Two-dose nasal spray

Abstract

A two-dose nasal spray is provided. The present invention relates to a novel nasal spray containing an aqueous solution or fluid containing an anxiolytic or anticonvulsant substance, which allows a patient to intranasally administer two identical, determined-volume sprays of the aqueous solution or liquid of the active agent, and which is independent of its spatial orientation and can be administered in any patient position (upright, sitting, lying down, or any intermediate position). The nasal spray can be used immediately without prior activation.

Description

[Technical Field]

[0001] The present invention relates to a novel nasal spray containing an active agent solution or fluid containing an anxiolytic or anticonvulsant active agent, which allows the patient to administer two identical, predetermined-volume sprays of the active agent solution or liquid into the patient's nose. The nasal spray is characterized by its ability to administer the dose regardless of the patient's spatial orientation, regardless of their position (upright, sitting, lying down, or any intermediate position). The nasal spray is ready to use and can be used without prior actuation. Preferably, the nasal spray can indicate whether a spray or a second spray has been administered or has been administered by looking at the nasal spray. Preferably, the spray can be administered by one hand by the patient or a third party. The active agent in the nasal spray of the present invention is preferably an anxiolytic, sedative, muscle relaxant, or anticonvulsant active agent, and is preferably a benzodiazepine or a GABA receptor agonist, such as midazolam or its derivatives or salts of these active agents (e.g., midazolam HCl). The nasal sprays according to the present invention may be used for sedation, premedication, or treatment of patients with claustrophobia, anxiety disorders, or panic attacks, and may be used to treat convulsions in CNS disorders, particularly epileptic or other seizure episodes (e.g., febrile convulsions). The present invention also relates to a method for qualitatively and quantitatively detecting orientation-independent uniform administration of an active agent in nasal applications by localizing locally precise nasal deposition of the active agent in nasal applications, as well as a nasal spray, preferably a dual-dose nasal spray, which has been shown to achieve locally precise, orientation-independent fluid administration of the active agent to the patient's nasal mucosa using the described detection method. The present invention also provides a method for characterizing patient-specific detection of locally precise deposition of the active agent in the nasal cavity, thereby assisting in its control. Furthermore, a method for hermetically sealing an active agent container according to the present invention against air is also provided. [Background technology]

[0002] Therapeutically usable anxiolytic, sedative, muscle relaxant, or anticonvulsant substances, such as the fast-acting benzodiazepine midazolam (8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazole[1,5-a][1,4]-benzodiazepine, including all of its salts), are known to those skilled in the art. Midazolam has sometimes been used as a drug for preparing anesthesia, for sedation, for treating seizures, for inducing sleep, and as a sedative or anti-anxiety agent (anxiolytic). This drug carries a significant risk of resistance and should preferably be prescribed or administered for only short periods of time. Midazolam is included on the World Health Organization's list of essential medicines. Midazolam can be administered orally, intravenously, intramuscularly, or by nasal or oral spray.

[0003] Administration of midazolam via nasal spray to treat acute cerebral seizures (epileptic seizures) is known. Midazolam in the form of a nasal spray is also used for sedation and to prepare patients prior to minor interventions. Midazolam nasal spray has also been occasionally used to provide comfort and reassurance to patients before or during lengthy imaging procedures (e.g., magnetic resonance imaging (MRT) or MRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT), partial computed tomography (CT), or a combination of these procedures) [J. Hollenhorst et al.; "Using intranasal midazolam"] spray to prevent claustrophobia induced Am. J. Roentgenol. 176, 865-868 (2001).

[0004] In nasal administration, therapeutically active agents are sprayed into the back of the nose, thus contacting the nasal mucosa. Depending on the dose and / or the active agent, drugs administered in this manner can act purely locally or systemically. In the case of midazolam, a systemic effect is desirable. Because the nasal cavity is lined with a thin, vascularized mucous membrane, drugs can rapidly enter the systemic circulation through a single epithelial cell layer (without first-pass metabolism by the liver or intestine). In this way, rapid (within minutes) pharmacological effects can be achieved.

[0005] Intranasal application is particularly suitable for strong (potent) drugs, where only a limited amount of active agent must be applied onto the nasal mucosa to achieve a therapeutic effect.

[0006] A potential disadvantage of intranasal administration is the high variability in the amount of drug sprayed onto the nasal mucosa and subsequently reabsorbed. Such variability can result, for example, from incorrect or uneven handling of the nasal spray device [H. Kubik and MT 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 congestion in the upper airway, or if a large amount of nebulized fluid enters the oral cavity through the nose and is subsequently swallowed by the patient. When administered by a medical professional, the amount ingested after nasal administration is generally similar to or higher than after the corresponding oral administration [BA Coda, AC Rudy, SM 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: a randomized dose-response study"; Aerodiol Study Group. Lancet 353: 1574-1578 (1999)]. Most importantly, a non-invasive method that does not require blood sampling and allows for flexible detection by localizing precise application of the administered spray with corresponding resorption.

[0007] Several clinical trials have already been published regarding the use of intranasal midazolam for anxiolytic pretreatment in MRI patients.

[0008] In a prospective Phase I clinical study in eight healthy subjects, the mean bioavailability of midazolam after nasal administration was found to be between 76 ± 12% and 92 ± 15%. For formulations administering 1 mg of midazolam, the mean C was between 28.1 ± 9.1 and 30.1 ± 6.6 ng / ml after 9.4 ± 3.2 and 11.3 ± 4.4 minutes. (max) In each case, the absorption of the active agent was already measurable in the first plasma sample [M. Haschke et al.; "Pharmacokinetics and pharmacodynamics of nasally delivered midazolam"; Br. J. Clin. Pharmacol. 69 (6): 607-616 (2010)].

[0009] A prospective multicenter phase III clinical study [Tschirch FTC 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)]. Patients in the unit dose group (UDG) received 1% (w / v) midazolam with 4% cyclodextrin derivative (e.g., CAVASOL® W7M Pharma; manufacturer: Wacker Chemie) as a penetration enhancer. Patients in the multiple-dose group (MDG) received a single spray of 0.1 ml of an active agent solution containing 0.5% (w / v) midazolam into one nostril via a single-dose nasal spray. Patients in the multiple-dose group (MDG) received a single spray of 0.1 ml of an active agent solution containing 0.5% (w / v) midazolam into each nostril via a multiple-dose nasal spray. This corresponds to two applications of the same total 1 mg of midazolam base. Analysis of the results from both groups (4 centers, 108 claustrophobic patients) demonstrated that nasally applied low-dose midazolam is a patient-friendly solution for easing MRI examinations in claustrophobic patients. UDG nasal spray was significantly superior to MDG nasal spray.

[0010] Further research [Tschirch FTC et al.; ”Low-dose intranasal versus oral midazolam for “routine body MRI of claustrophobic patients”; Eur. Radiol. 17: 1403-1410 (2007)] compared the effectiveness of low-dose intranasal midazolam (1-2 mg) with oral midazolam (7.5 mg) in treating claustrophobic patients prior to routine MRI. This study (at a single testing site) randomly assigned 72 patients to two equal-sized groups. Patients in test group TG1 received 7.5 mg of midazolam orally 15 minutes before the MRI scan. Patients in test group TG2 received 7.5 mg of midazolam twice a day from a nasal spray containing 0.5 mg of midazolam per spray, followed by 1-2 doses as needed. Patients in the TG2 group received multiple nebulizations (totaling 1.0-2.0 mg of midazolam base). MRI examinations were successfully performed in 97% of cases, without any associated side effects. MRI imaging quality was significantly higher in patients in the TG2 group compared with those in the TG1 group (p<0.001). The conclusion was that low-dose intranasal midazolam is an effective and patient-friendly solution to avoid anxiety in claustrophobic patients during extensive body MRI examinations. In this respect, the anxiolytic effect of nasally administered midazolam was significantly superior to that of the orally administered form.

[0011] Based on initial studies using these "low-dose midazolam" formulations, midazolam nasal sprays have become frequently used in clinical practice to prepare patients for lengthy imaging procedures (e.g., MRI scans). Until now, such midazolam nasal sprays have often been produced in small quantities in licensed hospital or public pharmacies. However, simple decantation does not allow optimal adjustment of the concentration and dose for nasal administration. The difficulty in preparing the solution lies, inter alia, in the pH-dependent nature of the active agent, whose solubility fluctuates with each pH change. Active agent solutions prepared in this manner are stable only within the acidic range (below a pH of 3.8 or less, depending on the active agent content), with higher pH values ​​resulting in precipitation of the active agent. Therefore, in practice, the ideal pH must be titrated and stabilized with dilute hydrochloric acid. Optimal stability of the benzodiazepine ring and its solubility can be achieved in this way. Additionally, the solution should be isotonic to physiological conditions to ensure optimal local tolerance on the nasal mucosa. Because these midazolam nasal sprays are not necessarily manufactured in clean rooms, there is a risk of microbial contamination during manufacturing and / or storage. Microbial growth can be prevented by adding preservatives such as benzalkonium chloride (typically 0.01% w / v) and / or, if necessary, EDTA (typically 0.1% w / v). However, adding preservatives to the solution in nasal sprays often causes irritation of the nasal mucosa. This irritation is often perceived as unpleasant by patients and can therefore negatively impact the desired patient sedation during diagnostic procedures.

[0012] A further disadvantage of modern extemporaneous nasal spray preparations is variability between specific batches, which can lead to differences in the amount of active agent administered. This can be caused by variations in the spray device, for example, in traditional nasal spray devices, due to incorrect operation of the spray head (pushing it to the side) or insufficient filling of the spray tube. Therefore, with modern nasal sprays, it is often difficult to control and verify how much active agent is actually sprayed into the patient's nose. For the spray device to function properly, patients often must stand or sit upright to ensure that the spray tube is safely submerged in the solution and does not inhale air. During the preparation phase, i.e., just before the patient lies on the MRI table, an upright position is easily achieved. However, once the patient is lying on the examination table and the table is inserted into the imaging device for patient examination, administration in an upright position is virtually impossible. If a patient becomes restless while reclining during an imaging procedure, modern nasal sprays can seriously hinder the administration of additional doses of sedative or even force the procedure to be aborted. Re-spraying a second time while reclining is virtually impossible because the spray head will no longer refill. If the re-administered dose is too small or inapplicable, the patient will remain restless. Conversely, if the dose is too large, the patient may no longer be able to adequately respond to staff instructions during the procedure. It is clear that patients should lie as still as possible during the procedure and respond only to instructions from the operating staff (e.g., to inhale and exhale). Inadequate sedation can result in poor imaging output quality, requiring the procedure to be repeated. Considering that imaging devices and procedures are very expensive and that the corresponding equipment must be utilized effectively, such re-administration or delay of imaging procedures results in unnecessary high costs and must be avoided due to the limited resources of the healthcare system. The increased stress factor for the patient due to poor imaging results or repeated measurements should not be underestimated.Above all, clinical studies show that the administration of low-dose midazolam can significantly improve imaging quality, especially in problematic patients who become agitated in these examination situations; therefore, better image quality, along with anxiolysis, will facilitate better diagnosis.

[0013] Patients commonly report a fear of the "tube" or cramped examination space (claustrophobia) when they are admitted to the hospital or later enter the MRI room. Patients often also confess that the long, tubular magnet and its confinement are extremely uncomfortable. This can even lead to patients refusing to undergo the procedure. Furthermore, the coil and the additional devices required for the procedure (e.g., helmet, headset, breathing belt, pillow, belt, ECG electrodes, cap, and positioning belt) can be quite uncomfortable and create additional problems for the patient. Individual patients may find it inherently more difficult to remain still, which may be partially disease-dependent (e.g., due to Parkinson's disease, dementia, or other CNS disorders) or the result of imminent stressful situations that are unique to the patient and often completely new. Many patients also complain of exposure to extremely high noise levels during MRI scans, despite the frequent provision of noise-protective headphones or attempts to provide calming distraction through music over headphones. All of these factors lead to certain disturbances that may negatively impact the quality of the examination.

[0014] After clarifying whether the patient is prone to panic attacks and whether medical reasons for the test are problematic (e.g., due to respiratory depression, allergies, or myasthenia gravis, or because the patient regularly takes strong CNS-acting medications), the attending clinician recommends and provides the patient with a nasal spray. After consent, the patient receives final information about the test procedure. Modern nasal sprays must be administered while seated on the examination table. Generally, nasal sprays are first thoroughly filled by spraying one or two times into the air to fully fill the spray tube. One spray is then administered into each nostril, one on the right and one on the left. This often results in a brief, anticipated irritation. Patients respond differently to this, sometimes even positively, once the effect is clearly felt. Approximately one to two minutes after nasal application, patients no longer resist the MRI scan and readily agree to be prepared for the test procedure. Further spraying is rarely necessary at this initial stage. The patient is now ready for the final examination position. Various additional devices, such as coils, can now be easily installed. The patient can then be transferred to the MRI magnet without the difficulties of using a positioning laser for centering. In sick patients, this is often not possible without premedication. Another major advantage is the "low sedation" effect, which therefore makes it very appealing to patients, even when using sleep-inducing drugs. Because the doses used are so small, patients can easily and very well follow the instructions of the technician in charge (conscious sedation). This not only facilitates communication but also speeds up the examination procedure. Patients who fall asleep during the examination (which is itself common, for example, when using high intravenous doses of the substance midazolam) can no longer follow instructions and compromise the examination "by breathing," i.e., they cannot hold their breath, and spontaneous breathing results in poor or even diagnostically unusable image quality.Spontaneous breathing can be reduced by using a breathing belt, but this leads to longer measurement times which are uncomfortable for the patient and which must also be avoided for cost reasons.

[0015] If the patient shows further anxiety and / or restlessness during the test, the nasal spray can be used to administer an additional spray, i.e., redose the active agent. However, this is rather limited due to the patient's supine position, as the patient must also move from the test position. Furthermore, attempts must be made to administer the spray while the patient is supine in order to maintain their position. This is hindered by the poor filling of modern nasal sprays. If the patient is wearing a head coil during the test, it is virtually impossible to use modern nasal sprays, as the peri-nasal space is too narrow to orient the spray correctly. Additionally, it is not possible to reliably fill the spray device without imposing additional uncontrollable strain on the patient.

[0016] After image acquisition is complete, the patient, lying on the examination table, is removed from the MR magnet. The patient can sit up and get dressed. As a precaution, many centers do not allow patients to drive themselves after using the nasal spray. Understandably, there is little data on the necessity of this precaution. Because partially active metabolites are formed during the breakdown of midazolam, patients should remain quiet for at least 4 hours before driving or operating machinery. In this situation, it must be considered that some patients may have a significantly stronger reaction, metabolize the active agent more slowly, or are taking concomitant medications that enhance its effect.

[0017] When using multi-use nasal sprays, some patients are at risk of transmitting disease between patients. In large laboratories where many patients undergo such diagnostic imaging tests, special attention must be paid to hygiene. When using multi-use nasal sprays, the spray head may come into contact with the epithelium of several patients, and if the same head is used on subsequent patients, microbial transmission may occur. Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus epidermidis, and Staphylococcus aureus are found among others in the normal bacterial flora of healthy individuals. While these microorganisms do not necessarily lead to infection, they can substantially increase the microbial load, which can be particularly problematic for immunosuppressed 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]. The spray head must be changed for each new patient. However, this is quite tedious, as staff must be trained accordingly and each change must be recorded and verified to comply with hygiene regulations. Changing the spray head also requires readjusting the pump and its function to prevent accidentally applying too much or too little active agent.

[0018] Further important application possibilities exist in all cases where acute anxiety or panic disorder must be overcome as quickly as possible.The great advantage of nasal application, which allows the active agent to rapidly become bioavailable, can be used to optimize the treatment of acute anxiety or panic disorder.Nebulization achieves good anxiolysis and vagal attenuation, thereby creating favorable conditions for any intervention that may be performed.Nebulization has been used successfully not only in the above-mentioned example of MRI, but also in dental intervention, minimally invasive surgery, or any type of invasive intervention.Nebulization is also suitable as a premedication for preparing anesthesia or starting further anesthesia procedures.Similarly, the successful use in so-called "aggressive" therapeutic procedures (interventions), restlessness, and anxiety, and even in difficult-to-approach patients, some of whom are aggressive, restless, or disoriented, is also part of the present invention.

[0019] Not only is the reliable and safe administration of medications in emergency situations, but the proper administration of medications in space-constrained situations is often a major challenge.

[0020] Such situations, where reliable and rapid application of emergency medications is necessary, exist especially in epileptic or spastic patients who cannot be adequately stabilized with basic anticonvulsants and who, in the event of convulsions, must be treated quickly and effectively with anti-anxiety or anticonvulsant substances (e.g., midazolam). Seizures or epileptic fits or attacks can occur at any time and in a completely unpredictable manner in daily life. Patients often lie in unfavorable positions or are difficult to access for rapid drug administration (patient movement, depending on the situation or position, can hinder application). Patients or their relatives often face difficult situations regarding how best to administer medication as quickly as possible. Furthermore, spasticity or the associated jaw-clenching attacks can cause patients to become rigid, making emergency medication approaches, and especially their oral administration, impossible. To avoid the risk of choking or self-harm, patients often must be moved into a defensive position. An upright position is virtually impossible, so lateral recumbency is preferred. Valuable time during emergency treatment can be lost due to repositioning. Therefore, a position-independent device for administering solutions of active agents is necessary and of great practical importance in practice.

[0021] Other clinical situations in which administration is negatively influenced by rather external factors are radiological tomography examinations (MRI, CT, SPECT, or PET) or preoperative interventions (dental interventions, minimally invasive interventions, etc.), as well as gastrointestinal endoscopy. During the preparation phase, i.e., just before the patient lies down on the examination table, an upright position is easily achieved. However, once the patient is on the examination table, administration in an upright position is virtually impossible.

[0022] Modern multi-dose sprayers must first be loaded before administration. For this reason, at least two sprays are induced for testing purposes (e.g., sprayed into air) to ensure safe and successful administration in an upright position. Furthermore, repeated induction of sprays in a lying-down position using conventional multi-dose sprayers is not possible. A redraw must be performed each time, i.e., after each spray in a lying-down position. Thus, emergency nasal treatment with conventional multi-dose sprayers is only possible to a very limited extent. Furthermore, aspiration of air can lead to the application of unequal volumes, which is undesirable.

[0023] Thus, the inherent and inherent obstacles to administering drugs in the above-mentioned situations pose great difficulties for the affected patient, the patient's relatives, and the nursing staff who intervene. [Prior art documents] [Non-patent literature]

[0024] [Non-Patent Document 1] M. Haschke et al., Br. J. Clin. Pharmacol. (2010) 69(6):607-616 [Non-patent document 2] Tschirch FTC et al., JMRI(2008)28:866~872 [Non-patent document 3] Tschirch FTC et al., Eur.Radiol.(2007)17:1403-1410 Summary of the Invention [Means for solving the problem]

[0025] The present invention has been made in view of the above-mentioned state of the art, and it is an object of the present invention to provide a nasal spray device which allows for the intranasal administration of a defined amount of an anxiolytic, sedative, muscle relaxant or anticonvulsant active agent (benzodiazepine or derivative / GABA receptor agonist, e.g., midazolam or its derivative or a salt thereof), which allows for uniform administration in any patient position (e.g., the patient is upright, sitting, lying down or any other position or intermediate position), regardless of the spatial orientation of the nasal spray. The nasal spray should also allow for the administration of a second spray of an equal (identical) volume of active agent solution or fluid, i.e., the volume of the first spray and the volume of the second spray are approximately equal, and therefore the amount of active agent dissolved therein. In this way, if it is found that the patient is not lying sufficiently still in the testing device, a further spray of an equal dose of active agent can be administered to the patient.

[0026] A solution to this problem is to provide a nasal spray containing an aqueous solution or fluid containing an anxiolytic, sedative, muscle relaxant, or anticonvulsant active agent, which allows the patient to receive two spray puffs, each having an equal, determined volume of the aqueous solution or fluid of the active agent. The nasal spray facilitates uniform administration in any patient position (upright, sitting, lying down, or any intermediate position), regardless of the patient's spatial orientation. The nasal spray is preferably ready for use without prior activation.

[0027] The present invention thus provides a nasal spray containing an aqueous solution or fluid containing an anxiolytic, sedative, muscle relaxant, or anticonvulsant active agent, comprising: a) two atomizations or two sprays, each having the same determined volume of an aqueous solution or liquid of the active agent, can be administered intranasally to the patient by nasal spray; b) It is independent of the spatial orientation of the nasal spray and allows for equal administration of the dose in any patient position (upright, sitting, lying down, or any intermediate position); Regarding nasal sprays.

[0028] In the context of the present invention, the term spray can be interchangeably used with the term puff or spray (German: Spruehstoss) where appropriate, although this is not relevant for the use of the term spray in connection with compound words, for example in "nasal spray", since in this case spray refers to the device and not the action.

[0029] In one embodiment, the two-dose nasal spray consists of the following four components: a) a driving element, called an actuator, including a spray device, the driving element including a spring, a hollow needle, and a spray device; b) vial holder; c) activator container (e.g., vial made of glass, metal, or solid plastic); d) A tight-sealing plug, preferably made of a medically approved rubber or similar material.

[0030] Preferably, the drive element comprises a spring and an injection needle.

[0031] In a preferred embodiment, the active agent reservoir contains a therapeutic agent that acts anxiolytically, sedatively, muscle relaxant, or antispastically.

[0032] In a further embodiment, triggering of the spray does not rely on air pressure due to direct displacement of the active agent container against the plug by pressure on the actuation element, and the nasal spray preferably can administer the spray directly without actuation. Preferably, the nasal spray device of the present invention can determine whether the nasal spray is unused or whether one or two further sprays have been administered.

[0033] The dual dose nasal spray of the present invention allows the patient or a third party to administer the spray with one hand.

[0034] The therapeutic agent in the nasal sprays of the present invention is preferably a benzodiazepine or GABA receptor agonist, such as midazolam or a salt of these active agents.

[0035] As such, the dual-dose nasal spray is particularly suitable for sedating, premedicating, or treating patients with claustrophobia, panic attacks, or anxiety disorders, or for treating convulsions in CNS disorders, particularly epileptic or other seizure episodes (e.g., febrile convulsions).

[0036] The dual-dose nasal spray allows the active agent to be administered intranasally to the patient, where it is injected into or applied to the nasal mucosa in any conceivable form, and then reabsorbed there.The administration should be as uniform as possible and can be carried out in any patient position (for example, standing, sitting, or lying (supine, prone, or lateral)).In this situation, the spatial orientation of the nasal spray is not limited, which is made possible by the following structural elements: a) Direct displacement of the activator container (glass vial) against the plug by finger pressure; b) precise control and blocking of shear movements independent of spatial orientation; c) Airtight sealing by a plug for an activator container containing an activator filled under vacuum; d) A driving element (also called an actuator) consisting of a spring and a hollow needle (riser) pushes the activator fluid up under pressure, dispensing the activator fluid in the form of a spray from the end of the actuator in a spraying device.

[0037] In the context of the present invention, airtight sealing means, on the one hand, hermetically sealing the activator solution, and also means that as little residual air as possible or no residual air is left in the activator container, so that the activator container is evacuated or air-free.

[0038] The airtight seal of the filled active agent container (see FIG. 4) and the configuration of all four components described above (a: drive element; b: vial holder; c: active agent container and plug) allow the nasal spray of the present invention to behave like a pre-filled syringe. The nasal spray of the present invention can be used to administer a single dose of active agent in any spatial orientation. The block system, as shown in FIG. 2, is defined by the vial holder and the actuator, which allows controlled displacement of the active agent container relative to the drive element, thereby dispensing a precise volume of active agent fluid through the hollow needle.

[0039] Below, preferred embodiments of a dual dose nasal spray according to the present invention are described, and although reference is made to the figures for an initial understanding, the invention should not be construed in any way as being limited to the nasal spray device depicted in these figures. [Brief explanation of the drawings]

[0040] [Figure 1] Figure 1 shows a schematic diagram of a dual-dose nasal spray configuration according to the present invention and its major components: A is the driving element, also referred to as the actuator, B is the vial holder, C is the active agent container (e.g., a glass vial), and D is the rubber plug. On the right is a schematic diagram of a preferred four-component configuration of the nasal spray device, (E) with an integrated actuator, and (F) without an actuator.

[0041] [Figure 2]Figure 2 shows a schematic diagram of the blocking mechanism of a two-dose nasal spray. BP indicates the blocking points, at which the spray device is blocked during the first spray (BP1) or the second spray (BP2), respectively. Figure 2A shows the two-dose nasal spray in its starting position (BP1 and BP2 are at their lowest positions). Figure 2B shows how the actuator is compressed by a first mechanical pressure from the bottom. The hollow needle pierces the plug, displacing the glass vial toward the rubber plug, forcing fluid through the hollow needle of the actuator and inducing the first spray. This displaces the vial holder to a first position, where the blocking mechanism for the first spray, located between the actuator and the vial holder, is secured to a small anchor at BP1. Thus, two doses cannot be delivered in a single spray. In Figure 2C, the same mechanism as in Figure 2B is then subjected to pressure from below. The remaining volume is sprayed, but the difference is that the plug is completely at the bottom of the glass vial, and the vial holder is at the highest position at this time.This can ensure double dose spraying, and no further spraying can occur.In addition, after application, there is no return pressure, and the bottom is completely shifted to the top, so the user will notice that the nasal spray is already empty.

[0042] [Figure 3] Figure 3 shows the localized precise deposition of the active agent solution after application of the nasal spray of the present invention, depending on the orientation of the nasal spray in space. The top left image shows a CT image before application. The following images show CT images after application, each depicting the orientation of the nasal spray in space with a schematic diagram of the nasal spray showing the orientation in which it was administered (top right image - straight up; middle right image - horizontal; bottom right image - straight down). The remaining images represent administration in intermediate orientations. The application angle between the nasal spray and the nose is constant in these cases. The high-contrast active agent solution appears bright and is clearly visualized.

[0043] [Figure 4]Figure 4 shows in Figure 4a a schematic diagram of a preferred method for hermetically sealing an activator container. The activator solution is filled into the activator container under atmospheric pressure. Preferably, the filling occurs immediately before the sealing procedure shown in Figure 4. The lower part of Figure 4a, A, shows the activator container, which is open at the top and filled with the activator solution (gray), with a sealed chamber located above and a cylinder and plug inserted into the top end. This step is performed under atmospheric pressure. The arrow-shaped gray triangle depicts the sealing gasket in contact with the sealed chamber, and the gray rectangle on the plug indicates the area where the plug edge allows for hermetic closure.

[0044] Figure 4a B shows the activator container pressed against the sealed chamber. In this way, an airtight seal is formed. Air inside the closed system is sucked out through the side outlet (see arrow). This is done in a time-controlled manner under controlled suction. The area of ​​negative pressure inside the closed system is shown shaded. The light grey area indicates the sealing point. The thick arrow below the activator container points in the direction in which the activator container is pressed against the seal.

[0045] In Figure 4a, C, the entire system (activator container and sealed chamber) is pushed upwards, placing the cylinder in the activator container in its defined position (first large arrow). Immediately afterwards, the piston lowers the plug to the surface of the activator solution, and the expansion of the rubber plug's rim fixes it close to the glass vial (see second large arrow). This step is performed under negative pressure (air is constantly being sucked out). The shaded area indicates the area of ​​negative pressure. This step fixes the plug close to the surface of the activator solution.

[0046] Figure 4a, D shows how the closed activator container and sealed chamber are pushed downwards (large black arrow), thereby again withdrawing the cylinder (without the plug) from the activator container. The area above the plug is now again at atmospheric pressure (air evacuation has stopped). The plug is now fixed directly above the activator solution in the activator container (indicated by the vertical gray stripe on the side of the plug). If an air gap forms between the plug and the activator solution, negative pressure will be created at this location.

[0047] FIG. 4aE shows how the sealed active agent container is lowered to its original position and separated from the sealed chamber. The closed active agent container can now be assembled into a nasal spray of the present invention. The sealed chamber can be reused and a new active agent container can be hermetically sealed with a plug. How to automate the method described in FIG. 4 is known to those skilled in the art.

[0048] Figure 4b shows the filled, hermetically sealed activator container. The image shows that the rubber plug hermetically seals the activator solution, with only minimal residual air remaining between the plug and the activator solution.

[0049] [Figure 5] Figure 5 shows the mass uniformity (mg of active substance applied to the nasal mucosa) for two sprays depending on the orientation of the nasal spray. Figure 5a shows a series of measurements for the first spray, and Figure 5b shows a series of measurements for the second spray. Ten measurement points (one nasal spray per measurement) are shown for each direction of the nasal spray. The dashed line indicates the target value (100 μl per spray), and the solid line indicates the 15% (85 mg - 115 mg) acceptance criterion required according to the United States Pharmacopoeia, the strictest standard for pharmaceutical manufacturing compliance. DETAILED DESCRIPTION OF THE INVENTION

[0050] Note the displacement of the vial holder relative to the lower end of the actuator in the two-dose nasal spray according to FIG. 2. This is visible when the operator looks at the two-dose nasal spray from below. This allows the patient, nursing staff, or physician to determine whether the nasal spray will deliver two, one, or no more doses. In this way, previous use, i.e., the openness of the spray device, is clearly visible. Preferably, the spray device of the nasal spray of the present invention is blocked after the second dose, and therefore cannot deliver any further doses. This increases safety compared to multi-dose sprays and avoids improper use.

[0051] Preferably, the nasal spray of the present invention contains 200-230 μl, 215±15 μl, 230±10 μl, 225±10 μl, or 225±5 μl of active agent solution, fluid, or powder. Each spray of the two-dose nasal spray of the present invention can apply a volume of 75, 80, 90, 100, 110, 120, 125, 130, 140, or 150 μl (each with a volume range of ±25%) of aqueous solution or fluid containing the active agent, and in particularly preferred embodiments, each spray can spray a volume of 100±15 μl, 100±10 μl, or preferably 100±5 μl of fluid containing the active agent onto the nasal mucosa. To this end, the nasal spray is filled with 200 to 300 μl of an aqueous solution or fluid of the active agent, and in a particularly preferred embodiment, the nasal spray is filled with 230±10 μl of a fluid (advantageously a solution) containing the active agent.

[0052] Depending on the intended application, an isotonic aqueous fluid containing the active agent is dispensed so that a therapeutic dose of 0.25 mg to 5 mg or 1.0 mg to 10 mg of the active agent (e.g., midazolam, its derivatives, or salts of these active agents) can be administered with each spray. The active agent fluid (preferably an aqueous fluid) containing the therapeutic active agent may further 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 can be used in the nasal spray of the present invention are well known to those skilled in the art and are described in relevant textbooks. The aqueous fluid containing the active agent midazolam has a precisely defined pH, preferably between 2.8 and 3.8 (preferably between 3.0 and 3.5), depending on the concentration. These limits may be selected by those skilled in the art with narrower tolerances or adjusted as needed, depending on the specifications. Possible additional additives include additives that help adjust osmolality (e.g., salts, glucose), solubilizers (e.g., cyclodextrins), penetration enhancers (e.g., dextrin, cyclodextrin, chitosan, or derivatives thereof, which improve the uptake of the active agent across the nasal mucosa), humectants (e.g., glycerol, propylene glycol), or chelating agents such as EDTA or DTPA. In the case of anhydrous sprays, midazolam must be dissolved or suspended in a solubilizer. At this time, it may not be possible to maintain the above-mentioned pH value and isotonicity. Powdered nasal sprays may also be used in the form of a mixture of the active agent, mainly micronized midazolam, which may be mixed with various carrier substances, such as cyclodextrins.

[0053] In a preferred embodiment, the two-dose nasal spray contains no preservatives, i.e., the fluid formulation in the nasal spray contains only midazolam HCl in an isotonic aqueous NaCl solution. Preferably, such formulations are prepared sterilely so that the corresponding two-dose nasal spray can be stored for extended periods (preferably greater than 10 months, more preferably 12 months, even more preferably 18 months, or most preferably 24-36 months) without loss of quality. The advantage of this preservative-free nasal spray formulation is its reduced allergy, irritation, and interaction with ciliary movement on the nasal mucosa.

[0054] As shown schematically in Figure 4a, the activator container is preferably filled with an activator solution and sealed. First, the open-top activator container is filled with the desired amount of activator. The activator container is then introduced into a sealed chamber containing a plunger-like device. A plug is secured to the bottom end of the plunger-like device, sealing the activator container airtight. At this point, the sealed chamber and activator container form a closed system. Air is drawn into the closed system through an opening on the side of the sealed chamber, leaving the activator in the container unchanged. Experiments have shown that a negative pressure of approximately 600 to 900 mbar must be used to bring the plug as close as possible to the surface of the activator solution. Experiments have shown that the preferred suction time to achieve the desired negative pressure in this system is 0.5 to 1.5 seconds. The plunger-like device lowers a rubber plug into the activator container to the height of the top of the activator, minimizing the formation of any voids between the plug and the surface of the activator being filled. In this way, the sealed and filled active agent container behaves like a filled syringe, allowing the active agent fluid of the nasal spray of the present invention to be applied in any spatial orientation. The orientation independence of the application of two equal sprays has been tested by those skilled in the art using several samples, and their suitability has been documented in accordance with general pharmaceutical requirements (FDA, PHEUR) (two uniform sprays, each with a volume of 100 μl ± 15%, see FIG. 5).

[0055] The applied vacuum (see FIG. 4B), which creates a negative pressure in the system, can preferably be constantly monitored and recorded. The desired negative pressure in the closed system is preferably controlled by the suction time. Validation experiments have shown that a suction time of about 1 second is generally sufficient to place the plug in the activator container so that, whenever possible, no or only a minimal amount of residual air remains between the plug and the surface of the activator fluid (compare FIG. 4b).

[0056] As can be seen in Figure 5, the above-described method for hermetically sealing the active agent container allows the active agent container to be incorporated into a nasal spray according to the present invention. This facilitates the production of a nasal spray for administering two sprays of equal, determined amounts of active agent or identical volumes of active agent solution, which can deliver the active agent uniformly in any patient position (upright, supine, or any intermediate position) regardless of the spatial orientation of the nasal spray. The resulting nasal spray meets the requirements of pharmacopoeias of regulatory agencies (e.g., in the United States).

[0057] The above-described method for hermetically sealing an activator container is suitable for use on an industrial scale, in particular because the space in which negative pressure must be created is very small and the suction time is only about 1 second.

[0058] Preferably, a visual inspection is performed on each sealed and filled activator container. Visual control can be performed by a camera (computer-controlled if necessary). The distance between the plug and the surface of the activator fluid is controlled. Those skilled in the art can establish acceptance criteria for the maximum allowable distance through validation experiments. This allows automated screening for improperly sealed and / or incorrectly filled activator containers.

[0059] The nasal spray of the present invention operates as follows: Finger pressure on the drive element (actuator) displaces a plug into the activator container, generating pressure that forces the activator fluid through a hollow needle housed in the drive element and into the upper helix of the actuator, where it is dispensed as a spray (see Figure 2). A blocking mechanism (compare the numbers in Figure 2) between the vial holder and the actuator allows for the delivery of two controlled sprays, each of equal volume.

[0060] Preferred is a two-dose nasal spray, in which two controlled sprays of midazolam HCl, each 0.2 to 5 mg, and particularly preferably 0.278 to 5.56 mg, can be administered sequentially to a patient as an isotonic aqueous solution, regardless of whether the sprayer is held upright, horizontal, or inverted, or any intermediate position. The two sprays can be administered in rapid succession or sequentially, preferably with the second spray in the other nostril. A two-dose nasal spray allows for distribution of the active agent over a wide area on the surface of the nasal mucosa, which proves advantageous in terms of rapid resorption and bioavailability.

[0061] In a particularly preferred embodiment, the nasal spray can be used directly without further preparation or actuation to administer the active agent, i.e., the nasal spray is a ready-to-use ("ready-to-use") two-dose nasal spray.

[0062] As described above, the two-dose nasal spray consists of four pre-fabricated main components. These four main components may be sterilized (steam, ethylene oxide, and / or gamma sterilization). The two-dose nasal spray is then assembled from these four main components, and the active agent reservoir is also filled with active agent fluid, to obtain the desired two-dose nasal spray according to the present invention.

[0063] The filling of the activator containers, preferably glass vials, is carried out in a closed environment using a needle and a high-precision metering pump that can precisely dispense the desired volume of activator solution (e.g., 200-300 μl) into the activator container. The degree of filling of each activator container is controlled and documented by photography. For this purpose, the light intensity of the diffracted beam at the glass interface above and below the plug is measured and compared. This therefore allows for precise control of the degree of filling in the activator container.

[0064] The dual-dose nasal spray shown in Figure 2 allows for the administration of only two consecutive sprays. When pressed for the first time, the upper rubber seal is pierced and displaced upward to a specific position (BP1 / BP2 and the inner shaft). The amount of active agent fluid dispensed (spray volume) is controlled via the side anchors (see BP1 and BP2 in Figure 2). A spring allows the spray to "restart" and then be actuated a second time (Figure 2, bottom center image). The maximum volume that can be dispensed at this time is determined by the remaining volume, which is determined by the highest stop position of the upper, thinner nasal cylinder (Figure 2, bottom right image). The lateral shaft, together with points BP1 and BP2, further controls the position and thus the precise application of the two sprays. The side anchors result in two-stage application. The dual-dose nasal spray is designed so that the spray mechanism is blocked and depleted after the second spray is delivered. Therefore, the dual-dose nasal spray can no longer be used. In practice, it would be safely disposed of in accordance with regulatory requirements.

[0065] After production, the dual-dose nasal spray according to the present invention is preferably packaged in a cardboard or plastic box, where each box may contain one or several metered-dose sprays, each containing a package insert explaining how to use the nasal spray of the present invention. For storage and distribution, several boxes can be packaged in a further box (large box). This allows for the simultaneous application of emergency medication through both nostrils without delay in case of emergency.

[0066] Before delivery of the two-dose nasal spray according to the invention to the final customer, quality control is performed by HPLC to verify the density, pH, and osmolality of the formulation and active agent (a validated procedure similar to the European Pharmacopoeia). In addition, microbiological analysis is performed on each batch. As described above, the fill volume in the active agent container is controlled during the filling process. For each production batch, the dosage uniformity of the two-dose nasal spray must be verifiably controlled according to the Pharmacopoeia.

[0067] In the dual-dose nasal spray of the present invention, the ejected fluid does not displace air as in commonly used nasal sprays, but instead uses a movable plunger that is pierced when the spray mechanism is activated. This system allows for intranasal administration of the spray in any patient position (i.e., whether the patient is standing, sitting, lying down, or in any other position), regardless of the spatial orientation of the nasal spray. This significantly distinguishes the dual-dose nasal spray of the present invention from state-of-the-art nasal sprays, such as conventional multi-dose nasal sprays.

[0068] The closed system promotes the microbiological integrity of the primary pharmaceutical container from the time of sterile manufacture of the nasal spray to the time of use. Aseptic filling of the two-dose nasal spray according to the present invention avoids the use of potentially irritating preservatives in the formulation of the pharmaceutical substance. The two-dose nasal spray according to the present invention is stable upon storage.

[0069] The dual-dose nasal spray of the present invention is a rapid, ready-to-use device that can be operated by the patient with one hand, if necessary. The dual-dose nasal spray of the present invention is suitable and applicable to diagnostic imaging procedures such as MRI scans, and does not affect the diagnostic device, and its function or integrity is not affected by the diagnostic device (e.g., the magnetic radiation of the device or its magnetic force), and does not cause magnetic interference or other artifacts during the imaging procedure.

[0070] The two-dose nasal spray of the present invention can also be applied orally if necessary.This can be done when the nose is blocked (for example, due to local pathological changes) or when local application is limited due to colds or common infections related to the nasal passage.Possible contraindications are, for example, recent rhinoplasty, polyps, or other acute inflammation in the nasal cavity.

[0071] The two-dose nasal spray according to the invention is particularly suitable for various indications, such as claustrophobia or similar anxiety disorders with or without restlessness before entering or being positioned for an MRI or similar machine (PET, SPECT, radiotherapy machine, or even CT). Claustrophobic patients are already sedated about 1-2 minutes after intranasal administration of one or two sprays from the two-dose nasal spray, allowing them to successfully undergo an MRI examination without any problems.

[0072] Furthermore, the use of the two-dose nasal spray of the present invention can overcome or reduce various similar fears, such as those associated with minimally invasive interventions, dental interventions, pediatric interventions, various diagnostic procedures, and symptomatic treatment steps prior to gastrointestinal examinations. Further uses include premedication prior to anesthesia procedures, surgical interventions, or similar procedures. Being a ready-to-use device, the two-dose nasal spray can be used immediately in any patient position, regardless of the spatial orientation of the nasal spray. Therefore, the two-dose nasal spray can also be used very effectively in emergency situations, particularly in the above-mentioned interventions. Further applications relate to use in geriatrics, in therapeutic interventions that are rather painful, in cases of anxiety or restlessness, and in difficult or restless patients who are difficult to approach.

[0073] The low doses of midazolam commonly used for anxiety disorders (preferably 0.25-5.0 mg) do not produce noticeable sedation in the patient ("conscious sedation"), allowing the patient to follow the instructions of the technician or paramedic administering the test.

[0074] The two-dose nasal spray can be administered to patients by physicians or paramedics, or even by nurses or technicians involved in the examination or intervention if necessary. This has the advantage of allowing for rapid intervention independent of the patient's position, even in difficult patients or when compliance is poor. The two-dose nasal spray also allows patients to administer the nasal spray themselves if needed.

[0075] In a further embodiment of the invention, if necessary, during an MRI or similar (radiological) examination or intervention as described above, an additional spray of the two-dose nasal spray according to the invention can be administered to the patient or self-administered as described above, so that the patient's position does not change during the examination or intervention. This is extremely important during MRI examinations (T1, T2, diffusion, ADC, dynamic, native, and those using gadolinium as a contrast agent) where the contrast changes and the patient must not move. This greatly simplifies re-administration and avoids misapplication.

[0076] Accordingly, the present invention also relates to a method for treating a patient in the context of an MRI or similar (radiological) examination, characterized in that the patient is administered a nebulization with a two-dose nasal spray according to the present invention immediately before the MRI examination, or the patient is re-administered a nebulization with a two-dose nasal spray according to the present invention while in the MRI device (e.g. in the event of recurrent anxiety or restlessness during the examination).

[0077] High-dose anticonvulsants are also suitable for treating seizures in patients, such as myoclonic seizures, which can be caused by a variety of convulsions, such as epileptic disorders or other neurological diseases, or by CNS crises and febrile convulsions.

[0078] Thus, the dual-dose nasal spray of the present invention can also contain a high dose of a solution or fluid of the active agent. The patient population that benefits from such a high-dose nasal spray is typically children, adolescents, young adults, or other patients with tonic-clonic epileptiform spasms or convulsions leading to seizures and febrile seizures. Idiopathic epileptic seizures or similar CNS attacks occur suddenly, often without obvious symptoms, and are accompanied by a reduced level of consciousness that may sometimes last only a short time. Affected individuals may only respond to their surroundings in a limited way, respond with mouth or head movements, suddenly scream, become unable to remember anything further, fall or writhe, hyperextend their head and neck, convulse, involuntarily bite their tongue or cheek, and often foamy saliva exit their mouths. As a result of mild hypoxia, the patient's skin may turn slightly blue. Affected muscles may suddenly lose tone, causing the affected individual to fall or lose their legs. Seizures can sometimes last very long and be dangerous. Furthermore, these attacks can destroy areas of the central nervous system (CNS). Symptoms vary greatly depending on the affected area of ​​the brain. In affected individuals who have already experienced such attacks, some early signs may be detectable, such as discomfort, irritability, headache, certain sensory disturbances, noises, hallucinations, or certain auras. This allows for the early use of midazolam nasal spray to suppress the seizures. In this way, even spastic tonic-clonic seizures can be reduced and / or shortened at best. Midazolam can also be administered orally (tablets) or rectally, but these dosage forms have the distinct disadvantage of not allowing the active agent to act immediately.

[0079] Recently introduced oral midazolam solutions have the disadvantage that the active agent is reabsorbed slowly (30–60 minutes, depending on the degree of gastric and / or duodenal filling). After reabsorption, first-pass hepatic passage occurs via the portal vein, resulting in reduced efficacy due to the first-pass effect. Nasal administration avoids the first-pass effect, and the nasal spray allows the active agent to be delivered to the bloodstream more rapidly and with a higher bioavailability (approximately 80%).

[0080] The two-dose nasal spray of the present invention allows relatives or other caregivers, particularly those with epilepsy who suffer from spastic biting seizures, to quickly, safely, and easily administer anticonvulsants directly without prior activation. As already mentioned, nasal administration using the nasal spray of the present invention is significantly superior to oral or rectal administration due to its rapid bioavailability without first-pass effects, rapid action, and ease of application. This offers a significant advantage to relatives or other caregivers who care for the patient or even treat them in emergencies. When using the multi-dose nasal spray, the patient's head must be in an upright position. To achieve this, relatives are forced to somehow hold the patient in a sitting or upright position to allow nasal administration. This is not necessary with the two-dose nasal spray of the present invention, because it can be administered flexibly in any patient position, regardless of the spatial orientation of the nasal spray. Thus, the two-dose nasal spray of the present invention is particularly suitable in emergencies, as it can quickly halt rapid worsening of seizures.

[0081] It should be noted that in this situation, administration of a single dose is often insufficient, since the dose response depends on the patient's weight (a sufficient dose of active agent in the case of an attack is approximately 0.02-0.05 mg / kg body weight). Sometimes, administration of a second dose may be necessary. The use of the two-dose nasal spray according to the present invention allows for the administration of a second spray containing a second dose of active agent, either immediately or at a later time. This is an advantage compared to other commercially available products, such as Nazolam® (MEDIR BV, Doorn, Netherlands).

[0082] Typically, high doses of the active agent midazolam (1-10 mg) are applied intranasally when a patient is experiencing any type of CNS crisis, seizure (e.g., febrile seizure), epileptic disorder, and / or seizures associated therewith. High-dose treatment may be indicated for the early stages of a seizure or similar symptoms of a CNS disorder. The nasal spray of the present invention can be administered by the patient in any position (ready-to-use) or by a third party involved in emergency treatment. Nasal uptake is rapid, and the calming effect occurs very quickly.

[0083] Measurements of the bioavailability of the active agent following administration of midazolam using a dual-dose nasal spray according to the present invention indicate that a high bioavailability (>83%) is achieved. Significant plasma concentrations are achieved 2 minutes after administration due to the absence of first-pass reabsorption via the nasal capillaries. Peak plasma levels were measured 5-10 minutes after administration (although high standard deviations were evident). This demonstrates very rapid local uptake of the active agent. The elimination half-life (t1 / 2β) corresponds to 1.5-3.5 hours.

[0084] Administration of midazolam via nasal spray can cause local irritation of the nasal mucosa. However, this usually subsides within 10–20 seconds after administration. The reason for this reversible irritation is likely due to the low pH of the nasal spray fluid (preferably pH 3.0–3.5). Possibly, nasal irritation may also be caused, or partially caused, by preservatives that may be present. This can be reduced by using penetration enhancers (dextrin and derivatives, chitosan and derivatives) as additives, along with humectants (propylene glycol, glycerol) or even chelating agents (EDTA, DTPA).

[0085] When administering midazolam using the dual-dose nasal spray according to the present invention, known and usual precautions must be taken to avoid undesirable side effects. For example, higher doses may cause respiratory distress or respiratory failure. However, reported cases are extremely rare (one case reported in the last 12 years). Myasthenia gravis may also be exacerbated by the administration of midazolam. There have also been reports of contradictory or paradoxical effects in children. In general, similar undesirable adverse events may occur, especially in elderly patients.

[0086] Those skilled in the art know how to manufacture or prepare the drive element as described above. Further components can be purchased. Those skilled in the art can easily assemble the components into the finished nasal spray. The vial holder is usually made of synthetic material or plastic. It serves to lift the (often pre-filled) container with the active agent. The plug serves to facilitate an airtight connection between the drive element and the active agent container. The rubber plug is preferably made of rubber suitable for pharmaceutical use, but may also be made of other corresponding plastic materials known to those skilled in the art.

[0087] The construction design of the nasal spray is depicted in Figures 1 and 2. The nasal spray according to Figure 1 is assembled so that finger pressure causes the active agent container (preferably a glass vial) to displace directly against a rubber plug, thereby enabling air pressure independent spray induction. The nasal spray device according to Figure 1 allows for precise orientation independent control and blocking of displacement motion (Figure 2), thereby determining the integrated volume that controls the functionality of the actuator (Figure 2).

[0088] Preferably, the nasal spray according to the present invention is characterized in that it is possible to determine whether or not it is still unused.

[0089] The nasal spray according to the invention is characterized in that the displacement of the vial holder relative to the lower end of the actuator from the bottom side can be seen, and thus it is possible to see whether the nasal spray has already been used or whether one or two sprays have already been triggered. Preferably, the nasal spray according to the invention is characterized in that when assembled, it contains a blocking mechanism (compare Figure 2) which ensures that the first spray is delivered in a controlled manner without simultaneously triggering the second spray.

[0090] Preferably, the nasal spray according to the present invention allows for the administration of one or two sprays without the need for a prior actuation of the nasal spray.

[0091] In this way, sprays can be administered directly to or by the patient, one-handed, without preparatory action, with the volume of each spray being selected so that the aqueous fluid is injected or sprayed onto the nasal mucosa and can be reabsorbed therefrom.

[0092] The nasal spray according to the present invention can be used to administer a dose of 0.25 mg to 5 mg of an anxiolytic, sedative, muscle relaxant, or anticonvulsant active agent to achieve conscious sedation.

[0093] By using the nasal spray according to the invention, a dose of 1 to 10 mg of an anxiolytic, sedative, muscle relaxant or anticonvulsant active agent can be administered to achieve an anticonvulsant effect.

[0094] The active agent solutions preferred herein in the nasal sprays according to the invention can further contain preservatives, such as 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 can also be used, especially for allergy sufferers or in cases of known hypersensitivity.

[0095] Preferred active agent solutions in nasal sprays according to the invention have a pH value between 2.8 and 3.8, preferably between 3.0 and 3.5. Anhydrous fluids or powders also have no measurable pH.

[0096] Preferred active agent solutions in nasal sprays according to the present invention are isotonic.

[0097] Nasal sprays according to the present invention are preferably prepared sterilely.

[0098] Nasal sprays according to the present invention preferably do not cause magnetic interference.

[0099] The nasal spray according to the invention is suitable for treating patients with claustrophobia or anxiety disorders and administers 0.56 mg of midazolam HCl per spray (equivalent to 0.50 mg of midazolam base) per spray.

[0100] The nasal spray according to the invention is suitable for sedation or premedication, and the nasal spray according to the invention administers, for example, 0.278 to 5.56 mg of midazolam HCl per spray (equivalent to 0.25 mg to 5 mg of midazolam base) per spray.

[0101] The nasal spray according to the invention is suitable for treating patients with claustrophobia or anxiety disorders or for treating patients with epileptic or other seizures, in which treatment, as described above, with the nasal spray according to the invention, high doses of active agent are required, for example 1 to 10 mg of midazolam per spray or 0.02 mg to 0.5 mg of midazolam per kg of patient body weight per spray.

[0102] The nasal spray according to the invention is used, on the one hand, for the treatment of patients in the context of MRI or similar (radiological, radiotherapy) examinations (or further imaging devices in the form of tubes or similar), whereby a spray from the nasal spray according to the invention is administered to the patient immediately before the MRI examination. If necessary, an additional spray from the nasal spray according to the invention can be administered to the patient before or during the examination.

[0103] On the other hand, the nasal spray according to the present invention is used for the treatment of patients having neurologically induced attacks, whereby a spray from the nasal spray according to the present invention is administered to the patient, whereby, if necessary, another spray from the nasal spray according to the present invention can be administered to the patient.

[0104] Thus, the advantages of the dual dose nasal spray according to the present invention are as follows:

[0105] Rapid and specific anxiolytic effect during the preparation phase for MRI table and similar diagnostic examinations (PET, SPECT, CT) or any kind of minimally invasive intervention (dental, surgical, anesthesia induction), accelerating the workflow and facilitating the planned intervention in the patient.

[0106] · Administration of low-dose midazolam improves cooperation with technical staff during MRI examinations (conscious sedation) or various minimally invasive interventions.

[0107] · Improved imaging quality (MRI) due to fewer motion artifacts and better compliance with the above mentioned interventions.

[0108] ·Less CNS or systemic toxicity due to lower peak concentrations of the active agent, midazolam.

[0109] Temporary sedation.

[0110] The administration of the active agent is well-controlled and can be done through both nostrils.

[0111] The dual-dose nasal spray can be used with uniform efficacy whether the patient is lying down, sitting, upright, or in any other position, including the lateral position, without regard to spatial orientation of the nasal spray.

[0112] The two-dose nasal spray is supplied ready-to-use and can be used immediately.

[0113] The double-dose nasal spray is used on only one patient and therefore meets high hygiene standards.

[0114] The formulation in the two-dose nasal spray can be filled aseptically in a closed system, eliminating the need for preservatives.

[0115] In emergencies involving nasal obstruction or localized restriction, the nasal spray can be sprayed directly into the mouth quickly and efficiently without any preparation.

[0116] The two-dose nasal spray meets the regulatory requirements for registration with, for example, Swissmedic, EMA, and / or FDA.

[0117] Nasal sprays allow various midazolam formulations, such as anhydrous solutions, suspensions, or even powders, to be administered either nasally or, in emergencies, bucally.

[0118] A preferred embodiment of the two-dose nasal spray of the present invention is described below. Using this two-dose nasal spray, an active agent solution (preferably a midazolam solution, but also a liquid or powder mixture) can be administered within a very short time in a safe, locally precise, and fast-acting manner, in a uniform manner, independent of the patient's position (e.g., sitting upright, lying on their back, or lying on their side), independent of the spatial orientation of the nasal spray, and without the need for any preparatory action to activate the spray device (a ready-to-use nasal spray device). This is of the utmost benefit to medical professionals and relatives, and has not been achieved until now. The advantages of such orientation-independent, position-independent, safe, and uniform application of medication play an important role in both emergency treatment of patients with seizures and premedication of patients prior to diagnostic tests such as MRI.

[0119] The locally precise targeted administration of an active agent solution using the nasal spray device of the present invention is documented and verified by the following experimental tests and the resulting data. This verification was performed using a novel measurement procedure combined with a high-resolution CT imaging examination device, although other (tomographic) imaging techniques with appropriate spatial resolution or imaging quality are possible. The novel experimental procedure allows the characterization of the nasal spray in terms of locally precise administration of the active agent (droplet distribution) and, for the first time, allows the real-time evaluation of the effectiveness of the application system, i.e., the analysis of the localization of locally precise administration of the nasally administered active agent. Because nasal sprays and nasal applications are used locally and systemically, respectively, the distribution of the active agent, its surface distribution, and its physical wetting on the mucosal surface have a significant impact on the effectiveness of the system. As the gold standard, nuclear medicine methods (scintigraphy, SPECT, PET, possibly combined with MR or CT for fusion imaging) are often used to evaluate the nasal deposition of drugs administered nasally with various applicators. However, these X-ray methods have important drawbacks in terms of practical applicability.

[0120] · Often has limited spatial resolution (e.g., 3-5 mm, 5-10 mm, or 6-12 mm).

[0121] From a time perspective, measurements must often be taken over a period of approximately 20-30 minutes, and therefore short time frames cannot be displayed. Images therefore show a superposition of a longer time frame, with marker confluence (gravitation) on the mucosal surface lasting approximately 30 minutes. This makes the assessment of nasal deposition incomplete. Due to the long measurement time, dynamic images are not possible. Therefore, the time course of nasal distribution, and especially the initial distribution, cannot be displayed.

[0122] Imaging analysis involves relatively high radiation exposure.

[0123] Nowadays, detailed patient-specific replicas of the nasal cavity can be prepared based on radiological tomography such as CT scans [Warnken ZN 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 remains unclear regarding whether active agents reach the desired location within the nasal cavity after nasal administration. The present invention provides a method that enables patient-specific detection of the precise local deposition of active agents after nasal administration. In particular, the method disclosed herein makes it possible to determine whether and in what amount active agents reach any nasal sinus or main nasal cavity after nasal administration.

[0124] Computed tomography (CT), abbreviated as CT, is a radiological imaging procedure with high spatial and temporal resolution for layered imaging (3D acquisition). Anatomical structures across individual layers can be displayed as CT images based on the X-ray absorption profile of an object. Calculated thin-section images are generated from the absorption values ​​of X-ray signals passing through the body. Technological improvements in spatial resolution can improve image quality, thereby displaying anatomical structures in greater detail. Meanwhile, novel techniques are enabling low-radiation examinations in daily clinical use. To better characterize and localize nasal deposition on the nasal mucosa across the various nasal cavities, a contrast agent (e.g., iodine-containing solution, gadolinium-containing contrast agent, or other positive- or negative-acting contrast agent) is loaded into a nasal application system. After application to the nose (patient, subject, or replica) using a nasal applicator, a CT image is acquired. The absorption profile across the entire nasal cavity allows high-contrast droplets to be depicted on the surface of the nasal mucosa and delineated from the surrounding tissue. The droplets appear with striking contrast against a background that absorbs less X-rays. This allows for clear visualization of both surface humidification and the distribution of high-contrast fluids. Thus, localization and quantification of the sprayed fluid can be performed relatively quickly after application (X-ray absorption). Time courses (kinetics) can be displayed. The iodinated contrast agents used are approved iodine-containing solutions, suspensions, or powders with different concentrations, viscosities, or osmolalities. A skilled artisan can select a suitable contrast agent for the application in an appropriate concentration, possibly adding it to midazolam or other active agents if visualization is desired. In this case, a diluted solution of iodinated contrast agent (e.g., Iopamiro®) with an iodine concentration of 92 mg / ml was used. In principle, any possible high-contrast substance (fluid, solid, or gaseous) can be used in various concentrations or dosages. It is advantageous to use a mixture of substances similar to the pharmaceutically active agent solution used, so that the basic characteristics of the nasal spray device can be adequately characterized. The use of a solution of iodinated contrast agent allows optimal visualization of aqueous solutions and their distribution.Furthermore, the powder mixture may be used to display and characterize the nasal deposition of the nasal spray. As already mentioned, the nasal spray device of the present invention allows for localized and volumetrically accurate administration 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).

[0125] The nasal spray device is characterized by a computed tomography nasal deposition technique, for which the nasal spray device, filled with an aqueous solution of iodine or other contrast agent, must be applied from various angles to a nasal model (hereafter also called a nasal replica).

[0126] Nasal replicas can be prepared using a variety of techniques. The nasal models used in the experiments described below were designed based on human CT images and fabricated using either casting or 3D printing (various nasal cavity shapes from various patients were modeled in this manner). Nasal models are preferably made of synthetic resins or plastics selected to avoid artifacts during CT imaging and to allow adequate contrast between the applied iodine solution, fluid, or powder and the anatomical structures of the model (different X-ray densities between the replica surface and the contrast agent). For visualization of surface deposition, it is advantageous to use replicas with a finely textured surface free of surrounding tissue, possibly with a hydrophilic coating or exposed to air absorption.

[0127] To characterize the nasal spray device, the nasal replica is tilted and then stabilized. The constant application angle defines the spatial position of the nasal spray device during administration. The tested nasal spray device then reliably administers a solution, fluid, or powder of an active agent containing a contrast agent. Immediately after administration, computed tomography or another imaging technique is used to localize, characterize, and verify the precise administration. The distribution of active agent solution or fluid droplets or powder particles on the inner surface of the nasal cavity of the nasal replica, due to the added contrast agent, is clearly visible on CT images or similar devices. In this case, high-resolution CT images showed that the contrast agent had spread to the middle and upper anterior nasal cavity. Such measurements can also be performed in individual patients with unclear ENT conditions or to enhance application safety.

[0128] In order to visualize and localize orientation-independent, uniform, and timely (ready-to-use nasal applicator) nasal deposition with the nasal spray of the present invention, the following prerequisites are important: the use of a contrast-containing substance (solution, mixture, powder, gas, emulsion, etc., often containing an iodine-containing contrast agent, a gadolinium-containing contrast agent, or other high-contrast substance) that can be loaded into the nasal applicator or nasal spray.

[0129] The application of contrast agent with or without an active agent should ideally simulate or detect nasal distribution, i.e., have similar characteristics (flow, atomization, or surface charge) as would be obtained by applying a pharmaceutical solution, fluid, or powder mixture of the active agent that may be used.

[0130] Furthermore, the nasal replica should be suitable for CT measurements or similar examination procedures. In particular, the replica should allow quantification at pixel level, i.e., at the grid point (voxel level). For this purpose, the use of a CT scanner or similar method with the possibility of scanning or displaying high-resolution images must be ensured.

[0131] The nose model used in this experiment is made of synthetic resin and / or plastic, selected to not introduce artifacts in CT imaging or possible alternative methods.

[0132] The nasal spray is filled with an iodine contrast agent-containing solution, fluid, or powder mixture, and the spray is injected into the nostrils of the nasal model at a defined application angle (reference: nose bridge). The angle between the nasal spray and the nasal model must be kept constant (preferably at a physiological introduction angle) to allow for repeated and verified measurements of individual measurement points. Application is standardized by using a fixed holder for the nasal spray to ensure reproducible measurements. Image capture begins immediately after application of the solution, fluid, or powder mixture via the spray. Image capture is completed within a few seconds, before subsequent accumulation of deposited droplets, suspensions, or powders (caused by gravity) occurs. Thanks to the high temporal resolution of the CT device used, we were able to demonstrate the orientation independence of nasal application (compare the images shown in Figure 3). The CT scanner used in these experiments preferably has a high resolution (e.g., 0.04 mm to 1 mm). This resolution allows for good quality visualization of both the nasal anatomical structures and droplets deposited on the internal plastic surface of the nasal model.

[0133] The measured CT images must be processed using post-processing techniques to better visualize the contrast agent on the radio-low-density nasal mucosa. Various 3D techniques for full volume visualization are available, as are subtraction techniques. In particular, a native image can be subtracted from the contrast image, allowing the visualization of only the applied contrast agent, excluding background and anatomical structures. This allows the visualization of anatomical structures either isolated from or superimposed on the contrast agent image. Figure 3 shows CT images in various application positions (standing, lying, etc.) along with the corresponding application angles. The first image, unapplied, of the nasal replica or model was taken before contrast application (top left). This nasal model exhibits no CT artifacts, and anatomical microstructures are clearly visible. The remaining five images show CT image captures after application of the nasal spray from various angles. The deposition of iodine-containing droplets in the nasal cavity is shown as bright spots, thus providing localization. From a qualitative standpoint, solutions, fluids, or powders administered using nasal sprays have similar distributions regardless of the direction of application.

[0134] Pixel (voxel) independent quantification of the deposited contrast agent (here, an iodine-containing contrast agent solution) is performed by various methods known to those skilled in the art (e.g., region growing, Hounsfield unit threshold, iodine mapping, e.g., Binh DB, Nakajima T, Otake H et al. Iodine concentration calculated by dual-energy computed tomography

[1999] ). (DECT) as a functional parameter to evaluate thyroid metabolism in patients with hyperthyroidism in BMC Medical Imaging 2017; 17:43).

[0135] Therefore, the present invention also relates to a method for qualitative and / or quantitative detection (localization) of the local, precise, preferably uniform administration of an active agent in nasal applications, characterized in that the active agent is sprayed into a nasal model or into the living body of a patient, and the locally precise deposition of the active agent fluid or powder is measured, localized, and visualized using an imaging method, for example, by adding a contrast agent, a fluorescent marker, a dye, or other visualizeable substance. Preferably, the imaging method is a high-resolution (<4 mm), low-radiation, high-speed imaging method.

[0136] In one embodiment, the qualitative and / or quantitative detection method is characterized by demonstrating and quantifying in real time the nasal distribution of the active radio-absorbing agent and the time course (kinetics) of its elimination.

[0137] In one embodiment, the qualitative and / or quantitative detection method is characterized by the ability to reconstruct and display the surface structure of the nasal mucosa and nasal cavity in 2D / 3D at high resolution in three dimensions ("volume rendering").

[0138] In one embodiment, qualitative and / or quantitative detection methods are characterized by the ability to precisely localize and characterize the nasal deposition of active agent quantitatively and qualitatively for each individual patient.

[0139] Thus, in one embodiment, the nasal spray according to the present invention is characterized in that it has been shown by the above-mentioned qualitative and / or quantitative detection methods to achieve targeted, localized and precise administration of a liquid active agent to the nasal mucosa of a patient, regardless of the patient's position (upright, sitting, lying down, or any intermediate position).

[0140] This detection method can be used to verify whether a nasal spray meets the requirement of precisely dispensing a fluid or powder of an active agent locally onto the patient's nasal mucosa. Preferably, the nasal spray conforms to locally precise, targeted, and uniform dispensing regardless of the orientation of the nasal spray during the spraying procedure (e.g., straight up, horizontal, or straight down, and any intermediate positions).

[0141] This detection method allows for a reproducible qualitative and / or quantitative indication of nasal deposition of active agent solution, fluid, or powder after the nebulization procedure.

[0142] Dynamic recordings in replicas can be made over minutes or any length of time so that secondary distribution, possible removal via cilia, and osmolality or other factors that affect kinetics can also be monitored.

[0143] Although the detection method described above is illustrated using an artificial nose model, the detection method can also be performed directly in vivo in a patient.

[0144] Detection methods in humans (in vivo, patient or subject) preferably use low radiation doses, if only CT methods.

[0145] Preferably, dynamic recordings in humans (in vivo, patient or subject) are over a short time span, for example, a few minutes.

[0146] The above detection methods can also be used to better reconstruct and display the surface structure of the interface using spatial reconstruction techniques (3D). By very thinly coating the interface with iodine or other contrast material via a nasal spray, preferably a dual-dose nasal spray device, the interface can be displayed in 3D or projection with high resolution. This allows for specific display and contour mapping of the mucosa.

[0147] The above-described detection method can also be used for personalized, high-resolution detection to verify that the active agent reaches the desired location in the nasal cavity after nasal application. Due to the patient-specific and diverse anatomical structures of the nose and nasal cavity, it is appropriate to qualitatively and quantitatively localize and determine the nasal deposition of the active agent alone, or in powdered mixtures, solutions, or fluids, upon nasal application in a locally accurate manner. In this case, a detailed nasal replica having the features disclosed herein is prepared from a patient-specific radiological tomography examination of the nasal cavity (MRI / CT, ​​SPECT, or PET). In an exemplary embodiment, such a nasal replica can be designed based on a human CT recording and manufactured by either casting or 3D printing. The nasal model is preferably made of a synthetic resin or plastic selected to avoid artifacts in CT imaging and to allow adequate contrast between the applied iodine solution, fluid, or powder and the anatomical structures of the model (different X-ray densities between the replica and the contrast agent). An advantage for demonstrating surface deposition is the use of a replica with a finely textured surface free of surrounding tissue. The nasal deposition of the active agent is then analyzed and characterized using the above method. Furthermore, the dynamic distribution of the active agent may be characterized within a desired time period. This method allows for patient-specific validation of the suitability of a drug, treatment, or nasal spray device based on high-resolution, topographically accurate localization and characterization of the nasal deposition of the active agent in patient-specific replicas.

[0148] The present invention also relates to a nasal spray, preferably a dual-dose nasal spray, having the above-described characteristics, characterized in that it is demonstrated by the above-described method that the nasal spray is capable of achieving locally accurate, uniform, and possibly targeted administration of an active agent fluid or active agent powder onto the nasal mucosa of a patient.

[0149] The nasal sprays tested in this way allow for orientation-independent nasal administration of solutions, fluids, or powders of active agents to patients, preferably in medical emergencies and when administration is limited by space constraints.

[0150] The above-described method for airtight filling and hermetically sealing an active agent container for use in the nasal spray of the present invention can also be applied to other forms of active agent containers. Accordingly, the present invention also relates to a method for airtight sealing a container, in which sealing of the container by inserting a plug into the container occurs in a closed system. Preferred containers are glass or plastic ampoules with a filling volume of up to 2 ml.

[0151] Preferably, the container is sealed so that no, or as little air as possible, remains between the solution in the container and the plug.

[0152] Thus, the present invention also relates to a method for hermetically sealing an active agent container for use in a nasal spray against air, characterized in that inserting a plug into the active agent container is carried out in a closed system into which the active agent container having an active agent solution is inserted, and in that no air, or as little air as possible, remains between the active agent solution and the plug.

[0153] Preferably, this method is carried out in a closed system consisting of a sealed chamber, a movable plunger, and an outlet for sucking out air from within the closed system. The corresponding system and the corresponding procedure are shown diagrammatically in Figure 4a. The present invention provides, for example, the following items. (Item 1) 1. A nasal spray containing an aqueous solution or liquid containing an anxiolytic, sedative, muscle relaxant or anticonvulsant active agent, a) the nasal spray allows the patient to intranasally administer two sprays of the aqueous solution or liquid of the active agent, each having the same determined volume; b) the nasal spray allows for equal administration of the dose in any patient position (upright, sitting, lying down, or any intermediate position), independent of the spatial orientation of the nasal spray; Nasal spray. (Item 2) a) a driving element, called an actuator, which includes a spray device; b) vial holder; c) an activator container; and d) Plug The nasal spray according to item 1, which consists of the following four components: (Item 3) 3. The nasal spray according to claim 2, wherein the active agent container contains a therapeutic agent having an anxiolytic, sedative, muscle relaxant, or anticonvulsant effect. (Item 4) 4. The nasal spray according to any one of items 1 to 3, characterized in that the triggering of spraying does not depend on air pressure by direct displacement of the active agent container relative to the plug by pressure on the drive element. (Item 5) 5. The nasal spray according to any one of items 1 to 4, characterized in that the spray can be administered by the nasal spray without the need for prior actuation of the nasal spray. (Item 6) 6. The nasal spray according to any one of items 1 to 5, characterized in that it is possible to determine from the nasal spray whether or not nebulization has already been performed by the nasal spray. (Item 7) 7. The nasal spray according to any one of items 1 to 6, wherein it is possible to determine from the nasal spray whether a second spray has already been performed by the nasal spray. (Item 8) 8. Nasal spray according to any one of items 1 to 7, characterized in that the anxiolytic, sedative, muscle relaxant and / or anticonvulsant active agent is a benzodiazepine or a GABA receptor agonist, or a salt of said active agent. (Item 9) 9. Nasal spray according to any one of items 1 to 8, characterized in that the anxiolytic, sedative, muscle relaxant and / or anticonvulsant active agent is midazolam or a salt thereof. (Item 10) 10. The nasal spray according to any one of the preceding items, characterized in that it contains 200-230 μl, 215±15 μl, 230±10 μl, 225±10 μl, 225±5 μl, or 230 μl of the solution or liquid of the active agent. (Item 11) 11. Nasal spray according to any one of items 1 to 10, characterized in that with each spray a volume of 75 ml, 80 ml, 90 ml, 100 ml, 110 ml, 120 ml, 125 ml, 130 ml, 140 ml or 150 ml (each with a volume range of ±25%) of the aqueous solution or liquid of the active agent can be administered. (Item 12) Item 13. The nasal spray according to any one of items 1 to 11, characterized in that each spray can administer a volume of 100±15 μl, 100±10 μl, or 100±5 μl, or 100 ml of the aqueous solution or liquid of the active agent. With each spray, a) 0.25 mg to 5 mg of an anxiolytic or anticonvulsant active agent may be administered; or b) 1.0 mg to 10 mg of an anxiolytic or anticonvulsant active agent can be administered; 13. The nasal spray according to any one of items 1 to 12. (Item 14) With each spray, a) 0.278 mg to 5.56 mg of midazolam HCl (equivalent to 0.25 mg to 5 mg of midazolam base) can be administered, or b) 1.11 mg to 11.12 mg of midazolam HCl (equivalent to 1 mg to 10 mg of midazolam base) can be administered; or c) 0.02 mg to 0.05 mg of midazolam can be administered per kg of the patient's body weight. 9. The nasal spray according to any one of items 1 to 8. (Item 15) A method for qualitative and / or quantitative detection of locally precise administration, localization, and quantification of an active radio-absorbing agent, e.g., iodine, by nasal application, characterized in that the active agent is sprayed into a nasal model or into a patient's body, and locally precise deposition of the active agent solution, liquid, or powder is measured and localized using high-resolution (<4 mm), low-radiation, high-speed imaging, optionally in combination with contrast agents, fluorescent markers, dyes, or other visualizeable substances. (Item 16) 16. The method according to item 15, characterized in that the time course (kinetics) of nasal distribution and elimination of the active radio-absorber can be shown and quantified in real time. (Item 17) 17. The method according to item 15 or 16, characterized in that the surface structure of the nasal mucosa and nasal cavity can be reconstructed and shown three-dimensionally ("volume rendering") with high resolution in 2D / 3D. (Item 18) 18. The method according to any one of items 15, 16 or 17, characterized in that said method allows for precise localization and characterization of the nasal deposition of the active agent in an individual patient, both quantitatively and qualitatively. (Item 19) 19. The nasal spray according to any one of items 1 to 14, characterized in that the method according to any one of items 15 to 18 shows that targeted, localized and precise administration of the liquid of the active agent to the nasal mucosa of a patient can be achieved regardless of the patient's position (upright, sitting, lying down or any intermediate position). (Item 20) 20. A method for hermetically sealing an active agent container for use in a nasal spray according to any one of items 1 to 14 and 19, wherein inserting a plug into the active agent container is carried out in a closed system into which the active agent container with a solution of the active agent is inserted, and wherein no air or as little air as possible remains between the solution of the active agent and the plug. (Item 21) 21. The method according to item 20, characterized in that the closed system consists of a sealed chamber, a movable cylinder having a piston, and an outlet for sucking out air within the closed system.

Claims

[Claim 1] 1. A nasal spray containing an aqueous solution or liquid containing an anxiolytic, sedative, muscle relaxant or anticonvulsant active agent, a) the nasal spray allows the patient to intranasally administer two sprays of the aqueous solution or liquid of the active agent, each having the same predetermined volume; b) the nasal spray allows for equal administration of the dose in any patient position (upright, sitting, lying down, or any intermediate position), independent of the spatial orientation of the nasal spray; Nasal spray.

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