Roentgenol.176, 865-868 (2001).

[0007] For intranasal administration, the therapeutically active agent is sprayed deep into the nose and thus comes into contact with the nasal mucosa. Depending on the dose and/or the active agent, a drug administered in this way may act exclusively locally or systemically. In the case of midazolam, a systemic effect is desired. Because the nasal cavity is lined with a thin, well-vascularized mucosa, a drug can rapidly reach the systemic circulation directly through a single layer of epithelial cells (without first-pass metabolism in the liver or intestine). In this way, a rapid pharmacological effect can be achieved (within minutes).

[0008] Intranasal application is particularly suitable for strong (potent) drugs for which only a limited amount of an active agent needs to be applied to the nasal mucosa to achieve the therapeutic effect. A potential disadvantage of intranasal administration is the high variability in the amount of drug sprayed onto the nasal mucosa and subsequently reabsorbed. This variability can be due, for example, to incorrect or inconsistent handling of the nasal spray device [H. Kubik and M. T. Vidgren; “Nasal delivery systems and their effect on deposition and absorption”; Adv. Drug Deliv. Rev. 29: 157-177 (1998)]. Problems can also arise if the patient has upper respiratory tract congestion or if a large amount of sprayed fluid enters the oral cavity from the nose and is then swallowed by the patient. When administered by a healthcare professional, the amount absorbed after nasal administration is generally comparable to or greater than that after a corresponding oral administration [B. A. Coda, A. C. Rudy, S. M. Archer, and D. P. Wermeling; “Pharmacokinetics and bioavailability of single-dose intranasal hydromorphine hydrochloride in healthy volunteers”; Anesth Analg. 97: 117-123 (2003) or J. Studd, B. Pornel, I. Marton, J. Bringer, C. Varin, Y. Tsouderos, and C. Christiansen; “Efficacy and acceptability of intranasal 17 beta-oestradiol for menopausal symptoms: randomised dose-response study”; Aerodiol Study Group. Lancet 353: 1574-1578 (1999), respectively]. Most importantly, non-invasive methods without blood extraction allow for ad hoc detection by precisely applying the administered spray with the corresponding reabsorption.

[0010] Several clinical trials related to the intranasal use of midazolam for anxiolytic pretreatment of MRI patients have already been published.

[0012] In a prospective phase I clinical study with 8 healthy test subjects, the mean bioavailability of midazolam after nasal administration was found to be between 76 ± 12% and 92 ± 15%. Formulations delivering 1 mg of midazolam produced mean C<(max.)> values between 28.1 ± 9.1 and 30.1 ± 6.6 ng/ml after 9.4 ± 3.2 to 11.3 ± 4.4 minutes. In each case, absorption of the active agent could be measured in the first plasma samples [M. Haschke et al.; “Pharmacokinetics and pharmacodynamics of nasally delivered midazolam”; Br. J. Clin. Pharmacol. 69 (6): 607-616 (2010)].

[0014] In a prospective, multicenter, phase III clinical trial [Tschirch F. T. C. et al.; “Multicenter Trial: Comparison of two different formulations and application systems of low-dose nasal midazolam for routine magnetic resonance imaging of claustrophobic patients”; JMRI 28: 866-872 (2008)], two formulations were examined. Patients in the unit-dose group (UDG) received a 0.1 mL spray of active agent solution containing 1% (w/v) midazolam and, as a penetration enhancer, 4% of a cyclodextrin derivative (e.g., CAVASOL® W7M Pharma: Manufacturer: Wacker Chemie AG, Munich) from a single-dose nasal spray into one nostril. Patients in the multiple-dose group (MDG) received a 0.1 ml spray of the active agent solution containing 0.5% (w/v) midazolam from a multi-dose nasal spray in each nostril, corresponding to two applications with a total of 1 mg of midazolam base. Analysis of the results from both groups (a total of 108 claustrophobic patients across 4 centers) showed that low-dose midazolam administered nasally is a patient-friendly solution for alleviating MRI examinations in claustrophobic patients. The multi-dose nasal spray was significantly superior to the multi-dose nasal spray.

[0016] In an additional study [Tschirch F. T. C. et al.; “Low-dose intranasal versus oral midazolam for routine body MRI of claustrophobic patients”; Eur. Radiol. 17: 1403-1410 (2007)], the efficacy of low-dose (1 to 2 mg) intranasal midazolam was compared with that of oral midazolam (7.5 mg) in the treatment of claustrophobic patients prior to routine MRI examinations. In this study (one examination center), 72 patients were randomly assigned to two equally sized groups. In the TG1 test group, patients received 7.5 mg of oral midazolam 15 minutes before the MRI examination. Patients in the TG2 trial group received two, and optionally one to two additional sprays later, of a nasal spray containing 0.5 mg of midazolam per spray (totaling 1.0 to 2.0 mg of midazolam base). In 97% of cases, MRI examinations could be performed successfully and without relevant side effects. The quality of the MRI images was significantly higher in patients in the TG2 group compared to the TG1 group (p < 0.001). The conclusion was that low-dose intranasal midazolam is an effective and patient-friendly solution for alleviating anxiety in claustrophobic patients across a wide range of MRI examinations. In this respect, the anxiolytic effect of nasally administered midazolam was significantly superior to that of orally administered midazolam.

[0018] Based on these initial studies with low-dose midazolam, midazolam nasal sprays have been used in clinical practice for quite some time in preparing patients for long-duration diagnostic imaging procedures (e.g., MRI scans). Until now, such midazolam nasal sprays have often been produced in small quantities in hospital pharmacies or public pharmacies with manufacturing licenses. However, the concentration and dosage cannot be optimally adjusted for nasal application by simple decanting. The challenge in preparing the solution lies particularly in the pH-dependent recomplexation of the active agent, with its solubility changing with each pH change. Solutions of the active agent produced in this way are stable only in the acidic range (below pH 3.8 and lower, depending on the active agent content); at higher pH values, the active agent precipitates. In practice, the ideal pH must therefore be titrated and stabilized with dilute hydrochloric acid. Therefore, optimal stability and solubility of the benzodiazepine ring can be achieved. Furthermore, the solutions should be made isotonic under physiological conditions to ensure optimal local tolerance of the nasal mucosa. Since these midazolam nasal sprays do not necessarily need to be produced in sterile rooms, there is a risk of contamination by germs during production and/or storage. The spread of germs can be prevented by the addition of preservatives such as benzalkonium chloride (usually 0.01% w/v) and/or optionally EDTA (usually 0.1% w/v). However, the addition of preservatives to the solution in nasal sprays frequently results in irritation of the nasal mucosa. This irritation is often perceived as unpleasant by patients and can therefore adversely affect the desired sedation of the patient during the diagnostic procedure.

[0019] An additional disadvantage of extemporaneous nasal spray preparations according to the prior art is a certain batch-to-batch variability that can lead to differences in the amount of active agent administered. This can be caused, for example, by variations in the spray device, by incorrect operation of the spray head (sideways pressure), or by insufficient filling of the spray tube in the classic nasal spray device. Therefore, with prior art nasal sprayers, it is often difficult to control and ensure how much active agent is actually sprayed into the patient's nose. For proper operation of the spray device, the patient often needs to be standing or sitting upright so that the spray tube is safely immersed in the solution and does not draw in air. The upright position is easy to achieve during the preparation phase, i.e., shortly before the patient lies down on the MRI table. However, once the patient lies down on the examination table and the table is inserted into the imaging device, administration in an upright position is virtually impossible. If the patient becomes restless during the imaging process, administering an additional dose of the sedative with the state-of-the-art nasal spray can be severely hampered or may even force the examination to be stopped. Repeating the spray while the patient is lying down is practically impossible, as the spray head will no longer fill. If the re-administered dose is too low or cannot be administered, the patient will remain restless. Conversely, if the dose is too high, the patient will no longer be able to respond adequately to the staff's instructions during the examination procedure. Clearly, the patient must remain as still as possible during the examination procedure and should only respond to the operating staff's instructions (e.g., exhalation and inhalation). If insufficient sedation is achieved, the image quality may be too poor, necessitating a repeat examination. Since imaging devices and examination procedures are very expensive, and proper instrument use is essential, repeating or delaying such imaging procedures incurs unnecessarily high costs, which must be avoided given the limited resources of the healthcare system. The increased stress on the patient resulting from inadequate image results or repeated measurements should also not be underestimated. Clinical studies have shown that image quality, particularly in difficult patients who become agitated during such examinations, can be significantly improved by administering low-dose midazolam. This, combined with anxiolysis, also facilitates better diagnosis through improved image quality.

[0021] Typically, a patient will report either upon admission or later, upon entering the MRI examination room, that they are afraid of the "tube" or the confined examination space (claustrophobia). Frequently, the patient also mentions significant discomfort with the long, tubular shape of the magnet and the feeling of confinement. This can even lead to the patient refusing to undergo the examination. Furthermore, the additional coils and devices required for the examination (e.g., helmets, earphones, breathing belts, pillows, belts, ECG electrodes, earplugs, postural belts) lead to corresponding stiffness, causing further discomfort for the patient. Individual patients inherently have more difficulty remaining still, which is partly due to the underlying condition (e.g., Parkinson's disease, dementia, or other CNS disorders) or a result of the impending stressful situation, which is unique and often entirely new to the patient. Many patients also complain about exposure to extremely loud noise during an MRI scan, even when noise-canceling headphones are often offered or a calming distraction with music is attempted. All of these factors lead to a degree of anxiety, which can negatively affect the quality of the examination.

[0023] After clarifying whether the patient is prone to panic attacks and whether an examination is problematic for medical reasons (e.g., due to respiratory depression, allergies, myasthenia gravis, or because the patient regularly takes medications that act on the central nervous system), the attending physician will recommend the use of the nasal spray, and it must be provided to the patient. After giving their consent, the patient will receive final information about the examination procedure. Nasal spraying, in accordance with current practice, should be administered with the patient seated on the examination table. Generally, the nasal spray is first primed by spraying once or twice into the air to ensure the spray tube is filled. Then, one spray is administered into each nostril, on both the right and left sides. This often results in brief irritation, which the patient is informed about beforehand. Each patient reacts differently to this, sometimes even positively, as they clearly feel an effect. As soon as approximately 1 to 2 minutes after nasal application, the patient no longer refuses the MRI examination and readily accepts preparation for the procedure. Additional sprays are rarely required in this initial phase. The patient is then prepared for the final examination position. Various additional devices, such as coils, can now be easily positioned. The patient can then be transferred to the MRI scanner without difficulty, using the positioning laser for centering. In affected patients, this is often not possible without prior medication. Another important advantage is the "low sedation" effect and, consequently, the patient's high level of alertness despite the use of a sleep-inducing drug. The doses used are so low that the patient can easily follow the instructions of the assisting technicians (conscious sedation). This not only facilitates communication but also speeds up the examination procedure. Patients who fall asleep during the examination (as is often the case, for example, when higher doses of midazolam are used) can no longer follow instructions and impair the examination by breathing; that is, they cannot control their breathing and, due to spontaneous respiration, the image quality is lower or even non-diagnostic. The use of breathing belts can reduce spontaneous breathing, but this leads to longer measurement times, which is uncomfortable for the patient and should also be avoided for cost reasons.

[0024] If, during the examination, the patient again exhibits anxiety and/or restlessness, an additional spray could be administered with the nasal sprayer, i.e., the active agent could be dosed again. However, due to the patient's supine position, this is quite limited, as the patient must also be moved from the examination position. Furthermore, an attempt should be made to administer the spray while the patient is lying down to maintain that position. This is impeded by the low filling capacity of the nasal sprayer according to the prior art. If the patient is wearing a head coil during the examination, a prior art nasal sprayer is practically impossible to use because the space around the nose is too small to orient the nasal sprayer in the correct position. Moreover, filling the spray device cannot be guaranteed without causing additional, uncontrolled discomfort to the patient.

[0026] After the image acquisition is complete, the patient, lying on the examination table, is removed from the MRI magnet. They can sit up and dress independently. As a precaution, many centers do not allow patients to drive after using the nasal spray. Understandably, there is almost no data regarding the necessity of such precautions. Since partially active metabolites are generated during the breakdown of midazolam, a safety rest period of at least 4 hours should be observed before driving or operating machinery. In this context, it is necessary to consider that some patients experience a significantly stronger reaction, have a slower metabolism of the active agent, or are taking concomitant medications that potentiate the effect.

[0028] When multi-use nasal sprays are used, there is a risk of disease transmission from one patient to another. In large examination centers where a large number of patients undergo such diagnostic imaging examinations, special care must be taken with regard to hygiene. When multi-use nasal sprays are used, the spray head may come into contact with the epithelium of several patients, resulting in the transmission of germs if the same head is used for subsequent patients. The normal bacterial flora of healthy individuals includes, among others, Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus epidermidis, and Staphylococcus aureus. Even though these germs do not necessarily lead to infection, they can substantially increase the bacterial load, which can be a particular problem for immunocompromised patients [Ylikoski J. et al., “Bacterial flora in the nasopharynx and nasal cavity of young healthy men”, ORL Journal Otorhinolaryngol Relat Spec., 1989; 51 (1): 50-55]. Spray heads must be changed for each new patient. However, this is very cumbersome because staff must be trained accordingly, and each change must be recorded and verified to comply with hygiene regulations. Changing the spray head also requires rechecking the pump and its function to avoid erroneously applying too high or too low a dose of the active agent.

[0030] There are additional important application possibilities in all cases where acute anxiety or panic disorders need to be overcome as quickly as possible. The great advantage of nasal application, with its rapid bioavailability of the active agent, makes it optimally suitable for the treatment of acute anxiety or panic disorders. The spray provides good anxiolysis and vagal attenuation, creating favorable conditions for all possible interventions. In addition to the MRI examples mentioned, the spray has been used successfully in dental procedures, minimally invasive surgical procedures, and all types of invasive interventions. As a premedication, the spray is also suitable for preparing for anesthesia or for initiating additional anesthetic procedures. Similarly, successful use in so-called "aggressive" therapeutic procedures (interventions), restlessness and anxiety, as well as in patients who are difficult to approach, including aggressive, restless, or disoriented patients, is also included in this disclosure.

[0032] Reliable and safe drug administration in emergency situations, but also appropriate drug administration in space-constrained situations, is often a major challenge.

[0034] Such a situation requires the reliable and rapid administration of emergency medication, among others, in epileptic or spastic patients who cannot be sufficiently stabilized despite baseline antiepileptic medication and, in the event of seizures, must be treated quickly and effectively with an anxiolytic or anticonvulsant (such as midazolam). Seizures or epileptic attacks can occur completely unpredictably at any time in daily life. Often, the patient is in an unfavorable or difficult-to-access position for rapid medication administration (depending on the scenario or position, the patient's movement hinders administration). The patient or family members frequently face the difficult situation of how best to administer the medication as quickly as possible. Furthermore, the spasm or bite devices associated with it lead to rigidity in the patient, making an approach, or particularly the oral administration of emergency medication, impossible. The patient often needs to be placed in a protective position to prevent asphyxiation or self-harm. Lateral positioning is the priority, as vertical positioning is practically impossible. Valuable time in emergency treatment can be lost due to repositioning. Therefore, position-independent devices for administering the active agent solution are essential and of great practical importance.

[0035] Other clinical situations in which administration is negatively affected more by extrinsic factors include radiological tomography examinations (MRI, CT, SPECT, or PET) or preoperative procedures (such as dental procedures or minimally invasive interventions), as well as gastrointestinal endoscopy. An upright position is easy to achieve during the preparation phase, that is, shortly before the patient lies down on the examination table. However, once the patient is on the examination table, administration in an upright position is practically impossible.

[0036] Multi-dose nasal sprays, according to the state of the art, must be primed before administration. For this purpose, at least two test sprays are activated (e.g., sprayed into the air) to ensure safe and successful administration in an upright position. Furthermore, with traditional multi-dose nasal sprays, it is not possible to repeatedly activate sprays in a position other than upright. Each time, i.e., after each spray in a non-upright position, the device must be primed again. Therefore, emergency nasal treatment with traditional multi-dose nasal sprays is only possible to a very limited extent. In addition, air aspiration can result in uneven application of volumes, which is undesirable. The intrinsic and extrinsic impairments that arise when administering drugs in the situations mentioned above thus pose a significant challenge for the affected patient, their family, and the attending nursing staff.

[0037] The effect of formulation variables and breathing patterns on the nasal deposition site in an anatomically correct model is described by Yang Guo et al. in Pharmaceutical Research Vol. 22, No. 11, pp. 1871–1878 (2005). A review of nasal drug delivery devices—features and performance from a clinical perspective—was published by Per Gisele Djupesland in Drug Delivery and Translational Research Vol. 3, No. 1, pp. 42–62 (2012). The evaluation of nasal spray deposition pattern in a silicone human nose model using a color-based method has been described in Pharmaceutical Research Vol. 27, No. 1, pp. 30–36 (2009). A nasal spray device is disclosed in US patent 2017/136477. An intranasal delivery device is disclosed in document US 2010/113426.

[0038] Detailed description of the invention

[0039] The invention is defined in independent claim 1. Preferred embodiments of the invention are disclosed in the dependent claims.

[0040] This disclosure was made in view of the prior art described above. The purpose of this disclosure is to provide a nasal spray device with which a defined quantity of an anxiolytic, sedative, muscle relaxant, or anticonvulsant active agent (a benzodiazepine or GABA receptor derivative/agonist such as midazolam or a derivative thereof or its salt, respectively) can be administered intranasally, and where uniform administration is possible regardless of the spatial orientation of the nasal spray in any other patient position (e.g., standing, sitting, lying down, or any other or intermediate patient position). The nasal spray also allows for the administration of a second spray with an equal (equivalent) volume of the solution or fluid of the active agent. That is, the volume of the first and the volume of the second spray are approximately equal, and therefore, the amount of the active agent dissolved in them is also approximately equal. In this way, an additional equally dosed spray of the active agent can be administered to the patient once it becomes obvious that the patient is not still enough in the examination device.

[0041] The solution to this problem is to provide a nasal spray containing an aqueous solution or fluid with an active anxiolytic, sedative, muscle relaxant, or anticonvulsant agent, with which two sprays or puffs of an equal, defined volume of each aqueous solution or fluid of the active agent can be administered to a patient. The nasal spray is designed to facilitate uniform administration regardless of the sprayer's orientation in any patient position (standing, sitting, lying down, or any position in between). The nasal spray may preferably be used directly without prior activation.

[0042] The disclosure therefore refers to a nasal spray containing an aqueous solution or fluid with an anxiolytic, sedative, muscle relaxant or anticonvulsant active agent, characterized in that:

[0043] a) With the nasal spray, two sprays or two puffs of spray, each with a defined equivalent volume of the aqueous solution or liquid of the active agent, can be administered intranasally to the patient; b) wherein the nasal spray allows for equal administration of the dose, regardless of the spatial orientation of the nasal spray and in any position of the patient (standing, sitting, lying down, or in any intermediate position).

[0044] In the context of the present invention, the term spray may be interchangeably replaced by the term puff or the term spray puff (German: Sprühstoss), as appropriate. However, this does not refer to the term sprayer when used in connection with combined terms, for example in “nasal sprayer,” because in that case it refers to a device and not an activity.

[0045] In one embodiment, the bidosis nasal spray consists of the following four components:

[0046] a) an actuating element including the spraying device called an actuator, which includes a spring and a hollow needle as well as a spraying device;

[0047] b) a road support;

[0048] c) an active agent container (for example, a vial made of glass, metal or a solid plastic);

[0049] d) a hermetically sealed cap, preferably a cap made of rubber or a similar material approved for pharmaceutical purposes.

[0050] Preferably, the actuating element comprises a spring and an injection needle.

[0051] In a preferred embodiment, the active agent container contains an anxiolytic, sedative, muscle relaxant or antispasmodic therapeutic agent.

[0052] In a further embodiment, the activation of the spray is independent of air pressure by the direct displacement of the active agent container against the pressure plug towards the actuating element, so that, with the nasal sprayer, a spray can preferably be administered directly and without activation. Preferably, it can be identified from the disclosed nasal spray device whether the nasal sprayer has not been used or whether one or even two sprays have been delivered.

[0053] Using the disclosed bidosis nasal spray, the patient can administer a one-handed spray by himself or by means of a third party.

[0054] The therapeutic substance in the nasal spray is preferably a benzodiazepine or a GABA receptor agonist such as midazolam or a salt of these active agents.

[0055] Therefore, the double-dose nasal spray is particularly suitable for the treatment of sedation, premedication of patients with claustrophobia, panic attacks or anxiety disorders or for the treatment of seizures in CNS diseases, particularly epileptic seizures or other manifestations of seizures (e.g. febrile seizures).

[0056] Using the double-dose nasal spray, the active agent can be administered intranasally to a patient, where the active agent is injected into or applied to the nasal mucosa in any conceivable manner and is reabsorbed there. The administration should be as uniform as possible and can be performed in any patient position (e.g., standing, sitting, or lying down (supine, prone, or lateral position)). The orientation of the nasal spray in space is not limiting in this context, which is made possible by the following construction elements:

[0057] a) direct displacement of the active agent container (glass vial) against the stopper by finger pressure; b) precise control and locking spatially independent of the orientation of the displacement movement; c) airtight seal of the active agent container containing the active agent filled under reduced pressure with the stopper;

[0058] d) drive element (also called actuator), consisting of a spring, a hollow needle (riser tube), through which the active agent fluid is pushed upwards under pressure and dispensed at the actuator end in the form of a spray with a spraying device.

[0059] In conjunction with this disclosure, an airtight seal means, on the one hand, that the active agent solution is hermetically sealed and that no residual air, or as little as possible, remains in the active agent container. The active agent container is therefore evacuated or left airless.

[0060] The airtight seal of the filled active agent container (see Figure 4) and the composition of the four components as described above (a: actuating element; b: vial holder; c: active agent container and stopper) enables the nasal sprayer of the invention to behave like a pre-filled syringe. Using the disclosed nasal sprayer, a dose of each active agent can therefore be administered in any spatial orientation. A locking system, as illustrated in Figure 2 and defined by the vial holder and the actuator as an active unit, allows controlled displacement of the active agent container relative to the actuating element, and thus enables the dispensing of precise volumes of the active agent fluid through the hollow needle.

[0061] The following describes a preferred embodiment of the double-dose nasal spray according to this disclosure. For ease of understanding, reference is made to the figures, which should not be construed as limiting the invention in any way to the nasal spray devices described in these figures.

[0062] Figure 1 shows a schematic view of the composition of the double-dose nasal spray according to the present disclosure as well as its main components: the drive element A, also called the actuator, the vial holder B, the active agent container C (for example, a glass vial) and the rubber stopper D. To the right is a schematic view of the composition of the four components of the preferred nasal spray device, each with the actuator integrated in (E) and without the actuator (F).

[0063] Figure 2 shows a schematic view of the bidosis nasal spray locking mechanism. BP indicates the locking point at which the spray device is locked each time for the first spray (BP1) or the second spray (BP2), respectively. Figure 2A shows the bidosis nasal spray in the initial position (BP1 and BP2 as the lowest positions). In Figure 2B, it can be seen how the actuator is compressed by the first mechanical pressure from the bottom. The hollow needle pierces the stopper, and the glass vial moves toward the rubber stopper, so that the fluid is forced out through the hollow needle of the actuator, activating the first spray. The vial holder thus moves to the first position, in which the locking mechanism for the first spray between the actuator and the vial holder is engaged by the small anchor at BP1. Consequently, it is not possible to deliver two doses in a single spray. In Figure 2C, the same mechanism as in Figure 2B is followed, using pressure from below. The remaining volume is sprayed, but with the difference that the stopper is now completely at the bottom of the glass vial, and the vial holder is now in the highest position. This ensures double dosing of the spray, and additional spraying is not possible. Furthermore, the user will notice that the nasal sprayer is now empty, since there is no backpressure after application and the bottom portion is completely displaced upwards. Figure 3 provides a representation of the locally precise deposition of the active agent solution after application with the nasal sprayer, depending on the orientation of the nasal sprayer in space. The upper left image shows the CT scan before application. The subsequent images show the CT scan after application, where each image represents the orientation of the nasal spray in space by means of a schematic view of the nasal spray showing the position in which it is administered (top right image – vertically upwards; middle right image – horizontally; bottom right image – vertically downwards). The remaining images show administration in intermediate positions. The angle of application between the nasal spray and the nose is constant in these cases. The high-contrast dissolution of the active agent appears bright and is clearly visualized.

[0064] Figure 4a shows a schematic view of the preferred method for hermetically sealing the active agent container. The active agent solution is filled into the active agent container under atmospheric pressure. Preferably, the filling occurs immediately before the sealing procedure as shown in Figure 4. The lower portion of Figure 4aA shows the active agent container, which is open at the top and filled with the active agent solution (gray). At the top is the sealing chamber located above the cylinder, with the plug inserted at the upper end. This step is carried out under atmospheric pressure throughout the system. The gray arrow-shaped triangles represent sealing gaskets in the sealing chamber, and the gray rectangles on the plug show areas where the plug lips allow for a hermetic seal.

[0065] Figure 4a B shows the active agent container that has been pushed against the sealing chamber. A hermetic unit is thus formed. Air is drawn from the closed system through a side outlet (see arrow symbol). This is done in a time-controlled manner and under a controlled suction power. The area with negative pressure in the closed system is shown shaded. The light gray areas show the sealing points. The thick arrow under the active agent container points in the direction in which the active agent container is pushed against the seals.

[0066] In Figure 4a C, the entire system (active agent container and sealing chamber) is pushed upward, so that the cylinder in the active agent container is placed in its defined position (first large arrow). Immediately afterward, the piston lowers the stopper to the surface of the active agent solution, and the stopper is secured close to the glass vial by the expansion of the rubber stopper's lips (see second large arrow). This step is performed under negative pressure (constant air aspiration). The shaded area shows the area under negative pressure. Through this step, the stopper is secured close to the surface of the active agent solution.

[0067] Figure 4a D shows how the closed active agent container and sealing chamber (large black arrow) are pushed down, thereby removing the cylinder (without the plug) from the active agent container. The area above the plug is now again under atmospheric pressure (air aspiration has stopped). The plug is now fixed just above the active agent solution in the active agent container (shown by gray vertical strips next to the plug). If a gap were to form between the plug and the active agent solution, negative pressure would exist at this location.

[0069] Figure 4a E shows how the sealed active agent container lowered back into its original position and separated from the sealing chamber. The sealed active agent container can now be mounted on a disclosed nasal sprayer. The sealing chamber can be reused for the airtight sealing of a new active agent container with a stopper. A person skilled in the art knows how to automate the method described in Figure 4.

[0071] Figure 4b shows a hermetically sealed active agent container already filled. The image shows that the rubber stopper hermetically seals the active agent solution and that only minimal residual air remains between the stopper and the active agent solution.

[0073] Figure 5 shows the uniformity of the mass of the two sprays (in mg of active substance applied to the nasal mucosa), depending on the orientation of the nasal sprayer. Figure 5a shows the series of measurements for the first spray, and Figure 5b shows the series of measurements for the second spray. Ten measurement points are shown (one nasal sprayer per measurement) per nasal sprayer orientation. The dashed line shows the target value (100 μl per spray), and the solid lines show the 15% acceptance criteria (85 mg–115 mg) required according to the United States Pharmacopeia, which are the strictest for compliance in pharmaceutical production.

[0075] In the double-dose nasal spray according to Figure 2, the displacement of the vial holder relative to the lower edge of the actuator should be visible. This is visible when the operator views the double-dose nasal spray from below. This allows the patient, nursing staff, or physician to determine whether two, one, or no doses can still be administered with the nasal spray. Previous use, i.e., an opening in the spray device, is thus clearly visible. Preferably, the spray device in the nasal spray of this disclosure locks after the second dose, and therefore no further doses can be administered. This increases safety and prevents inappropriate use, compared to multi-dose sprays.

[0077] Preferably, the disclosed nasal spray contains 200 to 230 μl, 215 ± 15 μl, 230 ± 10 μl, 225 ± 10 μl or 225 ± 5 μl of the solution, fluid or powder of the active agent. With each spray of the double-dose nasal spray according to the present disclosure, a volume of 75, 80, 90, 100, 110, 120, 125, 130, 140 or 150 μl (with a volume range of ± 25% each) of the aqueous solution of the active agent or the fluid of the active agent can be applied, wherein, in a particularly preferred embodiment, with each spray, a volume of 100 ± 15 μl, 100 ± 10 μl, preferably 100 ± 5 μl of the fluid with the active agent can be sprayed onto the nasal mucosa. Up to this point, the nasal sprayer is filled with 200 to 300 μl of the aqueous solution or fluid of the active agent, wherein, in a particularly preferred embodiment, the nasal sprayer is filled with 230 ± 10 μl of a fluid containing the active agent (advantageously as a solution).

[0079] The isoosmolar aqueous fluid containing the active agent is dosed so that, with each spray, depending on the intended application, a therapeutic dose of 0.25 to 5 mg or 1.0 to 10 mg of the active agent (e.g., midazolam, a derivative thereof, or a salt thereof) can be administered. The active agent fluid (preferably an aqueous fluid) containing the therapeutic active agent may additionally contain a preservative such as benzalkonium chloride at a concentration of 0.01% w/v and EDTA at a concentration of 0.1% w/v. Additional approved preservatives or additives for fluid pharmaceutical formulations that may be used in the nasal sprays of this disclosure are well known to those skilled in the art and are described in relevant textbooks. Depending on the concentration, the aqueous fluid containing the active agent midazolam has a precisely defined, adjusted pH value, preferably between 2.8 and 3.8 (preferably between 3.0 and 3.5). Depending on the specification, these limits can be selected with a tighter tolerance or can be adjusted by a person skilled in the art. Possible additional additives include those that help adjust the osmolality (e.g., salts, glucose), solubilizers (e.g., cyclodextrins), penetration enhancers (which result in improved uptake of the active agent through the nasal mucosa, e.g., dextrins, cyclodextrin, chitosan, or derivatives thereof), wetting agents (e.g., glycerol, propylene glycol), or chelating agents such as EDTA or DTPA. For anhydrous sprays, the midazolam must be dissolved by means of solubilizers or suspended. It may therefore not be possible to maintain the aforementioned pH values, as well as isoosmolality. Powder nasal sprays may be used in the form of mixtures of the active agent based on micronized midazolam, possibly mixed with various carrier substances such as cyclodextrins.

[0081] In a preferred embodiment, the bidosis nasal spray does not contain preservatives, i.e., the fluid formulation in the nasal spray contains only midazolam HCl in an isoosmolar aqueous solution of NaCl.

[0082] Preferably, such a formulation is prepared aseptically so that the corresponding bidose nasal spray can be stored for a longer period (preferably more than 10 months, more preferably 12 months, even more preferably 18 months, or most preferably 24 to 36 months) without loss of quality. The advantage of this preservative-free nasal spray formulation is reduced allergenicity, irritation, and interaction with ciliary movement in the nasal mucosa.

[0083] As shown schematically in Figure 4a, the active agent container is preferably filled with the active agent solution and sealed. First, the desired amount of active agent is filled into the active agent container, which is open at the top. The active agent container is then inserted into a sealing chamber containing a plunger-like device. A plug is attached to the lower end of the plunger-like device, creating a hermetically sealed active agent container. The sealing chamber and the active agent container now form a closed system. Air is drawn into the closed system through an opening on the side of the sealing chamber, thus keeping the active agent in the container unchanged. Validation experiments have determined that a negative pressure of approximately 600 to 900 mbar must be used to position the plug as close as possible to the surface of the active agent solution. Experimentally, a preferred aspiration time of 0.5 to 1.5 seconds has been determined to achieve the desired negative pressure in the system. Using a plunger-like device, the rubber stopper is lowered into the active agent container until it reaches the top of the active agent, minimizing the gap between the active agent's filling surface and the stopper. Thus, the filled and sealed active agent container behaves like a full syringe, and the active agent fluid of the disclosed nasal spray can therefore be applied in any spatial orientation. The orientation-independent application of two nasal sprays was tested by a person skilled in the art with several samples, and their compliance with common pharmaceutical requirements (FDA, PHEUR) was documented (two uniform sprays with a volume of 100 μl ± 15% each, see Figure 5).

[0084] The applied vacuum that creates the negative pressure in the system (see Figure 4B) can preferably be continuously monitored and recorded. The desired negative pressure in the closed system is preferably controlled by the aspiration time. Through validation experiments, it has been found that an aspiration time of approximately 1 second is generally sufficient to place the plug in the active agent container in such a way that, as far as possible, no residual air or only a minimal amount of residual air remains between the plug and the surface of the active agent fluid (compare to Figure 4B).

[0085] As can be seen from Figure 5, the method described above for hermetically sealing an active agent container allows its incorporation into a nasal spray in accordance with this disclosure. This facilitates the production of a nasal spray for the administration of two sprays with an equal, defined amount of the active agent or an equivalent volume of the active agent solution, wherein the nasal spray allows for uniform administration of the active agent regardless of the spatial orientation of the nasal spray and in any patient position (standing, lying down, or any position in between). The resulting nasal spray meets the requirements of the Pharmacopoeias of the regulatory authorities (e.g., in the U.S.).

[0086] The method described above for hermetically sealing active agent containers is suitable for industrial-scale use, particularly since the space in which a negative pressure has to be created is very small and because the suction time is only about 1 second.

[0087] Preferably, a visual inspection is performed on each filled and sealed active agent container. The visual inspection can be carried out using a camera (optionally computer-controlled). The distance between the stopper and the surface of the active agent fluid is checked. Through validation experiments, a person skilled in the art can define acceptance criteria for the maximum permissible distance. This allows for automated classification of improperly sealed and/or incorrectly filled active agent containers.

[0088] The disclosed nasal spray operates as described below. Applying pressure with a finger to the actuating element (actuator) displaces the stopper into the active agent container, creating pressure that forces the active agent fluid upward through the hollow needle integrated into the actuating element into the upper spiral portion of the actuator and dispenses it as a spray (see Figure 2). The locking mechanism between the vial holder and the actuator (compare to the legend in Figure 2) allows for the delivery of two controlled sprays of equal volume.

[0089] A double-dose nasal spray is preferred, which allows for the successive administration to a patient of two controlled sprays of 0.2 to 5 mg each, particularly preferably 0.278–5.56 mg of midazolam HCl in an isotonic aqueous solution, regardless of whether the nasal spray is held vertically, horizontally, upside down, or in any intermediate position. The two sprays can be delivered in rapid succession or in a synchronized manner, and it is preferred that the second spray be delivered to the other nostril. The double-dose nasal spray allows for distribution of the active agent over a large area of the nasal mucosa, which proves advantageous in terms of rapid absorption and bioavailability.

[0090] In a particularly preferred embodiment, the nasal spray can be used directly without any additional preparation or activation to deliver the active agent, i.e., it is an over-the-counter (“ready-to-use”) double-dose nasal spray.

[0091] As mentioned above, the bidosis nasal spray consists of four main prefabricated components. These four main components can be sterilized (steam sterilization, ethylene oxide, and/or gamma radiation). The bidosis nasal spray is then assembled from these four main components, and the active agent container is also filled with the active agent fluid to obtain the desired bidosis nasal spray in accordance with this disclosure.

[0092] The active agent container, preferably a glass vial, is filled in a closed environment using a needle and a precision dosing pump. This allows the desired volume of the active agent solution (e.g., 200 to 300 μl) to be filled into the active agent container in precise doses. The fill level of each active agent container is monitored and photographically documented. For this purpose, the light intensities of the diffracted light beams at the glass boundaries below and above the stopper are measured and compared, thus precisely monitoring the fill level in the active agent container. With the two-dose nasal spray according to Figure 2, only two successive sprays can be administered. When the device is pressed for the first time, the upper rubber seal is pierced and displaced upwards to the designated point (BP1/BP2, as well as the internal shaft). The dispensed amount of active agent fluid (spray volume) is controlled by lateral anchors (see BP1 and BP2 in Figure 2). A spring-loaded mechanism "reactivates" the spray, allowing it to be activated a second time (Figure 2, lower middle image). The maximum volume that can still be dispensed is determined by the residual volume, which is defined by the maximum stop on the upper, narrower nozzle cylinder (Figure 2, lower right image). Lateral shafts with points BP1 and BP2 further control the position and thus ensure precise two-stage application. The lateral anchors facilitate two-stage application. The bidosis nasal sprayer is designed so that the spray mechanism locks and depletes after the second spray. Consequently, the bidosis nasal sprayer is no longer usable. In practice, it must be disposed of safely in accordance with regulatory requirements.

[0093] The two-dose nasal spray according to this disclosure shall be packaged after production, preferably in a box made of cardboard or plastic, wherein one box may contain one or more metered-dose sprays and each contains a package insert describing the use of the nasal spray of the invention. For storage and distribution, multiple boxes may be packaged within additional cartons (larger packs). In an emergency, this allows for simultaneous application of the emergency medication through both nostrils without further delay.

[0094] Before the bidose nasal spray, as described herein, is delivered to the end customer, quality control is performed to verify the density, pH, osmolality of the formulation, and the active agent by HPLC (a validated procedure similar to PH. Eur.). In addition, a microbiological analysis is performed for each batch. As described above, the amount of active agent in the container is controlled during the filling process. In each production batch, the uniformity of the dosage in the bidose nasal spray must be verified according to the Pharmacopoeia in a verifiable manner.

[0095] In the double-dose nasal spray according to this disclosure, the expelled fluid is not replaced by air as in commonly used nasal sprays. Instead, a movable plunger is used, which is pierced when the spraying mechanism is activated. This system allows for intranasal administration of the spray regardless of the spatial orientation of the nasal spray in any patient position (i.e., standing, sitting, lying down, or any other position). This significantly differentiates the double-dose nasal spray according to this disclosure from prior art nasal sprays such as conventional multi-dose nasal sprays.

[0096] The closed system facilitates the microbiological integrity of the primary drug container from the time of aseptic production until the time of use of the nasal spray. Aseptic filling of the double-bottle nasal spray according to the present invention eliminates the need for a potentially irritating preservative in the formulation of the pharmaceutical substance. The double-bottle nasal spray according to the present disclosure is stable after storage.

[0097] The bidosis nasal spray according to this disclosure is a ready-to-use device that can be operated with one hand, if necessary, by the patient. The bidosis nasal spray according to this disclosure is suitable and applicable for diagnostic imaging procedures such as MRI scans and does not affect the diagnostic device, nor is its function or integrity affected by the diagnostic device (e.g., by the device's magnetic radiation or magnetic forces). It also does not cause magnetic interference or other artifacts in the imaging procedure.

[0098] The double-dose nasal spray, as described herein, also allows for optional oral administration. This may be used if the nose is blocked (e.g., by local pathological changes) or if local application is limited in the case of a cold or common nasal infections. Possible contraindications include, for example, recent rhinoplasty, polyps, or other acute inflammations of the nasal cavities.

[0099] The bidosis nasal spray, as described herein, is particularly suitable for various indications, such as claustrophobia or a similar anxiety disorder, with or without restlessness, prior to entering or being positioned for MRI or similar equipment (PET, SPECT, radiotherapy equipment, or CT). The claustrophobic patient is sedated approximately 1 to 2 minutes after intranasal administration of one or two sprays of the bidosis nasal spray, thus enabling a successful MRI examination without any problems.

[0100] Furthermore, by using the Bidosis nasal spray in accordance with this disclosure, various similar anxieties can be overcome or reduced, such as those associated with minimally invasive procedures, dental procedures, pediatric procedures, various diagnostic procedures, and palliative care prior to gastrointestinal examinations. Additional uses include pre-medication before anesthetic procedures, surgical procedures, or similar procedures. Due to the ready-to-use device, the Bidosis nasal spray can be used immediately and regardless of the sprayer's orientation, regardless of the patient's position. Therefore, the Bidosis nasal spray can be used very effectively even in emergency situations or particularly in the aforementioned procedures. Additional applications include use in geriatrics, as well as in rather uncomfortable therapeutic procedures, in cases of anxiety or restlessness, and with restless, difficult-to-access patients.

[0101] Low-dose midazolam commonly used for anxiety disorders (preferably 0.25 to 5.0 mg) does not lead to noticeable sedation of the patient (“conscious sedation”). The patient can therefore follow the instructions of the attending technicians or medical assistants performing the examination.

[0102] A physician or medical assistant, or optionally a nurse or technician present during the examination or procedure, may administer the sprays to the patient using a double-ended nasal sprayer. This has the advantage of rapid intervention, even with difficult patients or in cases of non-compliance, regardless of the patient's position. Using the double-ended nasal sprayer, the patient may also optionally self-administer the intranasal spray.

[0103] In a further embodiment of the disclosure, if necessary, an additional spray is administered to the patient using the bidosis nasal spray in accordance with this disclosure during the MRI or a similar (radiological) examination or the aforementioned procedures, or, as mentioned above, it can be self-administered by the patient so that the patient's position during the examination or procedure is not altered. This is extremely important during an MRI examination with various contrast agents (T1, T2, diffusion, ADC, dynamic, native, and with gadolinium as the contrast agent) and the requirement that the patient cannot move. This significantly simplifies the repeat dose and prevents incorrect application.

[0104] This disclosure therefore also relates to a method for treating patients in the context of MRI or a similar (radiological) examination, characterized in that the spray with a bidosis nasal spray according to this disclosure is administered to the patient immediately before the MRI examination or in such a way that it is self-administered in the MRI device (e.g., with recurrent anxiety or restlessness during the examination).

[0105] Higher-dose anticonvulsant agents are also suitable for the treatment of seizures in patients. Such seizures (e.g., myoclonic seizures) may be caused by various seizures, including epileptic disorders, other neurological diseases, CNS seizures, and febrile seizures.

[0106] The double-dose nasal spray of the invention may therefore also contain a higher-dose solution or fluid of the active agent. The patient groups that benefit from such a high-dose nasal spray are typically children, adolescents, young adults, or other patients with tonic-clonic epilepsy-like spasms or seizures and convulsions up to and including febrile seizures.

[0107] Paroxysmal epileptic seizures or similar CNS attacks develop suddenly, often without clear signs and with a somewhat depressed level of consciousness that may sometimes last only a short time. Affected individuals respond to their environment in a limited way, responding with mouth or head movements, suddenly shouting, subsequently unable to remember, falling or writhing, excessively stretching the head and neck, experiencing cramps, involuntarily biting the tongue or cheek, and frequently developing frothy saliva. The patient's skin turns slightly blue as a result of low-grade hypoxia. Muscle tone in the affected muscles may suddenly decrease, causing the affected individuals to fall and their legs to buckle. Occasionally, the seizures last much longer and are dangerous. In addition, areas in the central nervous system (CNS) may be destroyed in such seizures. Depending on the affected area of the brain, the symptoms vary considerably. In affected patients who have already experienced such attacks, the initial signs may be partially detectable, such as dysphoria, irritability, headaches, certain sensory disturbances, noises, hallucinations, or a certain aura. This allows for the early use of midazolam nasal spray to get ahead of the attack. In this way, the spastic tonic-clonic attack can also be reduced and/or shortened in the best-case scenario. Midazolam can also be administered orally (tablets) or rectally, but these dosage forms have the distinct disadvantage that the active agent cannot act immediately.

[0108] Recently introduced oral midazolam solutions have the disadvantage that the active agent is reabsorbed in a delayed manner (30 to 60 minutes, depending on the degree of stomach and/or duodenal filling). After reabsorption, a first-pass effect occurs in the liver via the portal vein, which in turn leads to reduced efficacy. Using a nasal spray, the active agent can be delivered into the bloodstream much more rapidly and with much greater bioavailability (approximately 80%) since the first-pass effect can be avoided with nasal administration.

[0109] Using the double-dose nasal spray according to this disclosure, family members or other caregivers can quickly, safely, and easily administer the anticonvulsant directly without prior activation, especially to epileptics, for example, those experiencing spasmodic biting seizures. As already mentioned, due to its rapid bioavailability, fast action, and simple application without the first-pass effect, nasal administration using the nasal spray according to this disclosure is significantly superior to oral or rectal administration. This offers major advantages for family members or other caregivers who look after patients or even treat them in emergencies. When using a multi-dose nasal spray, the patient's head must be in an upright position. To achieve this, family members are forced to somehow keep the patient sitting or in an upright position to make nasal administration possible. This is not necessary with the double-dose nasal spray according to this disclosure, since ad hoc administration is possible regardless of the nasal spray's orientation or the patient's position. Therefore, the double-dose nasal spray according to this disclosure is especially suitable for emergencies because it can stop a rapid deterioration of the attack early on.

[0110] In this context, it should be noted that sometimes a single dose may not be sufficient, as the dose response depends on the patient's body weight (a sufficient dose of the active agent for attacks is often approximately 0.02 to 0.05 mg/kg of body weight). Sometimes a second dose may be required. Using the two-dose nasal spray as described herein, a second spray with a second dose of the active agent can be administered immediately or at a later time. This is an advantage compared to other common products such as Nazolam® (MEDIR B.V., Doorn, The Netherlands).

[0111] Higher doses of the active agent midazolam (1-10 mg) are typically administered intranasally when a patient is experiencing any type of CNS seizure, convulsion (e.g., febrile seizures), epileptic disorders, and/or seizures associated with them. Treatment with higher doses may be indicated in the early stages of seizures or with symptoms of similar CNS disorders. The nasal spray, as described herein, can be self-administered in any position (ready to use) or by a third party involved in emergency treatment. Intranasal uptake is rapid, and the calming effect has a very quick onset.

[0112] Measurement of the bioavailability of the active agent after administration of midazolam using the dosed nasal spray according to the present invention shows that high bioavailability (>83%) is achieved. Since there is no first-pass effect with reabsorption through the nasal capillaries, a significant plasma concentration is achieved as early as 2 minutes after administration. Peak plasma concentration levels were measured 5 to 10 minutes after administration (however, high standard deviations were observed). This demonstrates that local uptake of the active agent is very rapid. The mean excretion time (t1/2β) ranges from 1.5 to 3.5 hours.

[0113] Administration of midazolam via nasal spray may lead to local irritation of the nasal mucosa. However, this usually resolves within 10 to 20 seconds after administration. The cause of this reversible irritation is probably the low pH of the fluid in the nasal spray (preferably pH 3.0 to 3.5). Nasal mucosal irritation may also be caused, or partially caused, by preservatives that may be present. This can be reduced by using penetration enhancers as additives (dextrins and derivatives, chitosan and derivatives), wetting agents (propylene glycol, glycerol), or even chelating agents (EDTA, DTPA).

[0114] When midazolam is administered using a two-dose nasal spray according to this disclosure, the usual known precautions should be taken to avoid unwanted side effects. For example, a higher dose may lead to dyspnea or respiratory failure. However, reported cases are extremely rare (1 case has been reported in the last 12 years). Myasthenia gravis may also be exacerbated by the administration of midazolam. There are also reports of contradictory or paradoxical effects in children. Generally, similar unwanted adverse events may occur, especially in older patients.

[0115] The person skilled in the art knows how to produce or supply an actuating element as described above. Additional components may be purchased. The person skilled in the art can easily assemble the components into a finished nasal spray. The vial holder is usually made of a synthetic or plastic material. It serves to hold the container with the active agent (usually pre-filled). The stopper serves to facilitate a leak-proof connection between the actuating element and the active agent container. The rubber stopper is preferably made of a rubber suitable for pharmaceutical use but may also be made of other suitable plastic materials known to the person skilled in the art.

[0116] The design of the nasal sprayer is shown in Figure 1 and Figure 2. The nasal sprayer according to Figure 1 is constructed so that the active agent container (preferably a glass vial) can be directly displaced against the rubber stopper by pressing with a finger, thus enabling activation of the spray independently of the air pressure. The nasal spray device according to Figure 1 allows for precise, independent control of the orientation and a locking mechanism against the displacement movement (Figure 2), thereby enabling the integration of the actuator's volume control functionality (Figure 2).

[0117] Preferably, the nasal spray according to this disclosure is characterized in that it can be identified whether the nasal spray is still unused.

[0118] The nasal spray according to this disclosure is characterized in that the displacement of the vial holder against the lower edge of the actuator from the underside is visible, and therefore also whether the nasal spray has already been used or whether one or two sprays have already been activated. Preferably, the nasal spray according to this disclosure is characterized in that the assembled nasal spray contains a locking mechanism that ensures that a first spray is administered in a controlled manner without simultaneously activating a second spray (compare with Figure 2).

[0119] Preferably, one or two sprays can be administered with the nasal spray in accordance with this disclosure without the nasal spray needing to be activated beforehand.

[0120] In this way, the sprays can be administered directly to the patient or by the patient, with one hand and without preparatory steps. In this case, the volume of each spray is selected so that the aqueous fluid is injected or sprayed, respectively, onto the nasal mucosa and can be reabsorbed from it. Using the nasal spray in accordance with this disclosure, a dose of 0.25 to 5 mg of the anxiolytic, sedative, muscle relaxant, or anticonvulsant active agent can be administered to achieve conscious sedation. Using the nasal spray in accordance with this disclosure, a dose of 1 to 10 mg of the anxiolytic, sedative, muscle relaxant, or anticonvulsant active agent can be administered to achieve a spasmolytic effect.

[0121] The preferred active agent solution in the nasal spray described herein may additionally contain a preservative, for example, benzalkonium chloride at a concentration of 0.01% w/v and EDTA at a concentration of 0.1% (w/v). However, preservative-free nasal sprays may also be used, particularly by those with allergies or a known hypersensitivity.

[0122] The preferred active agent solution in the nasal spray according to this disclosure has a pH value between 2.8 and 3.8; preferably a pH value of 3.0 to 3.5. Anhydrous fluids or powders also do not have a measurable pH.

[0123] The preferred active agent dilution in the nasal spray according to this disclosure is isoosmolar. The nasal spray according to this disclosure is preferably prepared aseptically.

[0124] The nasal spray according to this disclosure preferably does not cause magnetic interference. The nasal spray according to this disclosure is suitable for the treatment of patients with claustrophobia or anxiety disorders, whereby, with each spray, 0.56 mg of midazolam HCl is administered per spray (corresponding to 0.50 mg of midazolam base).

[0125] The nasal spray according to this disclosure is suitable for sedation or premedication, so that with each spray, for example, 0.278 to 5.56 mg of midazolam HCl is administered per spray (corresponding to 0.25 to 5 mg of midazolam base).

[0126] The nasal spray according to the present disclosure is suitable for the treatment of patients with claustrophobia or anxiety disorders or for the treatment of patients with an epileptic seizure or other seizures, respectively, whereby, as described above, a higher dose of the active agent is required of, for example, 1 to 10 mg of midazolam per spray or 0.02 mg to 0.5 mg of midazolam per kg of the patient's body weight per spray with such treatment.

[0127] On the one hand, the nasal spray according to this disclosure is used for the treatment of patients in the context of MRI or a similar (radiological, radiotherapy) examination (or similar tube-shaped or similar imaging machines), whereby one spray from the nasal spray according to this disclosure is administered to the patient shortly before the MRI examination. If necessary, an additional spray from the nasal spray according to this disclosure may be administered to the patient before or during the examination.

[0128] On the other hand, the nasal spray according to this disclosure is used for the treatment of patients with a neurologically provoked attack, so that the patient is given one spray from the nasal spray according to this disclosure, so that, if necessary, the patient may be given another spray from the nasal spray according to this disclosure.

[0129] Therefore, the advantages of the bidose nasal spray according to this disclosure are as follows: - A rapid, specific anxiolytic effect during the preparation phase on the MRI table, as well as in similar diagnostic examinations (PET, SPECT, CT) or in all types of minimally invasive interventions (dental, surgical, induction of anesthesia), accelerates the workflow and facilitates the planned interventions on the patient. - The administration of low-dose midazolam leads to better cooperation with the technical staff during an MRI examination (conscious sedation) or various minimally invasive interventions.

[0130] - Improved image quality with fewer motion artifacts (MRI) and better compliance in the interventions mentioned above.

[0131] - Reduced CNS or systemic toxicity due to a lower peak concentration of the active agent midazolam. - Temporary sedation.

[0132] - The administration of the active agent is very controllable and possible through both nostrils.

[0133] - The bidosis nasal spray can be used with consistent efficiency in lying, sitting, or standing positions, or in any other patient position, for example, also in the lateral position. The spatial orientation of the nasal spray is not limiting in this case.

[0134] - The bidosis nasal spray is supplied ready to use and can be used immediately.

[0135] - A double-dose nasal spray is used on one patient only and therefore meets high hygienic standards.

[0136] - Since the formulation in the bidose nasal spray can be filled aseptically in a closed system, there is no need to use preservatives.

[0137] - In emergencies, with a blocked nose or local limitations, the nasal spray can be sprayed quickly, effectively and without any preparation directly into the mouth.

[0138] - The bidosis nasal spray meets regulatory requirements, for example for registration with Swissmedic, EMA and/or FDA.

[0139] - Various formulations of midazolam, such as anhydrous solutions, suspensions, or even powders, can be administered via nasal sprays, both nasally and orally, also in emergencies.

[0140] The preferred embodiment of the disclosed double-dose nasal spray is described below. Using this double-dose nasal spray, the active agent solution (preferably a midazolam solution, but also a fluid or powder mixture) can be administered very quickly, safely, locally precisely, and rapidly, regardless of the patient's position (e.g., standing, lying on their back, or in the lateral position), uniformly, regardless of the spatial orientation of the nasal spray, and without requiring any prior preparation for activation of the spray device (ready-to-use nasal spray device). This is most beneficial for healthcare professionals, as well as for family members, and was not previously available. This advantage of orientation-independent, position-independent, safe, and uniform drug application plays an important role both in the emergency treatment of patients experiencing seizures and in the premedication of patients prior to diagnostic examinations such as MRI.

[0141] The precise localized delivery of the active agent using the disclosed nasal spray device is documented and verified by the following experimental tests and the data obtained therefrom. This verification was performed using a novel measurement procedure in conjunction with high-resolution CT as the imaging examination device, whereas other imaging procedures (tomographic) with appropriate spatial resolution or image quality, respectively, are possible. The novel examination procedure allows for the characterization of nasal sprays with respect to their precise localized delivery of the active agent (droplet distribution) and, for the first time, enables the ad hoc evaluation of the effectiveness of the delivery system, i.e., the analysis of the localized precise delivery of an active agent administered nasally. Since nasal sprays and nasal applicators, respectively, are used both locally and systemically, the distribution of the active agent, its distribution on the surface, and its physical wetting of the mucosal surfaces have a significant influence on the effectiveness of the system. As a reference standard, nuclear medicine methods (scintigraphy, SPECT, PET, possibly combined with MR or CT as fusion imaging) are most frequently used to evaluate nasal deposition of drugs administered nasally with various applicators. However, these radiographic methods have significant drawbacks in terms of their practical utility:

[0143] - Spatial resolution (e.g., 3 to 5 mm, 5 to 10 mm, or 6 to 12 mm) is often limited.

[0145] - From a temporal perspective, frequent measurements must be taken over a period of approximately 20 to 30 minutes, which therefore cannot visualize short time periods. The images thus show an overlap of a longer time period with a confluence of markers on the mucosal surface of approximately 30 minutes (gravitational force). Therefore, the assessment of nasal deposition will be flawed. Due to the long measurement times, dynamic images are not possible. Therefore, the temporal progression of the nasal distribution, and especially the initial distribution, cannot be presented.

[0147] - Image analysis is associated with relatively high radiation exposure.

[0149] Today, it is possible to prepare detailed, patient-specific nasal replicas based on radiological tomography examinations such as CT [Warnken Z. N. et al.; “Personalized Medicine in Nasal Delivery: The Use of Patient-Specific Administration Parameters To Improve Nasal Drug Targeting Using 3D-Printed Nasal Replica Casts”; Mol. Pharmaceutics, 15, 1392-1402 (2018)]. In particular, high-resolution, patient-specific detection of whether an active agent reaches the desired locations in the nasal cavities during nasal application remains unclear. This disclosure provides a method that enables patient-specific detection of the locally accurate deposition of an active agent during nasal application. Specifically, the method disclosed herein allows for the assessment of whether and to what extent an active agent reaches any nasal sinus or major cavity via nasal application.

[0151] Computed tomography, abbreviated CT, is a radiology imaging procedure that provides high spatial and temporal resolution in layered images (3D acquisition). Based on the object's X-ray absorption profile, anatomical structures can be visualized layer by layer using CT images. Calculated cross-sectional images are generated from the absorption values of X-ray signals passing through the body. Through technical improvements in spatial resolution, image quality can be enhanced, allowing for greater detail in anatomical structures. Simultaneously, novel techniques have enabled the deployment of low-radiation examinations in daily clinical use. To better characterize and localize nasal deposition on the nasal mucosa, as well as throughout the different nasal cavities, the nasal delivery system is filled with a contrast agent (e.g., an iodine-containing solution, a gadolinium-containing contrast agent, or other positive- or negative-acting contrast agents). After application to the nose (patient, test subject, replica) using the nasal applicator, CT images are acquired. By tracing the absorption profile throughout the nasal cavity, high-contrast droplets on the nasal mucosa surface can be visualized and delineated from the surrounding tissue. The droplets appear with significant contrast against the background, which absorbs X-rays to a lesser degree. The surface wetting, as well as the distribution of the high-contrast fluid, can therefore be clearly described. In this way, the sprayed fluids can be located and quantified relatively quickly after application (X-ray absorption). The temporal evolution (dynamics) can be visualized. The iodinated contrast agents used are approved solutions, suspensions, or powders containing iodine that vary in concentration, viscosity, and osmolality. The practitioner can select a suitable contrast agent for application at an appropriate concentration and possibly add it to midazolam or other active agents if visualization is desired. In this case, dilute solutions of iodinated contrast agents (e.g., Iopamiro®) with an iodine concentration of 92 mg/ml were used. In principle, all possible high-contrast substances (fluid, solid, gaseous) can be used in varying concentrations or doses. To adequately characterize the basic properties of the nasal spray device, mixtures of substances similar to the solution of the pharmaceutically active agent to be used are advantageously employed. Using solutions of iodinated contrast agents allows for optimal visualization of aqueous solutions and their distribution. Powder mixtures can also be used to visualize and characterize the nasal deposition of a nasal spray. As mentioned earlier, the disclosed nasal spray device allows for locally precise and volumetrically accurate delivery in any orientation (spatial orientation) of the nasal spray device. This was verified by the experiments described below, and images were recorded (CT imaging procedure).

[0152] The characterization of nasal spray devices is carried out using a computed tomographic nasal deposition technique. For this purpose, nasal spray devices filled with aqueous solutions of iodine or other contrast agents must be sprayed from various directions onto a model of the nose (hereinafter also referred to as a nose replica).

[0153] The nose replica can be prepared in various ways. The nose model used in the experiments described below was designed based on human CT images and manufactured by casting techniques or 3D printing methods (even from several patients, thus modeling the variable shapes of the nasal cavity). The nose model preferably consists of synthetic resins or plastics selected so that they do not produce any artifacts in CT imaging and allow appropriate contrast between the applied iodine solution, fluid, or powder and the anatomical structure of the model (different X-ray densities between the surfaces of the replica and the contrast agent). The advantage of surface deposition is the use of a replica consisting of a finely structured surface texture without surrounding tissue, possibly a model with a hydrophilic coating or a model bathed by air absorption.

[0154] For the characterization of nasal spray devices, the nasal replica is placed in the desired (tilted) position and then stabilized. Due to the constant application angle, the spatial position of the nasal spray device during administration is defined. Subsequently, the administration of the solution, fluid, or powder of the active agent with the contrast agent is ensured by means of the nasal spray device under examination. Immediately after administration, the locally precise delivery is located by computed tomography or another imaging technique and thus characterized and verified. Due to the added contrast agent, the distribution of the droplets of the solution or fluid or the powder particles, respectively, of the active agent on the inner surface of the nasal cavity of the nasal replica is clearly visible in the CT images or similar devices. In the present case, it could be shown, based on the high-resolution CT images, that the contrast agent is dispersed in the anterior and middle superior nasal cavity. Such measurements can also be performed on an individual patient with ambiguous ENT conditions or to increase the safety of the application.

[0155] The following preconditions are important for presenting and localizing timely, uniform, orientation-independent nasal deposition (ready-to-use nasal application) with the disclosed nasal sprays: use of a substance containing a contrast agent (solution, mixture, powder, gas, emulsion, etc., frequently with iodine-containing contrast agents, gadolinium-containing contrast agents, or other high-contrast substances) with which the nasal applicators or nasal sprays can be filled.

[0156] The application of contrast agents with or without active agent will ideally simulate or detect nasal distribution, i.e., they will have similar properties (flow, nebulization, or surface charge) when applied as pharmaceutical solutions, fluids, or powder mixtures of the active agent that will possibly be used.

[0157] Furthermore, the nasal replica must be suitable for CT measurements or similar examination procedures. In particular, the replicas must also allow for quantification at the pixel level, i.e., with respect to the grid point (voxel level). To this end, the use of CT scanners or similar methods capable of scanning or displaying high-resolution images must be ensured.

[0158] The nose model used in the present experiment consists of synthetic resins and/or plastics selected in such a way that they do not produce artifacts in CT imaging or possible alternative methods.

[0159] The nasal sprayer is filled with the solution, fluid, or powder mixture containing iodine contrast agent, and the sprays are applied to the nostrils of the nasal model at defined application angles (reference: bridge of the nose). The angle between the nasal sprayers and the nasal model must be kept constant (preferably physiological introduction angles) so that individual measurement points can be measured and verified repeatedly. This application is standardized using a fixed holder for the nasal sprayer so that measurements can be performed reproducibly. Imaging begins immediately after the application of the solution, fluid, or powder mixtures via a sprayer. Imaging is completed within a few seconds before a confluence of the deposited droplets, suspensions, or powders occurs (caused by gravity). Thanks to the high temporal resolution of the CT device used, the independence of the nasal application position could be demonstrated (compare the images shown in Figure 3). The CT scanner used in these experiments preferably has a high resolution (e.g., from 0.04 mm to 1 mm). At this resolution, the anatomical structure of the nose, as well as the droplets deposited on the inner plastic surface of the nose model, can be visualized with good quality.

[0160] The measured CT scans must be processed using post-processing techniques for better visualization of the contrast agent on the nasal mucosa, which has low X-ray density. Various 3D techniques with full-volume visualization, as well as subtraction techniques, are possible. In particular, native images can be subtracted from the contrast images so that only the applied contrast agents are visualized without the background and anatomy. This allows visualization of anatomical structures separated from or superimposed by the contrast agent images. In the images shown in Figure 3, three CT scans are shown in various application positions (standing, lying down, and so on) with the corresponding application angles. First, a native image of the nasal replica or model was taken before the application of a contrast agent (top left). The nasal model shows no CT artifacts, and the fine anatomical structure is clearly visible. The other five images each show a CT scan captured from various angles after the application of the nasal sprays. The deposition of the iodine-containing droplets in the nasal cavity appears as bright spots and is therefore localized. Qualitatively, all application directions result in a similar distribution of the solutions, fluids, or powders, respectively, administered using the nasal spray.

[0161] Pixel-independent (voxel-independent) quantification of the deposited contrast agent (in this case an iodine-containing contrast agent solution) is performed using various methods known to a person skilled in the technique (e.g., region growth method, Houndsfield unit threshold, iodine mapping, see, e.g., Binh DB, Nakajima T, Otake Het al. Iodine concentration calculated by dual-energy computed tomography (DECT) as a functional parameter to evaluate thyroid metabolism in patients with hyperthyroidism in BMC Medical Imaging 2017; 17: 43).

[0162] This disclosure, therefore, also relates to a method for the qualitative and/or quantitative detection (localization) of the locally precise, preferably uniform, delivery of an active agent in a nasal application, characterized in that the active agent is sprayed onto a nasal model or in vivo on a patient, and the locally precise deposition of the fluid or powder of the active agent is measured, localized, and visualized using imaging methods, for example, by adding contrast agents, fluorescent markers, dyes, or other visualizable substances. Preferably, the imaging method is a rapid, high-resolution (<4 mm), low-radiation imaging method.

[0163] In one embodiment, the qualitative and/or quantitative detection method is characterized by the fact that the temporal course (dynamics) of the nasal distribution and the elimination of the active agent, which absorbs radiation, are shown and quantified in real time.

[0164] In one embodiment, the qualitative and/or quantitative detection method is characterized by its ability to volumetrically reconstruct (“volume representation”) and display with high resolution in 2D/3D the structure of the nasal mucosa surface and nasal cavities.

[0165] In one embodiment, the qualitative and/or quantitative detection method is characterized in that, with the method, the patient's individual nasal deposition of an active agent can be located and characterized qualitatively and quantitatively in a locally precise manner.

[0166] In one embodiment, the nasal spray according to this disclosure is characterized in that it has been shown, by the aforementioned qualitative and/or quantitative detection method, to achieve locally precise, targeted delivery of the active agent liquid to the nasal mucosa of a patient, regardless of the patient's position (standing, sitting, lying down, or in any intermediate position). Using this detection method, it can be verified whether or not a nasal spray meets the requirements for locally precise delivery of a fluid or powder of the active agent to the nasal mucosa of a patient. Preferably, the nasal spray achieves locally precise, targeted, and uniform delivery regardless of the orientation of the nasal spray during the spraying procedure (e.g., vertically, horizontally, downwards, and in any intermediate position).

[0167] The detection method allows for the qualitative and/or quantitative visualization of nasal deposition of the solution, fluid or powder of the active agent after the spraying procedure in a reproducible manner.

[0168] Dynamic recording in the replica can be carried out for several minutes or any period of time so that secondary distribution, possible removal by means of cilia, as well as osmotic or other factors that influence dynamics can also be monitored.

[0169] Although the above-mentioned detection method is described using an artificial nose model, the detection method can also be carried out directly in vivo in a patient.

[0170] The method of detection in humans (in vivo, patient or test person), insofar as it is a CT method, preferably uses low doses of radiation.

[0171] Preferably, dynamic recording in humans (in vivo, patient or test person) is for a short period of time, e.g., for a period of a few minutes.

[0172] The detection method described above can also be used to reconstruct and visualize the surface structure of interfaces using special (3D) reconstruction techniques. By coating thin layers of the interfaces with iodine or other contrast agents using a nasal spray, preferably a double-sided nasal spray device, the interfaces can be visualized in high resolution using a 3D or projection method. This allows for targeted visualization of the mucosa and contour mapping.

[0173] The detection method described above can also be used for customized high-resolution detection to demonstrate that an active agent reaches the desired locations in the nasal cavities after nasal application. Depending on the patient's specific, diverse anatomical structure of the nose and nasal cavities, it is appropriate to qualitatively and quantitatively locate and determine, in a locally precise manner, the nasal deposition of an active agent, either alone or in a powder, solution, or fluid mixture, in a nasal application. In this case, a detailed nasal replica with the characteristics disclosed herein is prepared from patient-specific radiological tomographic examinations (MRI/CT, SPECT, or PET) of the nasal cavity. As an example embodiment, a nasal replica can therefore be designed based on CT scans of humans and produced using casting techniques or 3D printing methods. The nasal model preferably consists of synthetic resins or plastics selected to avoid artifacts in CT images and to allow appropriate contrast between the applied iodine solution, fluid, or powder and the model's anatomical structure (different X-ray densities between the replica and the contrast agent). For visualizing surface deposition, it is advantageous to use a replica with a fine-textured surface without surrounding tissue. The nasal deposition of the active agent is then analyzed and characterized using this method. Furthermore, the dynamic distribution of the active agent can be characterized over a desired time period. This method allows for patient-specific verification of the suitability of a drug, treatment, or nasal spray device based on the high-resolution and locally accurate localization and characterization of the nasal deposition of an active agent on a patient-specific nasal replica.

[0174] This disclosure also relates to a nasal spray, preferably a bidose nasal spray with the characteristics mentioned above, and characterized in that it is demonstrated, by the method mentioned above, that a possibly targeted, locally accurate uniform delivery of the active agent fluid or an active agent powder onto the nasal mucosa of a patient can be achieved with the nasal spray.

[0175] A nasal spray tested in this manner allows orientation-independent nasal administration of a solution, fluid, or powder of the active agent to a patient, preferably in medical emergencies and in cases where administration is limited by spatial restrictions.

[0176] The above-mentioned method for airless filling and airtight sealing of an active agent container for use in the disclosed nasal spray can also be applied to other types of active agent containers. Therefore, this disclosure also relates to a method for airless and airtight sealing of a container. The method is characterized in that the sealing of the container by inserting a stopper into the container takes place in a closed system. The preferred containers are glass or plastic ampoules with a filling volume of up to 2 ml.

[0177] Preferably, the container is sealed so that there is no air, or as little as possible, between the solution in the container and the stopper.

[0178] The disclosure also relates to a method for airtight, airtight sealing of an active agent container for use in a nasal spray, characterized in that the insertion of the plug into the active agent container is carried out in a closed system in which the active agent container with the active agent solution is inserted, where no or as little air as possible remains between the active agent solution and the plug.

[0179] Preferably, the method is carried out in a closed system consisting of a sealed chamber, a movable piston, and an outlet for drawing air from the closed system. A corresponding system and procedure are shown schematically in Figure 4a.

Claims (9)

1. CLAIMS 1. A method for the qualitative and/or quantitative detection, localized localization, and quantification of a radiation-absorbing active agent after nasal application with a nasal spray device, characterized in that, a) a replica nose model consisting of synthetic resins or plastics selected in such a way as to avoid producing any artifacts in CT imaging, and to allow sufficient contrast to provide a differentiated distribution pattern of the spray dose applied within the anatomical nasal structures of the nose model; b) bring the nose model to a desired inclined position and stabilize it; c) fill the nasal spray device with a solution of an active agent, which absorbs radiation, or any other contrast agent; d) spray the solution containing the radiation-absorbing active agent and the contrast agent with the nasal spray device into the nostril of the nose model at defined application angles using the bridge of the nose as a reference; and e) determine the distribution of droplets on the inner surface in the nasal cavity of the replica nose model by computed tomography with a fast, high-resolution, low-radiation imaging method whereby image capture is completed before a confluence of deposited droplets occurs and the nasal deposition of the agent is qualitatively localized and quantified and locally accurately characterized by post-processing methods. 2. The method according to claim 1, wherein the replica nose model has a finely structured inner surface texture with a hydrophilic coating without surrounding tissue. 3. A method according to claim 1 or 2, wherein the radiation-absorbing agent is selected from the group of iodine, gadolinium, or any other positive or negative action contrast agent. 4. A method according to any one of claims 1 to 3, wherein the fast, high-resolution, low-radiation imaging method has a resolution of < 4 mm. 5. A method according to any one of claims 1 to 4, wherein the fast, high-resolution, low-radiation imaging method has a resolution of 0.4 mm to 1 mm. 6. The method according to any one of claims 1 to 5, wherein the radiation-absorbing active agent is combined with either a contrast agent, a fluorescent marker, a dye, or any other visualizable substance. 7. The method according to any one of claims 1 to 6, wherein the radiation-absorbing active agent is combined with a therapeutic substance, such as midazolam. 8. The method according to any one of claims 1 to 7, characterized in that the temporal course or dynamics of the nasal distribution and elimination of the active agent, which absorbs radiation, is shown and quantified in real time. 9. The method according to any one of claims 1 to 8, characterized in that it volumetrically reconstructs by means of “volume representation” and displays in high resolution in 2D/3D the surface structure of the nasal mucosa and nasal cavities.